WO2018113201A1 - CHROMAN-6-SULFAMIDE RORγ REGULATOR AND USE THEREOF - Google Patents

CHROMAN-6-SULFAMIDE RORγ REGULATOR AND USE THEREOF Download PDF

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WO2018113201A1
WO2018113201A1 PCT/CN2017/087263 CN2017087263W WO2018113201A1 WO 2018113201 A1 WO2018113201 A1 WO 2018113201A1 CN 2017087263 W CN2017087263 W CN 2017087263W WO 2018113201 A1 WO2018113201 A1 WO 2018113201A1
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alkyl
group
optionally substituted
cycloalkyl
compound
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PCT/CN2017/087263
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French (fr)
Chinese (zh)
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金秋
秦引林
苏梅
马瑞
仇亚男
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南京柯菲平盛辉制药有限公司
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Definitions

  • the present invention relates to novel retinoic acid-related orphan receptor gamma (ROR ⁇ ) modulators, preparation methods thereof, pharmaceutical compositions containing the same, and their use in the treatment of ROR ⁇ -mediated inflammatory, metabolic and autoimmune diseases use.
  • ROR ⁇ retinoic acid-related orphan receptor gamma
  • RORs Retinoic acid receptor-related orphan receptors
  • RORs are a class of ligand-dependent transcription factors that are involved in reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, and immune system regulation. Play an important role in the physiological and pathological process.
  • RORs are a member of the nuclear receptor superfamily, including ROR ⁇ , ROR ⁇ , and ROR ⁇ .
  • ROR ⁇ is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood, and is related to physiological and pathological processes such as hepatic gluconeogenesis, lipid metabolism and atherosclerosis.
  • ROR ⁇ is mainly distributed in the central nervous system, including the brain, retina and pineal gland, and is mainly related to the treatment of sensitive information in the spinal cord, thalamus and cerebellum.
  • ROR ⁇ is highly expressed in the thymus and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas, and is associated with autoimmune diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
  • ROR ⁇ includes two subtypes of ROR ⁇ 1 and ROR ⁇ 2 (ROR ⁇ t).
  • ROR ⁇ 1 is expressed in a variety of tissues including thymus, muscle, kidney, and liver;
  • ROR ⁇ t is uniquely expressed only in cells of the immune system and plays a key role in thymus production, development of several secondary lymphoid tissues, and differentiation of Th17 lineage.
  • Th17 cells are subtypes of T helper cells that produce IL-17 and other pro-inflammatory cytokines.
  • Th17 cells play a key role in several mouse autoimmune disease models including: encephalomyelitis (EAE) and collagen-induced arthritis (CIA).
  • EAE encephalomyelitis
  • CIA collagen-induced arthritis
  • Th17 cells or their products are involved in the pathology of various human inflammation and autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, and asthma.
  • the main cause of the onset of autoimmune diseases is the intolerance of autoantigens and the development of autoinvasive effector T cells in infiltrating tissues.
  • Th17 cells are one of the important driving factors in the inflammatory process of tissue-specific autoimmunity.
  • Th17 cells are activated and are responsible for recruiting other inflammatory cells (neutrophils), which mediate the pathological changes of the target tissues. .
  • ROR ⁇ t has been reported to be a key regulator of Th17 cell differentiation, and Th17 cells have recently been found to be a subset of T helper cells that preferentially produce the cytokines IL-17A, IL-17F, IL-21 and IL-22. ROR ⁇ t induces transcription of genes encoding IL-17A and IL-17F in naive CD4+ T helper cells. ROR ⁇ t-deficient mice showed very few Th17 cells. The inhibition and deletion of ROR ⁇ t resulted in an improvement in EAE.
  • ROR ⁇ In view of the role of ROR ⁇ in the pathogenesis of disease, it is desirable to prepare compounds that modulate ROR ⁇ activity and are therefore useful in the treatment of ROR ⁇ -mediated inflammatory, metabolic and autoimmune diseases, such as respiratory diseases, asthma, chronic Obstructive pulmonary disease (COPD) and bronchitis, allergic diseases including allergic rhinitis and atopic dermatitis, cystic fibrosis, and lung allograft rejection.
  • COPD chronic Obstructive pulmonary disease
  • bronchitis allergic diseases including allergic rhinitis and atopic dermatitis, cystic fibrosis, and lung allograft rejection.
  • novel retinoic acid-related orphan receptor gamma (ROR ⁇ ) modulators a process for the preparation thereof, a pharmaceutical composition comprising the same, and their use in the treatment of ROR ⁇ -mediated inflammatory, metabolic and autoimmune The use in diseases.
  • ROR ⁇ retinoic acid-related orphan receptor gamma
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
  • R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
  • R 6 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a ROR ⁇ -mediated disease, Use in inflammatory, metabolic or autoimmune diseases.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid Arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease Inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, myas
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, rheumatoid joints Use in inflammation, psoriasis, ulcerative colitis or Crohn's disease.
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof,
  • R 5 is selected from the group consisting of benzene ring, pyridine ring, benzothiophene, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, a thiophene ring, a thiazole ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl a C 1 -C 6 alkoxy group, a C 1 -C 6
  • R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 Heterocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl; further preferably, The substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 2 -C 6 heterocycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl.
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof,
  • R 9 is selected from the group consisting of oxacyclopropane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, Piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituents selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl , C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl,
  • R 3 is -CH 2 R 9 or -R 9 ;
  • R 9 is selected from the group of any of the following substitutions: oxirane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydrogen -2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C
  • R 9 is selected from the group consisting of oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine;
  • the substituent is selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 ) C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, - C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, - C
  • the present invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein X is selected from O, NH or CH 2 ; more preferably X is selected from O or NH, and further preferably X is O.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof
  • R 1 , R 2 are each independently selected from hydrogen, hydroxy, halogen, amino, C 1-3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy or R 1 , R 2 combined It is an oxo group.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof
  • R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted -CH 2 C 3 - C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 8 heteroaryl, the substituent being selected from hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl or C 3- C 6 cycloalkyl; further preferably, R 4 is selected from hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heteroaryl, the substitu
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl; further preferably R 6 is selected from hydrogen, halogen, optionally Substituted C 1 -C 3 alkyl, the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 3 alkyl.
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof
  • X is O
  • n is 0 or 1
  • R 1 and R 2 are each independently selected from hydrogen, hydroxy, halogen, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or R 1 , R 2 is combined into an oxo group
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 4 -C 8 heterocycloalkane Any optionally substituted -CH 2 C 3 -C 8 cycloalkyl or optionally substituted C 6 -C 10 aryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 3 alkyl or C 3
  • the present invention also provides a compound of any one of Formulas Ia-Ij, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof
  • Subgroup of drugs :
  • R 3 , R 4 , R 5 , R 6 and n are as defined above.
  • R 3 is selected from the group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 , R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • s, t, u are independently selected from 0, 1, 2;
  • R 9 is selected from the group consisting of the following substituted oxirane, oxetane, cyclobutane Alkane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide Substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 8 heteroaryl group, the substituent group being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl;
  • R 5 is selected from the group optionally substituted: benzene ring, pyridine ring, benzothiophene, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene a ring, a thiazole ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl; R 6 is selected from hydrogen, halogen, optionally Substituted C 1 -
  • the present invention provides a compound of the formula (Ia-Ie, Ih, Ii, Ij), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or Subgroup of solvates or prodrugs:
  • R 3 , R 4 , R 5 , R 6 and n are as defined above.
  • the present invention provides a compound of the formula (Ia-Ie, Ij), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof or Subgroup of prodrugs:
  • R 3 , R 4 , R 5 , R 6 and n are as defined above.
  • R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring;
  • the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl, further preferably, the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl;
  • R 3 is -CH 2 R 9 or -R 9 ;
  • R 9 is selected from the group optionally substituted: oxetane, cyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, Pyrrolidine, piperidine, morpholine, pyridine; substituents selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 -cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
  • R 9 is selected from optionally substituted tetrahydro-2H-pyran, optionally substituted piperidine, optionally substituted oxetane or optionally substituted cyclobutane; the substituent is selected from H, C 1 -C 6 alkyl , C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
  • the present invention relates to a compound having the structure shown below, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a ROR ⁇ mediated disease Use, as well as in the preparation of a medicament for the treatment of a disease mediated by ROR ⁇ .
  • diseases mediated by ROR ⁇ include, but are not limited to, inflammatory, metabolic or autoimmune diseases.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid Arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease Inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, myas
  • the invention also provides a process for the preparation of a compound of the invention.
  • the compounds of the invention can be prepared by methods as shown in the synthetic scheme below.
  • all groups are as defined above unless otherwise stated.
  • TW Greene and PGM Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley &Sons are used as necessary.
  • these groups are removed using methods readily apparent to those skilled in the art; the choice of such methods, as well as the reaction conditions and their order of execution, are considered to be consistent with the preparation of the compounds of the invention.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and n are as defined above.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or -CH 2 C 3 -C 8 cycloalkyl, wherein the alkyl or cycloalkyl group may be one or more a substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl;
  • R 5 is selected from C 6 -C 10 aryl or C 2 -C 10 heteroaryl; wherein C 6 -C 10 aryl, C 2 -C 10 heteroaryl may be selected from one or more selected from the group consisting of hydrogen, halogen, Cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 - Substituent substitution of a C 6 alkylsulfonyl group;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 2 -C 10 heteroaryl, wherein said C 2 -C 8 heterocyclic ring
  • An alkyl group, a C 3 -C 8 cycloalkyl group, a C 6 -C 10 aryl group, a C 2 -C 10 heteroaryl group may be selected from one or more selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8- heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, - S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 al
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a ROR ⁇ -mediated disease, Use in inflammatory, metabolic or autoimmune diseases.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple Sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune Eye disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, severe Use in myasth
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, rheumatoid joints Use in inflammation, psoriasis, ulcerative colitis or Crohn's disease.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
  • R 5 is selected from: an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 - C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O) C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloal
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof,
  • R 5 is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, thiazole a ring, a furan ring or an oxazole ring;
  • the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 al
  • R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl or C 1 -C 6 alkylsulfonyl; the substituent is more preferably selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3- haloalkyl or -S(O 2 )C 1 -C 3 alkyl.
  • the present invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein R 9 is selected from the group optionally substituted: oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, Oroxazinone or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl , -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 cycl
  • R 3 is -CH 2 R 9 or -R 9 .
  • R 9 is selected from the group optionally substituted: oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, Oroxazinone or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl , -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8- heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 )(
  • R 9 is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, hydroxy or halogen, the substituent is
  • the present invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein X is selected from O, NH or CH 2 ; more preferably X is selected from O or NH, and further preferably X is O.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof,
  • R 1 ⁇ R 2 is independently selected from hydrogen, hydroxy, halogen, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or R 1 and R 2 are combined to form an oxo group.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof,
  • R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl.
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof
  • X is selected from O or NH
  • R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring
  • the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 alkylsulfonyl
  • R 3 is -CH 2 R 9 or -R 9
  • R 9 is selected from the group optionally substituted: oxirane , oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof
  • X is selected from O
  • R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring
  • the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy a C 1 -C 6 haloalkyl group or a C 1 -C 6 alkylsulfonyl group
  • R 3 is -CH 2 R 9 or -R 9
  • R 9 is selected from the following groups optionally substituted: oxirane, oxygen Heterocyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine, morpholin
  • the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof
  • X is O
  • n is 0 or 1
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, C 1-3 alkyl, C 1 -C 3 alkoxy, or R 1 And R 2 is bonded to an oxo group
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 3 alkyl
  • R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring
  • the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl
  • the present invention further provides a compound of the formula (I aj j), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a solvate thereof or a prodrug thereof Subgroup:
  • R 3 , R 4 , R 5 and n are as defined above.
  • R 3 is selected from the group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 .
  • R 7 , R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • s, t, u are independently selected from 0, 1, 2;
  • R 9 is selected from the group optionally substituted: oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, Oroxazinone or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl , -S(O 2 )C 1 -
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
  • R 5 is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, thiazole ring a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 alkylsulfonyl.
  • the present invention provides a compound of the formula (Ia-Ie, Ih, Ii, Ij), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or Subgroup of solvates or prodrugs:
  • R 3 , R 4 , R 5 and n are as defined above.
  • the present invention provides a compound of the formula (Ia-Ie, Ij), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof or Subgroup of prodrugs:
  • R 3 , R 4 , R 5 and n are as defined above.
  • R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane Or a C 1 -C 6 alkylsulfonyl group;
  • R 3 is -CH 2 R 9 or -R 9 .
  • R 9 is selected from the group optionally substituted: oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
  • R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane Or a C 1 -C 6 alkylsulfonyl group;
  • R 3 is -CH 2 R 9 or -R 9 .
  • R 9 is selected from optionally substituted tetrahydro-2H-pyran or optionally substituted piperidine; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 Cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
  • the present invention relates to a compound having the structure shown below or a stereoisomer thereof, and a mutual transformation
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a ROR ⁇ mediated disease Use, as well as in the preparation of a medicament for the treatment of a disease mediated by ROR ⁇ .
  • diseases mediated by ROR ⁇ include, but are not limited to, inflammatory, metabolic or autoimmune diseases.
  • the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid Arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease Inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, myas
  • the invention also provides a process for the preparation of a compound of the invention.
  • the compounds of the invention can be prepared by methods as shown in the synthetic scheme below.
  • all groups are as defined above unless otherwise stated.
  • TW Greene and PGM Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley &Sons are used as necessary.
  • these groups are removed using methods readily apparent to those skilled in the art; the choice of such methods, as well as the reaction conditions and their order of execution, are considered to be consistent with the preparation of the compounds of the invention.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
  • R 4 is selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted —CH 2 C 3 -C 8 cycloalkyl group, and the substituent is selected from C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
  • R 5 is selected from an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloal
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
  • R 5 is selected from: an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent group being selected from the group consisting of an amino group, a C 1 -C 3 alkylamino group, a C 1 -C 2 alkane a C 4 -C 8 heterocycloalkyl group or a hydroxy C 1 -C 6 haloalkyl group;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloal
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
  • R 5 is selected from: an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 - C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from a halogen-substituted C 1 -C 6 alkyl group or a hydroxy-substituted C 1 -C 6 alkyl group;
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
  • R 6 is H
  • R 1 and R 2 are each independently selected from a C 3 -C 8 cycloalkyloxy group
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
  • R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
  • R 4 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, An amino group, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group or a C 3 -C 8 cycloalkyl group;
  • R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
  • R 6 is H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
  • R 5 is selected from optionally substituted -CH 2 C 6 -C 10 aryl, optionally substituted -CH 2 C 2 -C 10 heteroaryl, the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkane a base, an amino group, a C 1 -C 3 alkylamino group, a C 2 -C 8 heterocycloalkyl group, a C 1 -C 2 alkyl C 4 -C 8 heterocycloalkyl group, a C 3 -C 8 cycloalkyl group, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • the compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
  • R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
  • R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
  • R 6 is selected from the group consisting of halogen, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
  • R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
  • Y is selected from C 1 -C 6 alkyl, NH or O;
  • R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8
  • n 0, 1, 2;
  • s, t, u are independently selected from 0, 1, 2;
  • X is selected from O, NR 10 , CR 10 ;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
  • n is selected from 0 and 1.
  • R 3 , R 4 , R 5 , R 6 and n may be as described above.
  • Alkyl means a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included.
  • C 1 -C 6 alkyl means a medium-sized alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl Wait.
  • the alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, halogen C 1 -C 6 alkyl, 4 to 8 membered heteroalicyclic, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy.
  • Alkylamino refers to a group in which one or two hydrogen atoms of the amino group are replaced by an alkyl group. Including an amino group substituted with a straight, branched or cyclic alkyl group, such as methylamino, dimethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, ring Propylamino, cyclobutylamino, pentylamino and the like. Preferred are lower straight, branched or cyclic alkyl substituted amino groups containing from 1 to 4 carbon atoms.
  • Cycloalkyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6-membered fused or polycyclic fused ring ("thickened” ring means each in the system The ring shares an adjacent pair of carbon atoms) with other rings in the system, one of which Or a plurality of rings having a fully connected ⁇ -electron system, examples of which are not limited to cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, Cycloheptane or cycloheptatriene. Cycloalkyl groups are substitutable and unsubstituted.
  • the substituent is preferably one or more groups each selected from the group consisting of hydrogen, hydroxy, thiol, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkane , lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, Amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, Alkylcarbonylamino, arylcarbonylamino.
  • Aryl means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a fully conjugated pi-electron system. “Aryl” includes:
  • a six-membered carbon aromatic ring such as benzene
  • a bicyclic ring in which at least one ring is a carbon aromatic ring such as naphthalene, anthracene or 1,2,3,4-tetrahydroquinoline;
  • an aryl group includes a six-membered carbon aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbon aromatic ring.
  • the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below.
  • the resulting ring system is a heteroaryl group rather than an aryl group.
  • Non-limiting examples of aryl groups are phenyl, naphthyl.
  • the aryl group can be substituted or unsubstituted.
  • preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkane Sulfur, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkyl Sulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonyl Amino group.
  • Heteroaryl means a monocyclic or fused ring radical of 5 to 14 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C In addition, it has a fully conjugated ⁇ -electron system. Heteroaryl refers to:
  • N N
  • O organic radical
  • S sulfur
  • a heteroaryl group includes a 5-6 membered heteroaromatic ring and a 5-6 membered cycloalkyl group.
  • one of the rings contains one or more heteroatoms and the attachment sites are on the heteroaromatic ring.
  • the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed one.
  • heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, imidate, pyrazine, pyridazine, anthracene, Azaindene, benzimidazole, benzotriazole, porphyrin, anthrone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like.
  • Preferred examples of such groups are benzene rings, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, pyrrole, pyrazole, imidazole, thiophene, thiazole, furan or oxazole.
  • One or all of the hydrogen atoms in the heteroaryl group may be substituted with hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, Lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, Alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkyl Carbonylamino, arylcarbonylamino.
  • Heterocycloalkyl means a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings, including a spiro ring system, each ring having 3 to 8 atoms in combination with one or a plurality of ring heteroatoms (selected from N, O or S(O) 0-2 ), and which may be optionally substituted independently by one or more, preferably one or two substituents, said substituents being selected From: hydrogen, hydroxy, mercapto, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl , lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl
  • heterocycloalkyl groups include, but are not limited to, oxirane, aziridine, pyridine, morpholin-3-one, thiomorpholine 1,1-dioxide, morpholinyl, piperazinyl, piperidine Pyridyl, azetidinyl, pyrrolidinyl, hexahydroazain, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl , tetrahydro-2H-pyranyl, thio-allinyl, quinuclidinyl and imidazolinyl, preferably W is selected from O, S or NR 12 , and each group is as described above, and the examples may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5- Dia
  • Alkoxy means -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Aryloxy means -O-aryl and -O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • Arylalkylene means an alkyl group, preferably a lower alkyl group as defined above, which is substituted by an aryl group as described above, for example -CH 2 phenyl, -(CH 2 ) 2 phenyl, -(CH 2 3 phenyl, CH 3 CH(CH 3 )CH 2 phenyl and its derivatives.
  • Heteroaryl alkylene denotes a lower alkyl, preferably as defined above, heteroaryl which is substituted as described above, for example, -CH 2 pyridinyl, - (CH 2) 2 pyrimidinyl, - ( CH 2 ) 3 imidazolyl and the like and derivatives thereof.
  • Haldroxy means an -OH group.
  • Indexl means a -SH group.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • Haloalkyl means an alkyl group substituted by a halogen, preferably a lower alkyl group as defined above, which is substituted by one or more of the same or different halogen atoms, for example -CH 2 Cl, -CF 3 , -CCl 3 , - CH 2 CF 3 , -CH 2 CCl 3 and the like.
  • Cyano means a -CN group.
  • Amino means a -NH 2 group.
  • Niro means a -NO 2 group.
  • Alkylsulfonyl means a -S(O 2 )C 1 -C 6 alkyl group wherein alkyl is as defined above.
  • Cycloalkyloxy means that H in the -OH group is substituted by a cycloalkyl group, wherein cycloalkyl is as defined above.
  • Optionally substituted includes both substituted and substituted unsubstituted ones, such as an optionally substituted alkyl group including an unsubstituted alkyl group and an alkyl group substituted with one or more substituents.
  • substituted by one or more groups means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.
  • a wavy line indicates a connection site
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, ortho-benzene Formic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid .
  • an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
  • “Pharmaceutical composition” refers to a combination of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with one or more pharmaceutically acceptable excipients.
  • auxiliary is generally selected from other chemical components other than the compounds described herein, such as pharmaceutically acceptable pharmaceutically acceptable carriers, or other pharmaceutical effects. Mixing of compounds and the like. The purpose of the pharmaceutical composition may be to facilitate the administration to the animal or to synergistic effects of the drug.
  • “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, various Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, B Glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil and the like.
  • the pharmaceutical composition of the foregoing may include, in addition to a pharmaceutically acceptable carrier and the like, an adjuvant commonly used in medicine, such as an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, A toner, a solubilizer, a thickener, a surfactant, a complexing agent, a protein, an amino acid, a fat, a saccharide, a vitamin, a mineral, a trace element, a sweetener, a coloring matter, a flavor, or a combination thereof.
  • an adjuvant commonly used in medicine such as an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, A toner, a solubilizer, a thickener, a surfactant, a complexing agent, a protein, an amino acid, a fat, a saccharide, a vitamin, a mineral, a trace element, a sweetener, a coloring matter, a flavor, or a combination thereof
  • the compounds of formula (I) according to the invention have a significant inhibitory effect on ROR ⁇ t, while ROR ⁇ t plays a very important role in inflammatory, metabolic and autoimmune diseases, and inhibition of ROR ⁇ t will result in the alleviation or effective treatment of these diseases.
  • Example 1 N-(4-ethylphenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide compound EXP Preparation of 1
  • the Exp1 (40mg, 0.09mmol, 1.0eq) was dissolved in MeOH (5mL), was added the compound NaBH 4 (10mg, 0.25mmol, 3.0eq ), stirred at room temperature for 2 hours. TLC showed the reaction was complete, the solvent was evaporated, and the solid compound Exp 2 (21 mg, yield: 52%) was obtained by prep-HPLC separation.
  • Hydroxylamine hydrochloride (20 mg, 0.29 mmol, 2.7 eq) was dissolved in 5 mL of dry ethanol, sodium acetate (50 mg, 0.61 mmol, 5.7 eq) was added at room temperature, stirred at room temperature for 15 min, then Exp 1 (50 mg, 0.11) Methyl, 1.0 eq) was dissolved in 1.0 mL of absolute ethanol and added to the reaction mixture. Stir overnight at room temperature and TLC showed approximately 30% of the starting material remained.
  • SR1001 is an inverse agonist of ROR ⁇ t, and as a positive reference, its structure is:
  • the first day of cell seed plate The 293T adherent cells were digested with 1 mL of trypsin for about 5 minutes. The digested cells were pipetted, transferred to a 15 mL centrifuge tube, and centrifuged at 1000 rpm for 5 min. Discard the old medium, resuspend the cells in fresh medium and dilute to the desired density.
  • the cell suspension was prepared at a cell density of 15,000 cells/well. Plate, 100 ⁇ L of cells per well. To prevent edge effects, 96-well cell culture plates were only plated with 60 wells in the middle of the plate, and 36 wells were filled with 100 ⁇ L of PBS per well. The cells were cultured at 37 ° C in a 5% CO 2 incubator.
  • transient transfection experiments were performed 24 hours after cell seed plating.
  • a transient plasmid ie, Gal4-ROR ⁇ -LBD: 25 ng/well; PgL4.3-luc: 25 ng/well
  • transfection reagent liposome 2000 concentration of 3 times DNA
  • a small molecule compound (a compound of SR1001 or Exp1-Exp34) can be added by transient transfection for more than 5 hours.
  • the cells were then cultured in a 5% CO 2 incubator at 37 °C. After about 24 hours, the cells were taken out, and the growth of the cells was observed under a microscope, and the cell culture plates were taken out of the cells. Then do the luciferase double reporter gene assay.
  • the cell culture medium was first aspirated, and then about 100 ⁇ L of PBS was added to wash the residual medium. After the mother liquor 5 ⁇ cell lysate was diluted to 1 ⁇ , 20 ⁇ L was added per well, and then the cells were lysed by shaking for about 20 min.
  • ++++ means IC 50 ⁇ 50 nM; +++ means IC 50 range is 50-200 nM; ++ means IC 50 range is 200-1000 nM; + means IC 50 >1000 nM; NA means undetected.
  • reaction buffer DTT and KF were dissolved in 1x buffer D. Final concentration: DTT 5 mM, KF 50 mM.
  • Detection plate wavelengths 665 nm and 615 nm; instrument: multi-label microplate detector.
  • IC 50 of the compound is calculated and dose-response curve: log inhibition rate was calculated by the compounds and compound concentration using Graphpad 5.0, to obtain dose-response curve and IC50 of the compound.
  • ROR ⁇ t plays a very important role in inflammatory, metabolic and autoimmune diseases, and inhibition of ROR ⁇ t will cause these diseases to be alleviated or Effective treatment.
  • respiratory diseases such as asthma, COPD
  • autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease

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Abstract

A compound as represented by formula (I), or a stereoisomer, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, a preparation method therefor, a pharmaceutical composition comprising these regulators, and use thereof in the treatment of RORγ-mediated inflammatory, metabolic and autoimmune diseases. The compounds have inhibitory activities against RORγ, and can be used in the treatment of inflammatory, metabolic and autoimmune diseases.

Description

一类色满-6-磺酰胺RORγ调节剂及其用途A type of color-filled-6-sulfonamide RORγ regulator and use thereof 技术领域Technical field
本发明涉及新颖的维甲酸相关孤儿受体γ(RORγ)调节剂、其制备方法、含有这些调节剂的药物组合物及其在治疗RORγ介导的炎性、代谢性和自身免疫性疾病中的用途。The present invention relates to novel retinoic acid-related orphan receptor gamma (RORγ) modulators, preparation methods thereof, pharmaceutical compositions containing the same, and their use in the treatment of RORγ-mediated inflammatory, metabolic and autoimmune diseases use.
背景技术Background technique
维甲酸受体相关的孤儿受体(retinoic acid receptor-related orphan receptors，RORs)是一类配体依赖的转录因子，在生殖发育、生理节律调节、新陈代谢紊乱、炎症发生以及免疫系统调节等一系列生理病理过程中扮演重要角色。RORs是核受体超家族中的一员，包括RORα、RORβ、RORγ。RORα主要分布在肝脏、骨骼肌、皮肤、肺、脂肪组织、肾脏、胸腺、大脑和血液中，与肝糖原异生、脂代谢、动脉粥样硬化等生理病理过程有关。RORβ主要分布在中枢神经系统中，包括大脑、视网膜和松果腺，主要与脊髓、丘脑、小脑皮质对敏感信息的处理方面有关。RORγ高表达于胸腺中，在肾脏、肝脏、心脏、骨骼肌、脂肪组织、睾丸、前列腺、胰腺中也有分布，与类风湿性关节炎、牛皮癣、多发性硬化症等自身免疫病有关。Retinoic acid receptor-related orphan receptors (RORs) are a class of ligand-dependent transcription factors that are involved in reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, and immune system regulation. Play an important role in the physiological and pathological process. RORs are a member of the nuclear receptor superfamily, including RORα, RORβ, and RORγ. RORα is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood, and is related to physiological and pathological processes such as hepatic gluconeogenesis, lipid metabolism and atherosclerosis. RORβ is mainly distributed in the central nervous system, including the brain, retina and pineal gland, and is mainly related to the treatment of sensitive information in the spinal cord, thalamus and cerebellum. RORγ is highly expressed in the thymus and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas, and is associated with autoimmune diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
RORγ包括RORγ1和RORγ2(RORγt)两个亚型。RORγ1在包括胸腺、肌肉、肾和肝在内的多种组织中表达；RORγt仅在免疫系统细胞中唯一表达，并在胸腺生成、若干二级淋巴组织的发育和Th17谱系分化中起关键作用。研究显示，RORγt为Th17细胞分化的关键调节剂。Th17细胞是T辅助细胞的亚型，其产生IL-17和其他促炎细胞因子。Th17细胞在若干种小鼠自身免疫性疾病模型(包括：脑脊髓炎(EAE)和胶原诱导的关节炎(CIA))中具有关键作用。此外，研究显示，Th17细胞或其产物与多发性硬化病、类风湿关节炎、银屑病、克罗恩病、哮喘在内的多种人类炎症和自身免疫性疾病的病理有关。自身免疫性疾病发病的主要原因是对自体抗原的不耐受和浸润组织的自动侵袭性效应子T细胞的发展。Th17细胞是组织特异性自身免疫中炎症性过程中重要的驱动因子之一，在疾病发展过程中，Th17细胞被激活并负责募集其他炎症细胞(中性粒细胞)，从而介导靶组织的病变。RORγ includes two subtypes of RORγ1 and RORγ2 (RORγt). RORγ1 is expressed in a variety of tissues including thymus, muscle, kidney, and liver; RORγt is uniquely expressed only in cells of the immune system and plays a key role in thymus production, development of several secondary lymphoid tissues, and differentiation of Th17 lineage. Studies have shown that RORγt is a key regulator of Th17 cell differentiation. Th17 cells are subtypes of T helper cells that produce IL-17 and other pro-inflammatory cytokines. Th17 cells play a key role in several mouse autoimmune disease models including: encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, studies have shown that Th17 cells or their products are involved in the pathology of various human inflammation and autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, and asthma. The main cause of the onset of autoimmune diseases is the intolerance of autoantigens and the development of autoinvasive effector T cells in infiltrating tissues. Th17 cells are one of the important driving factors in the inflammatory process of tissue-specific autoimmunity. During the development of the disease, Th17 cells are activated and are responsible for recruiting other inflammatory cells (neutrophils), which mediate the pathological changes of the target tissues. .
据报道，RORγt为Th17细胞分化的关键调节剂，最近发现Th17细胞是优先产生细胞因子IL-17A、IL-17F、IL-21和IL-22的T辅助细胞的亚组。RORγt诱导编码IL-17A和IL-17F的基因在初始CD4+T辅助细胞中的转录。RORγt缺陷的小鼠显示非常少的Th17细胞。RORγt的抑制、缺失使得EAE得到改善。 RORγt has been reported to be a key regulator of Th17 cell differentiation, and Th17 cells have recently been found to be a subset of T helper cells that preferentially produce the cytokines IL-17A, IL-17F, IL-21 and IL-22. RORγt induces transcription of genes encoding IL-17A and IL-17F in naive CD4+ T helper cells. RORγt-deficient mice showed very few Th17 cells. The inhibition and deletion of RORγt resulted in an improvement in EAE.
在哮喘患者中，已显示RORγt和IL-17A表达水平在唾液、肺、支气管肺泡灌洗(BAL)液和外周血中增加，且水平与疾病严重程度直接相关。除IL-17A以外，最近研究已显示IL-17家族的另一细胞因子IL-17F可在过敏性气道炎症中具有重要作用，且因此在气道疾病例如哮喘中具有重要影响。IL-17F基因在小鼠气道中的过度表达与气道中性白细胞增多症、细胞因子诱导、气道高反应性的增加和粘液分泌过多相关。In asthma patients, RORγt and IL-17A expression levels have been shown to increase in saliva, lung, bronchoalveolar lavage (BAL) fluid, and peripheral blood, and levels are directly related to disease severity. In addition to IL-17A, recent studies have shown that IL-17F, another cytokine of the IL-17 family, has an important role in allergic airway inflammation and thus has an important influence in airway diseases such as asthma. Overexpression of the IL-17F gene in the airways of mice is associated with airway neutrophilia, cytokine induction, increased airway hyperresponsiveness, and excessive mucus secretion.
鉴于RORγ在疾病的发病机制中所起的作用，期望制备调节RORγ活性并因此用于治疗RORγ介导的炎性、代谢性和自身免疫性疾病的化合物，所述疾病例如呼吸系统疾病哮喘、慢性阻塞性肺病(COPD)和支气管炎、包括过敏性鼻炎和异位性皮肤炎的过敏性疾病、囊性纤维化和肺同种异体移植排斥。In view of the role of RORγ in the pathogenesis of disease, it is desirable to prepare compounds that modulate RORγ activity and are therefore useful in the treatment of RORγ-mediated inflammatory, metabolic and autoimmune diseases, such as respiratory diseases, asthma, chronic Obstructive pulmonary disease (COPD) and bronchitis, allergic diseases including allergic rhinitis and atopic dermatitis, cystic fibrosis, and lung allograft rejection.
发明内容Summary of the invention
根据本发明，提供新颖的维甲酸相关孤儿受体γ(RORγ)调节剂、其制备方法、包含有这些调节剂的药物组合物及其在治疗RORγ介导的炎性、代谢性和自身免疫性等疾病中的用途。According to the present invention, there are provided novel retinoic acid-related orphan receptor gamma (RORγ) modulators, a process for the preparation thereof, a pharmaceutical composition comprising the same, and their use in the treatment of RORγ-mediated inflammatory, metabolic and autoimmune The use in diseases.
更具体地，一方面，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：More specifically, in one aspect, the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000001
Figure PCTCN2017087263-appb-000001
其中，among them,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基、C3-C8环烷基氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C8杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
R5选自任意取代的C6-C10芳基、任意取代的-CH2C6-C10芳基、任意取代的C2-C10杂芳基或任意取代的-CH2C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、氨基、C1-C3烷基胺基、C2-C8杂环烷基、C1-C2烷基C4-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基C1-C6卤代烷基或-S(O2)C1-C6烷基； R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
R6选自氢、卤素、羟基、氨基、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 6 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
另一方面，本发明提供一种药物组合物，其包含：式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药；一种或多种药学上可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗RORγ介导的疾病，如炎性、代谢性或自身免疫性疾病中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a RORγ-mediated disease, Use in inflammatory, metabolic or autoimmune diseases.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性疾病(如：过敏性鼻炎)、异位性皮肤炎、囊性纤维化、肺同种异体移植排斥、多发性硬化症、类风湿性关节炎、青少年类风湿性关节炎、骨关节炎、强直性脊柱炎、系统性红斑狼疮、银屑病、桥本氏病、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、炎性肠病(IBS)、炎性肠综合征(IBD)、斯耶格伦氏综合征、视神经炎、I型糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合征、银屑病关节炎、格雷氏病或巩膜炎等中的用途。 In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid Arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease Inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre Use in signs, psoriatic arthritis, Gracies or scleritis.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗哮喘、类风湿性关节炎、银屑病、溃疡性结肠炎或克罗恩氏病中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, rheumatoid joints Use in inflammation, psoriasis, ulcerative colitis or Crohn's disease.
在一种优选方案中，本发明涉及的结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中R5选自任意取代的以下基团：苯环、吡啶环、苯并噻吩、嘧啶环、哒嗪环、吡嗪环、喹啉、异喹啉、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、呋喃环或噁唑环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基；进一步优选的，取代基选自氢、卤素、氰基、C1-C4烷基、C2-C6杂环烷基、C3-C6环烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3烷基胺基或-S(O2)C1-C3烷基。In a preferred embodiment, the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, Wherein R 5 is selected from the group consisting of benzene ring, pyridine ring, benzothiophene, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, a thiophene ring, a thiazole ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl a C 1 -C 6 alkoxy group, a C 1 -C 6 haloalkyl group, a C 1 -C 3 alkylamino group or a -S(O 2 )C 1 -C 6 alkyl group; further preferably, the substituent is selected from Hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 2 -C 6 heterocycloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl.
优选的，R5选自任意取代的苯环、任意取代的苯并噻吩或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基；进一步优选的，取代基选自氢、卤素、氰基、C1-C4烷基、C2-C6杂环烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C3烷基胺基或-S(O2)C1-C3烷基。Preferably, R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 Heterocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl; further preferably, The substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 2 -C 6 heterocycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl.
在一种优选方案中，本发明涉及的结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基取代的C1-C6烷基、羟基或卤素；进一步优选的，取代基选自H、C1-C4烷基、C2-C6杂环烷基、C3-C6环烷基、-S(O2)C1-C3烷基、-S(O2)(CH2)mC3-C6环烷基、-S(O2)(CH2)m C2-C6杂环烷基、-C(O)C1-C4烷基、-C(O)(CH2)mC3-C6环烷基、-C(O)(CH2)m C2-C6杂环烷基、C2-C6杂芳基、C6-C8芳基、羟基取代的C1-C4烷基、羟基或卤素。In a preferred embodiment, the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, Wherein R 9 is selected from the group consisting of oxacyclopropane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, Piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituents selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl , C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 ) (CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C( O) (CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy substituted C 1 -C 6 alkyl, hydroxy or halogen; further Preferably, the substituent is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 6 heterocycloalkyl, C 3 -C 6 cycloalkyl, -S(O 2 )C 1 -C 3 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 6 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 6 heterocycloalkyl, -C(O)C 1- C 4 alkyl, -C(O)(CH 2 ) m C 3 -C 6 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 6 heterocycloalkyl, C 2 -C 6 heteroaryl, C 6 -C 8 aryl, hydroxy substituted C 1 -C 4 alkyl, hydroxy or halogen.
优选的，R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8 环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基取代的C1-C6烷基、羟基或卤素。更优选的，R9选自任意取代的以下基团：氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、羟基取代的C1-C6烷基、羟基或卤素；进一步优选的，取代基选自H、C1-C4烷基、卤素取代的C1-C3烷基、C2-C6杂环烷基、C3-C6环烷基、-S(O2)C1-C3烷基、-S(O2)(CH2)mC3-C6环烷基、-S(O2)(CH2)m C2-C6杂环烷基、-C(O)C1-C3烷基、-C(O)(CH2)mC3-C6环烷基、-C(O)(CH2)m C2-C6杂环烷基、羟基取代的C1-C3烷基、羟基或卤素。Preferably, R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the group of any of the following substitutions: oxirane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydrogen -2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy Substituted C 1 -C 6 alkyl, hydroxy or halogen. More preferably, R 9 is selected from the group consisting of oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; The substituent is selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 ) C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, - C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl a hydroxy-substituted C 1 -C 6 alkyl group, a hydroxyl group or a halogen; further preferably, the substituent is selected from the group consisting of H, C 1 -C 4 alkyl, halogen-substituted C 1 -C 3 alkyl, C 2 -C 6 Heterocycloalkyl, C 3 -C 6 cycloalkyl, -S(O 2 )C 1 -C 3 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 6 cycloalkyl, -S (O 2 )(CH 2 ) m C 2 -C 6 heterocycloalkyl, -C(O)C 1 -C 3 alkyl, -C(O)(CH 2 ) m C 3 -C 6 cycloalkyl , -C(O)(CH 2 ) m C 2 -C 6 heterocycloalkyl, hydroxy-substituted C 1 -C 3 alkyl, hydroxy or halogen.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中X选自O、NH或CH2；更优选的X选自O或NH，进一步优选的X为O。In a preferred embodiment, the present invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein X is selected from O, NH or CH 2 ; more preferably X is selected from O or NH, and further preferably X is O.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，R1、R2各自独立的选自氢、羟基、卤素、氨基、C1-3烷基、C1-C3烷氧基、C3-C6环烷基氧基或者R1、R2合并为氧代基。In a preferred embodiment, the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof, R 1 , R 2 are each independently selected from hydrogen, hydroxy, halogen, amino, C 1-3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy or R 1 , R 2 combined It is an oxo group.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C6杂环烷基、任意取代的-CH2C3-C6环烷基、任意取代的C6-C10芳基或任意取代的C2-C8杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基或C3-C6环烷基；进一步优选的，R4选自氢、任意取代的C1-C4烷基、任意取代的C3-C6环烷基、任意取代的C2-C6杂环烷基、任意取代的-CH2C3-C6环烷基、任意取代的C6-C8芳基或任意取代的C2-C6杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C3烷基或C3-C6环烷基。In a preferred embodiment, the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof, R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted -CH 2 C 3 - C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 8 heteroaryl, the substituent being selected from hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl or C 3- C 6 cycloalkyl; further preferably, R 4 is selected from hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 hetero a cycloalkyl group, an optionally substituted -CH 2 C 3 -C 6 cycloalkyl group, an optionally substituted C 6 -C 8 aryl group or an optionally substituted C 2 -C 6 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, Hydroxy, amino, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，R6选自氢、卤素、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；进一步优选的R6选自氢、卤素、任意取代的C1-C3烷基，取代基选自氢、卤素、羟基、氨基或C1-C3烷基。 In a preferred embodiment, the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof, R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl; further preferably R 6 is selected from hydrogen, halogen, optionally Substituted C 1 -C 3 alkyl, the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 3 alkyl.
应当理解，本发明还涉及上述优选方案的任意组合。下文中给出组合的一些实例。然而，本发明不限于这些组合。It should be understood that the invention also relates to any combination of the above preferred aspects. Some examples of combinations are given below. However, the invention is not limited to these combinations.
在一种优选的实施方案中：本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中：X为O；n为0或1；R1、R2各自独立的选自氢、羟基、卤素、氨基、C1-C3烷基、C1-C3烷氧基，或者R1、R2合并为氧代基；R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C6环烷基、任意取代的C4-C8杂环烷基、任意取代的-CH2C3-C8环烷基或任意取代的C6-C10芳基，取代基选自氢、卤素、羟基、氨基、C1-C3烷基或C3-C8环烷基；R5选自任意取代的苯环、任意取代的苯并噻吩或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3烷基胺基或-S(O2)C1-C3烷基；R6选自氢、卤素、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丁烷、环丁烷、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、卤素取代的C1-C3烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C3烷基、羟基或卤素。In a preferred embodiment: the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof Wherein: X is O; n is 0 or 1; and R 1 and R 2 are each independently selected from hydrogen, hydroxy, halogen, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or R 1 , R 2 is combined into an oxo group; R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 4 -C 8 heterocycloalkane Any optionally substituted -CH 2 C 3 -C 8 cycloalkyl or optionally substituted C 6 -C 10 aryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl; R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl; R 6 is selected from hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl; R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the group optionally substituted: oxetane, cyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; The substituent is selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 3 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 ) C 1 -C 3 alkyl, hydroxy or halogen.
在一种优选方案中，本发明还提供了式Ia-Ij任一结构所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组：In a preferred embodiment, the present invention also provides a compound of any one of Formulas Ia-Ij, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof Subgroup of drugs:
Figure PCTCN2017087263-appb-000002
Figure PCTCN2017087263-appb-000002
其中：R3、R4、R5、R6和n的定义如上所述。Wherein: R 3 , R 4 , R 5 , R 6 and n are as defined above.
在一种优选组合方案中，式(Ia-Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组，其中：In a preferred combination, a compound of formula (Ia-Ij), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a subset of a prodrug thereof, wherein :
R3选自基团-(CHR7)s-(Y)t-(CHR8)u-R9；R7、R8独立选自氢、C1-C6烷基、羟基；Y选自C1-C6烷基、NH或O；s、t、u独立地选自0、1、2；R9选自任意取代的以下基团氧杂环丙烷、氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基取代的C1-C6烷基、羟基或卤素；R 3 is selected from the group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ; R 7 , R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy; Y is selected from C 1 -C 6 alkyl, NH or O; s, t, u are independently selected from 0, 1, 2; R 9 is selected from the group consisting of the following substituted oxirane, oxetane, cyclobutane Alkane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide Substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl a C 6 -C 10 aryl group, a hydroxy-substituted C 1 -C 6 alkyl group, a hydroxyl group or a halogen;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C6杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C8杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C3-C6环烷基或C3-C6环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 8 heteroaryl group, the substituent group being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl;
R5选自任意取代的以下基团：苯环、吡啶环、苯并噻吩、嘧啶环、哒嗪环、吡嗪环、喹啉、异喹啉、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、呋喃环或噁唑环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基；R6选自氢、卤素、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基。R 5 is selected from the group optionally substituted: benzene ring, pyridine ring, benzothiophene, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene a ring, a thiazole ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl; R 6 is selected from hydrogen, halogen, optionally Substituted C 1 -C 6 alkyl, the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl.
进一步的，在一种优选方案中，本发明提供式(Ia-Ie、Ih、Ii、Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组：Further, in a preferred embodiment, the present invention provides a compound of the formula (Ia-Ie, Ih, Ii, Ij), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or Subgroup of solvates or prodrugs:
Figure PCTCN2017087263-appb-000003
Figure PCTCN2017087263-appb-000003
Figure PCTCN2017087263-appb-000004
Figure PCTCN2017087263-appb-000004
其中，R3、R4、R5、R6和n的定义如上所述。Wherein R 3 , R 4 , R 5 , R 6 and n are as defined above.
进一步的，在一种优选方案中，本发明提供式(Ia-Ie，Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组：Further, in a preferred embodiment, the present invention provides a compound of the formula (Ia-Ie, Ij), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof or Subgroup of prodrugs:
Figure PCTCN2017087263-appb-000005
Figure PCTCN2017087263-appb-000005
其中：R3、R4、R5、R6和n的定义如上所述。Wherein: R 3 , R 4 , R 5 , R 6 and n are as defined above.
下文中给出组合的一些实例。然而，本发明不限于这些组合。Some examples of combinations are given below. However, the invention is not limited to these combinations.
在一种优选组合方案中，式(Ia-Ie，Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组，其中：In a preferred combination, a compound of formula (Ia-Ie, Ij), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a subgroup of a prodrug ,among them:
R5选自任意取代的苯环、任意取代的苯并噻吩或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基，进一步优选的，取代基选自氢、卤素、氰基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3烷基胺基或-S(O2)C1-C3烷基；R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl, further preferably, the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl;
R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丁烷、环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、羟基或卤素。R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the group optionally substituted: oxetane, cyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, Pyrrolidine, piperidine, morpholine, pyridine; substituents selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 -cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
在一种优选组合方案中，式(Ia-Ie)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组，其中：In a preferred combination, a compound of formula (Ia-Ie), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a subset of prodrugs thereof, wherein :
R9选自任意取代的四氢-2H-吡喃、任意取代的哌啶、任意取代的氧杂环丁烷或任意取代的环丁烷；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、羟基或卤素。 R 9 is selected from optionally substituted tetrahydro-2H-pyran, optionally substituted piperidine, optionally substituted oxetane or optionally substituted cyclobutane; the substituent is selected from H, C 1 -C 6 alkyl , C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
另一方面，更具体的方案，本发明涉及结构如下所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：In another aspect, the present invention relates to a compound having the structure shown below, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000006
Figure PCTCN2017087263-appb-000006
Figure PCTCN2017087263-appb-000007
Figure PCTCN2017087263-appb-000007
Figure PCTCN2017087263-appb-000008
Figure PCTCN2017087263-appb-000008
另一方面，本发明提供一种药物组合物，其包含：式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药；一种或多种药学上可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗RORγ介导的疾病中的用途，以及制备治疗RORγ介导的疾病的药物中的应用。其中RORγ介导的疾病包括但不限于炎性、代谢性或自身免疫性疾病等。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a RORγ mediated disease Use, as well as in the preparation of a medicament for the treatment of a disease mediated by RORγ. Among the diseases mediated by RORγ include, but are not limited to, inflammatory, metabolic or autoimmune diseases.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性疾病(例如：过敏性鼻炎)、异位性皮肤炎、囊性纤维化、肺同种异体移植排斥、多发性硬化症、类风湿性关节炎、青少年类风湿性关节炎、骨关节炎、强直性脊柱炎、系统性红斑狼疮、银屑病、桥本氏病、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、炎性肠病(IBS)、炎性肠综合征(IBD)、斯耶格伦氏综合征、视神经炎、I型糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合征、银屑病关节炎、格雷氏病或巩膜炎等中的用途，优选其用于治疗哮喘、类风湿性关节炎、银屑病、溃疡性结肠炎、克罗恩氏病中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid Arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease Inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre Uses in signs, psoriatic arthritis, Gracies disease or scleritis, etc., preferably for use in the treatment of asthma, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease.
另一方面，本发明还提供本发明所述化合物的制备方法。In another aspect, the invention also provides a process for the preparation of a compound of the invention.
本发明化合物可通过如以下合成路线所示的方法来制备。在以下反应路线和下文中，除非另有说明，所有基团如前述中定义。也认识到，在下文所述的所有路线中，众所周知，根据有机合成的一般原理，必要时采用敏感或反应性基团的保护基(T.W.Greene和P.G.M.Wuts(1991)Protecting Groups in Organic Synthesis，John Wiley&Sons)；在化合物合成的适宜阶段，使用本领域技术人员容易明白的方法除去这些基团；这种方法的选择以及反应条件和它们的执行顺序应认为与本发明化合物的制备方法是一致的。The compounds of the invention can be prepared by methods as shown in the synthetic scheme below. In the following reaction schemes and hereinafter, all groups are as defined above unless otherwise stated. It is also recognized that in all of the routes described below, it is well known that, based on the general principles of organic synthesis, a protecting group of a sensitive or reactive group is used as necessary (TW Greene and PGM Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley &Sons); at appropriate stages of compound synthesis, these groups are removed using methods readily apparent to those skilled in the art; the choice of such methods, as well as the reaction conditions and their order of execution, are considered to be consistent with the preparation of the compounds of the invention.
一般反应路线： General reaction route:
Figure PCTCN2017087263-appb-000009
Figure PCTCN2017087263-appb-000009
路线2：Route 2:
Figure PCTCN2017087263-appb-000010
Figure PCTCN2017087263-appb-000010
路线3：Route 3:
Figure PCTCN2017087263-appb-000011
Figure PCTCN2017087263-appb-000011
其中，R1、R2、R3、R4、R5、R6、X和n的定义如前所述。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and n are as defined above.
关于本发明的另一种详细描述：Another detailed description of the invention:
本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：The present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000012
Figure PCTCN2017087263-appb-000012
其中R6为H， Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
R4选自氢、C1-C6烷基、C3-C8环烷基或-CH2C3-C8环烷基，其中所述烷基、环烷基可以被一个或多个选自氢、卤素、羟基、氨基、C1-C6烷基的取代基取代；R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or -CH 2 C 3 -C 8 cycloalkyl, wherein the alkyl or cycloalkyl group may be one or more a substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl;
R5选自C6-C10芳基或C2-C10杂芳基；其中C6-C10芳基、C2-C10杂芳基可以被一个或多个选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6烷基磺酰基的取代基取代；R 5 is selected from C 6 -C 10 aryl or C 2 -C 10 heteroaryl; wherein C 6 -C 10 aryl, C 2 -C 10 heteroaryl may be selected from one or more selected from the group consisting of hydrogen, halogen, Cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 - Substituent substitution of a C 6 alkylsulfonyl group;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自C2-C8杂环烷基、C3-C8环烷基、C6-C10芳基、C2-C10杂芳基，其中所述C2-C8杂环烷基、C3-C8环烷基、C6-C10芳基、C2-C10杂芳基可以被一个或多个选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基、卤素的取代基取代；R 9 is selected from C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 2 -C 10 heteroaryl, wherein said C 2 -C 8 heterocyclic ring An alkyl group, a C 3 -C 8 cycloalkyl group, a C 6 -C 10 aryl group, a C 2 -C 10 heteroaryl group may be selected from one or more selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8- heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, - S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 naphthenic a substituent substituted with -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy, halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
另一方面，本发明提供一种药物组合物，其包含：式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药；一种或多种药学上可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗RORγ介导的疾病，如炎性、代谢性或自身免疫性疾病中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a RORγ-mediated disease, Use in inflammatory, metabolic or autoimmune diseases.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性疾病(如：过敏性鼻炎)、异位性皮肤炎、囊性纤维化、肺同种异体移植排斥、多发性 硬化症、类风湿性关节炎、青少年类风湿性关节炎、骨关节炎、强直性脊柱炎、系统性红斑狼疮、银屑病、桥本氏病、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、炎性肠病(IBS)、炎性肠综合征(IBD)、斯耶格伦氏综合征、视神经炎、I型糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合征、银屑病关节炎、格雷氏病或巩膜炎等中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple Sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune Eye disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, severe Use in myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriatic arthritis, Gracies disease or scleritis.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗哮喘、类风湿性关节炎、银屑病、溃疡性结肠炎或克罗恩氏病中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, rheumatoid joints Use in inflammation, psoriasis, ulcerative colitis or Crohn's disease.
发明详述：Detailed description of the invention:
本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：The present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000013
Figure PCTCN2017087263-appb-000013
其中R6为H，Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基或任意取代的-CH2C3-C8环烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
R5选自：任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from: an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 - C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O) C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O) C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl , C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
在一种优选方案中，本发明涉及的结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中R5选自任意取代的以下基团：苯环、吡啶环、嘧啶环、哒嗪环、吡嗪环、喹啉、异喹啉、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、呋喃环或噁唑环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基。In a preferred embodiment, the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, Wherein R 5 is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, thiazole a ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 alkylsulfonyl.
优选的，R5选自任意取代的苯环或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基；取代基更优选的选自氢、卤素、氰基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基或-S(O2)C1-C3烷基。Preferably, R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl or C 1 -C 6 alkylsulfonyl; the substituent is more preferably selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3- haloalkyl or -S(O 2 )C 1 -C 3 alkyl.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素。In a preferred embodiment, the present invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein R 9 is selected from the group optionally substituted: oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, Oroxazinone or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl , -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8- heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen.
优选的，R3为-CH2R9或-R9。R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素。更优选的，R9选自任意取代的以下基团：氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、 -S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、羟基或卤素，取代基优选自H、C1-C3烷基、C2-C6杂环烷基、C3-C6环烷基、-S(O2)C1-C3烷基、-S(O2)C3-C6环烷基、-S(O2)CH2C3-C6环烷基、-S(O2)C2-C6杂环烷基、-S(O2)CH2C2-C6杂环烷基、-C(O)C1-3烷基、-C(O)C3-C6环烷基、-C(O)CH2C3-C6环烷基、-C(O)C2-C6杂环烷基、-C(O)CH2C2-C6杂环烷基、羟基或卤素；取代基进一步优选自H、C1-3烷基、-S(O2)C1-3烷基、-S(O2)C3-C6环烷基、-S(O2)CH2C3-C6环烷基、-S(O2)C2-C6杂环烷基、-S(O2)CH2C2-C6杂环烷基、-C(O)C1-C3烷基、羟基或卤素；取代基更进一步优选自H、羟基、卤素、C1-C3烷基、-S(O2)C1-C3烷基、-S(O2)C3-C4环烷基、-S(O2)CH2C3-C4环烷基、-S(O2)C2-C4杂环烷基、-S(O2)CH2C2-C4杂环烷基或-C(O)C1-C3烷基。Preferably, R 3 is -CH 2 R 9 or -R 9 . R 9 is selected from the group optionally substituted: oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, Oroxazinone or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl , -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8- heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen. More preferably, R 9 is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, hydroxy or halogen, the substituent is preferably selected from H, C 1 -C 3 alkyl, C 2 -C 6 heterocycloalkyl, C 3 -C 6 cycloalkyl, -S(O 2 )C 1 -C 3 alkyl, -S(O 2 )C 3 -C 6 cycloalkyl, -S (O 2 )CH 2 C 3 -C 6 cycloalkyl, -S(O 2 )C 2 -C 6 heterocycloalkyl, -S(O 2 )CH 2 C 2 -C 6 heterocycloalkyl, - C(O)C 1-3 alkyl, -C(O)C 3 -C 6 cycloalkyl, -C(O)CH 2 C 3 -C 6 cycloalkyl, -C(O)C 2 -C 6 heterocycloalkyl, -C (O) CH 2 C 2 -C 6 heterocycloalkyl, hydroxy or halo; more preferably selected from substituent group H, C 1-3 alkyl, -S (O 2) C 1- 3- alkyl, -S(O 2 )C 3 -C 6 cycloalkyl, -S(O 2 )CH 2 C 3 -C 6 cycloalkyl, -S(O 2 )C 2 -C 6 heterocycloalkane Base, -S(O 2 )CH 2 C 2 -C 6 heterocycloalkyl, -C(O)C 1 -C 3 alkyl, hydroxy or halogen; the substituent is still more preferably from H, hydroxy, halogen, C 1 -C 3 alkyl, -S (O 2 )C 1 -C 3 alkyl, -S(O 2 )C 3 -C 4 cycloalkyl, -S(O 2 )CH 2 C 3 -C 4 cycloalkyl, -S(O 2 ) C 2 -C 4 heterocycloalkyl, -S(O 2 )CH 2 C 2 -C 4 heterocycloalkyl or -C(O)C 1 -C 3 alkyl.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中X选自O、NH或CH2；更优选的X选自O或NH，进一步优选的X为O。In a preferred embodiment, the present invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein X is selected from O, NH or CH 2 ; more preferably X is selected from O or NH, and further preferably X is O.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，R1、R2各自独立的选自氢、羟基、卤素、氨基、C1-C3烷基、C1-C3烷氧基，或者R1、R2合并为氧代基。In a preferred embodiment, the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof, R 1 、 R 2 is independently selected from hydrogen, hydroxy, halogen, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or R 1 and R 2 are combined to form an oxo group.
在一种优选方案中，本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，R4选自氢、任意取代的C1-C6烷基或任意取代的C3-C8环烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基。In a preferred embodiment, the present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof, R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl.
应当理解，本发明还涉及上述优选方案的任意组合。下文中给出组合的一些实例。然而，本发明不限于这些组合。It should be understood that the invention also relates to any combination of the above preferred aspects. Some examples of combinations are given below. However, the invention is not limited to these combinations.
在一种优选的实施方案中：本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中X选自O或NH；R5选自任意取代的苯环或任意取代的吡啶环；其中取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基；R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10 杂芳基、C6-C10芳基、羟基或卤素；m选自0、1、2。In a preferred embodiment: the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof Wherein X is selected from O or NH; R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; wherein the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 alkylsulfonyl; R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the group optionally substituted: oxirane , oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituent selection From H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 ) (CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C (O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen; m is selected from 0, 1, 2.
在一种优选的实施方案中：本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中X选自O，R5选自任意取代的苯环或任意取代的吡啶环；其中取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基；R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；m选自0、1、2。In a preferred embodiment: the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof Wherein X is selected from O, and R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; wherein the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy a C 1 -C 6 haloalkyl group or a C 1 -C 6 alkylsulfonyl group; R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the following groups optionally substituted: oxirane, oxygen Heterocyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituent selected from H , C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O (CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl a group, a hydroxyl group or a halogen; m is selected from the group consisting of 0, 1, and 2.
在一种优选的实施方案中：本发明涉及结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其中：X为O；n为0或1；R1、R2各自独立的选自氢、羟基、卤素、氨基、C1-3烷基、C1-C3烷氧基，或者R1、R2合并为氧代基；R4选自氢、任意取代的C1-C6烷基或任意取代的C3-C6环烷基，取代基选自氢、卤素、羟基、氨基或C1-C3烷基；R5选自任意取代的苯环或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基或C1-C3烷基磺酰基；R3为-CH2R9或-R9；R9选自任意取代的四氢-2H-吡喃或任意取代的哌啶；取代基选自H、C1-C3烷基、-S(O2)C1-C3烷基、羟基或卤素。In a preferred embodiment: the invention relates to a compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof Wherein: X is O; n is 0 or 1; and R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, C 1-3 alkyl, C 1 -C 3 alkoxy, or R 1 And R 2 is bonded to an oxo group; R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 3 alkyl; R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy a C 1 -C 3 haloalkyl or C 1 -C 3 alkylsulfonyl group; R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from optionally substituted tetrahydro-2H-pyran or any substitution Piperidine; the substituent is selected from H, C 1 -C 3 alkyl, -S(O 2 )C 1 -C 3 alkyl, hydroxy or halogen.
在一种优选方案中，本发明还提供了式(I a-I j)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组：In a preferred embodiment, the present invention further provides a compound of the formula (I aj j), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a solvate thereof or a prodrug thereof Subgroup:
Figure PCTCN2017087263-appb-000014
Figure PCTCN2017087263-appb-000014
Figure PCTCN2017087263-appb-000015
Figure PCTCN2017087263-appb-000015
其中：R3、R4、R5和n的定义如上。Wherein: R 3 , R 4 , R 5 and n are as defined above.
下文中给出组合的一些实例。然而，本发明不限于这些组合。Some examples of combinations are given below. However, the invention is not limited to these combinations.
在一种优选组合方案中，式(Ia-Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组，其中：In a preferred combination, a compound of formula (Ia-Ij), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a subset of a prodrug thereof, wherein :
R3选自基团-(CHR7)s-(Y)t-(CHR8)u-R9。R7、R8独立选自氢、C1-C6烷基、羟基；Y选自C1-C6烷基、NH或O；s、t、u独立地选自0、1、2；R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 3 is selected from the group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 . R 7 , R 8 are independently selected from hydrogen, C 1 -C 6 alkyl, hydroxy; Y is selected from C 1 -C 6 alkyl, NH or O; s, t, u are independently selected from 0, 1, 2; R 9 is selected from the group optionally substituted: oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine, Oroxazinone or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl , -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8- heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基或任意取代的-CH2C3-C8环烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
R5选自任意取代的以下基团：苯环、吡啶环、嘧啶环、哒嗪环、吡嗪环、喹啉、异喹啉、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、呋喃环或噁唑环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基。R 5 is selected from the group consisting of benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene ring, thiazole ring a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 alkylsulfonyl.
进一步的，在一种优选方案中，本发明提供式(Ia-Ie、Ih、Ii、Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组：Further, in a preferred embodiment, the present invention provides a compound of the formula (Ia-Ie, Ih, Ii, Ij), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or Subgroup of solvates or prodrugs:
Figure PCTCN2017087263-appb-000016
Figure PCTCN2017087263-appb-000016
Figure PCTCN2017087263-appb-000017
Figure PCTCN2017087263-appb-000017
其中：R3、R4、R5和n的定义如上。Wherein: R 3 , R 4 , R 5 and n are as defined above.
进一步的，在一种优选方案中，本发明提供式(Ia-Ie，Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组：Further, in a preferred embodiment, the present invention provides a compound of the formula (Ia-Ie, Ij), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof or Subgroup of prodrugs:
Figure PCTCN2017087263-appb-000018
Figure PCTCN2017087263-appb-000018
其中：R3、R4、R5和n的定义如上。Wherein: R 3 , R 4 , R 5 and n are as defined above.
下文中给出组合的一些实例。然而，本发明不限于这些组合。Some examples of combinations are given below. However, the invention is not limited to these combinations.
在一种优选组合方案中，式(Ia-Ie，Ij)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组，其中：In a preferred combination, a compound of formula (Ia-Ie, Ij), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a subgroup of a prodrug ,among them:
R5选自任意取代的苯环或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基；R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane Or a C 1 -C 6 alkylsulfonyl group;
R3为-CH2R9或-R9。R9选自任意取代的以下基团：氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、羟基或卤素。R 3 is -CH 2 R 9 or -R 9 . R 9 is selected from the group optionally substituted: oxetane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
在一种优选组合方案中，式(Ia-Ie)的化合物，或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药的亚组，其中：In a preferred combination, a compound of formula (Ia-Ie), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a subset of prodrugs thereof, wherein :
R5选自任意取代的苯环或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6烷基磺酰基；R 5 is selected from an optionally substituted benzene ring or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkane Or a C 1 -C 6 alkylsulfonyl group;
R3为-CH2R9或-R9。R9选自任意取代的四氢-2H-吡喃或任意取代的哌啶；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、羟基或卤素。R 3 is -CH 2 R 9 or -R 9 . R 9 is selected from optionally substituted tetrahydro-2H-pyran or optionally substituted piperidine; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 Cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
另一方面，更具体的方案，本发明涉及结构如下所示的化合物或其立体异构体、互变 异构体或其药学上可接受的盐或其溶剂合物或者前药：On the other hand, a more specific aspect, the present invention relates to a compound having the structure shown below or a stereoisomer thereof, and a mutual transformation An isomer or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000019
Figure PCTCN2017087263-appb-000019
Figure PCTCN2017087263-appb-000020
Figure PCTCN2017087263-appb-000020
另一方面，本发明提供一种药物组合物，其包含：式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药；一种或多种药学上可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof; One or more pharmaceutically acceptable excipients.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗RORγ介导的疾病中的用途，以及制备治疗RORγ介导的疾病的药物中的应用。其中RORγ介导的疾病包括但不限于炎性、代谢性或自身免疫性疾病等。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of a RORγ mediated disease Use, as well as in the preparation of a medicament for the treatment of a disease mediated by RORγ. Among the diseases mediated by RORγ include, but are not limited to, inflammatory, metabolic or autoimmune diseases.
另一方面，本发明提供式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药其用于治疗哮喘、慢性阻塞性肺病(COPD)、支气管炎、过敏性疾病(例如：过敏性鼻炎)、异位性皮肤炎、囊性纤维化、肺同种异体移植排斥、多发性硬化症、类风湿性关节炎、青少年类风湿性关节炎、骨关节炎、强直性脊柱炎、系统性红斑狼疮、银屑病、桥本氏病、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、炎性肠病(IBS)、炎性肠综合征(IBD)、斯耶格伦氏综合征、视神经炎、I型糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合征、银屑病关节炎、格雷氏病或巩膜炎等中的用途，优选其用于治疗哮喘、类风湿性关节炎、银屑病、 溃疡性结肠炎、克罗恩氏病中的用途。In another aspect, the present invention provides a compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or prodrug thereof, for use in the treatment of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases (eg allergic rhinitis), atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid Arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease Inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre Use in plaque, psoriatic arthritis, Gracies or scleritis, preferably for the treatment of asthma, rheumatoid arthritis, psoriasis, Use in ulcerative colitis, Crohn's disease.
另一方面，本发明还提供本发明所述化合物的制备方法。In another aspect, the invention also provides a process for the preparation of a compound of the invention.
本发明化合物可通过如以下合成路线所示的方法来制备。在以下反应路线和下文中，除非另有说明，所有基团如前述中定义。也认识到，在下文所述的所有路线中，众所周知，根据有机合成的一般原理，必要时采用敏感或反应性基团的保护基(T.W.Greene和P.G.M.Wuts(1991)Protecting Groups in Organic Synthesis，John Wiley&Sons)；在化合物合成的适宜阶段，使用本领域技术人员容易明白的方法除去这些基团；这种方法的选择以及反应条件和它们的执行顺序应认为与本发明化合物的制备方法是一致的。The compounds of the invention can be prepared by methods as shown in the synthetic scheme below. In the following reaction schemes and hereinafter, all groups are as defined above unless otherwise stated. It is also recognized that in all of the routes described below, it is well known that, based on the general principles of organic synthesis, a protecting group of a sensitive or reactive group is used as necessary (TW Greene and PGM Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley &Sons); at appropriate stages of compound synthesis, these groups are removed using methods readily apparent to those skilled in the art; the choice of such methods, as well as the reaction conditions and their order of execution, are considered to be consistent with the preparation of the compounds of the invention.
一般反应路线：General reaction route:
路线1：Route 1:
Figure PCTCN2017087263-appb-000021
Figure PCTCN2017087263-appb-000021
路线2：Route 2:
Figure PCTCN2017087263-appb-000022
Figure PCTCN2017087263-appb-000022
其中R1、R2、R3、R4、R5、X和n的定义如前所述。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above.
本发明涉及的结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：The present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000023
Figure PCTCN2017087263-appb-000023
其中R6为H， Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
R4选自任意取代的C1-C6烷基、任意取代的C3-C8环烷基或任意取代的-CH2C3-C8环烷基，取代基选自C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted —CH 2 C 3 -C 8 cycloalkyl group, and the substituent is selected from C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
R5选自任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl , C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
本发明涉及的结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：The present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000024
Figure PCTCN2017087263-appb-000024
其中R6为H，Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基，或者R1、R2合并为氧代基； R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基或任意取代的-CH2C3-C8环烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
R5选自：任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氨基、C1-C3烷基胺基、C1-C2烷基C4-C8杂环烷基、或羟基C1-C6卤代烷基；R 5 is selected from: an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent group being selected from the group consisting of an amino group, a C 1 -C 3 alkylamino group, a C 1 -C 2 alkane a C 4 -C 8 heterocycloalkyl group or a hydroxy C 1 -C 6 haloalkyl group;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, - S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 Alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl , C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
本发明涉及的结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：The present invention relates to a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
Figure PCTCN2017087263-appb-000025
Figure PCTCN2017087263-appb-000025
其中R6为H，Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, or R 1 ,R 2 combined into an oxo group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基或任意取代的-CH2C3-C8环烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted -CH 2 C 3 -C 8 cycloalkyl, the substituent being selected from hydrogen, Halogen, hydroxy, amino or C 1 -C 6 alkyl;
R5选自：任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、 氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from: an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 - C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自卤素取代的C1-C6烷基或羟基取代的C1-C6烷基；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from a halogen-substituted C 1 -C 6 alkyl group or a hydroxy-substituted C 1 -C 6 alkyl group;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
本发明结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，还可以：The compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
Figure PCTCN2017087263-appb-000026
Figure PCTCN2017087263-appb-000026
其中R6为H，Where R 6 is H,
R1、R2各自独立的选自C3-C8环烷基氧基；R 1 and R 2 are each independently selected from a C 3 -C 8 cycloalkyloxy group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C8杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
R5选自任意取代的C6-C10芳基、任意取代的-CH2C6-C10芳基、任意取代的C2-C10杂芳基或任意取代的-CH2C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、氨基、C1-C3烷基胺基、C2-C8杂环烷基、C1-C2烷基C4-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9； R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
本发明结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，还可以：The compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
Figure PCTCN2017087263-appb-000027
Figure PCTCN2017087263-appb-000027
其中R6为H，Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基、C3-C8环烷基氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
R4选自任意取代的C2-C8杂环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, An amino group, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group or a C 3 -C 8 cycloalkyl group;
R5选自任意取代的C6-C10芳基、任意取代的-CH2C6-C10芳基、任意取代的C2-C10杂芳基或任意取代的-CH2C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、氨基、C1-C3烷基胺基、C2-C8杂环烷基、C1-C2烷基C4-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基； R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
本发明结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，还可以：The compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
Figure PCTCN2017087263-appb-000028
Figure PCTCN2017087263-appb-000028
其中R6为H，Where R 6 is H,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基、C3-C8环烷基氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C8杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
R5选自任意取代的-CH2C6-C10芳基、任意取代的-CH2C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、氨基、C1-C3烷基胺基、C2-C8杂环烷基、C1-C2烷基C4-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from optionally substituted -CH 2 C 6 -C 10 aryl, optionally substituted -CH 2 C 2 -C 10 heteroaryl, the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkane a base, an amino group, a C 1 -C 3 alkylamino group, a C 2 -C 8 heterocycloalkyl group, a C 1 -C 2 alkyl C 4 -C 8 heterocycloalkyl group, a C 3 -C 8 cycloalkyl group, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or -S(O 2 )C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基； R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
本发明结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，还可以：The compound of the present invention having the structure of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, may also be:
Figure PCTCN2017087263-appb-000029
Figure PCTCN2017087263-appb-000029
其中，among them,
R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基、C3-C8环烷基氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C8杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
R5选自任意取代的C6-C10芳基、任意取代的-CH2C6-C10芳基、任意取代的C2-C10杂芳基或任意取代的-CH2C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、氨基、C1-C3烷基胺基、C2-C8杂环烷基、C1-C2烷基C4-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
R6选自卤素、羟基、氨基、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基； R 6 is selected from the group consisting of halogen, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
m选自0、1、2；m is selected from 0, 1, 2;
s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
X选自O、NR10、CR10；X is selected from O, NR 10 , CR 10 ;
R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
n选自0、1。n is selected from 0 and 1.
进一步优选的，所述的R3、R4、R5、R6和n的定义可以如上所述。Further preferably, the definitions of R 3 , R 4 , R 5 , R 6 and n may be as described above.
本发明在说明书和权利要求中的术语具有下述含义。The terms of the invention in the specification and claims have the following meanings.
“烷基”指饱和的脂族烃基团。包括1至20个碳原子的直链或支链基团。C1-C6烷基指含有1至6个碳原子的中等大小烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。优选的是含有1至4个碳原子的低级烷基，更优选是含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的，当被取代时，优选的基团为：卤素、C2-C6烯基、C6-C10芳基、C5-C10杂芳基、卤代C1-C6烷基、4至8元杂脂环基、羟基、C1-C6烷氧基、C6-C10芳氧基。"Alkyl" means a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included. C 1 -C 6 alkyl means a medium-sized alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl Wait. Preferred are lower alkyl groups having 1 to 4 carbon atoms, more preferably lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, iso Butyl or tert-butyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, halogen C 1 -C 6 alkyl, 4 to 8 membered heteroalicyclic, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy.
“烷基胺基”是指氨基中的一个或两个氢原子被烷基取代的基团。包括被直连、支链或环状烷基取代的氨基基团，如甲氨基、二甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、异丁氨基、叔丁氨基、环丙氨基、环丁氨基、戊氨基等。优选的是含有1至4个碳原子的低级直连、支链或环状烷基取代的氨基。"Alkylamino" refers to a group in which one or two hydrogen atoms of the amino group are replaced by an alkyl group. Including an amino group substituted with a straight, branched or cyclic alkyl group, such as methylamino, dimethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, ring Propylamino, cyclobutylamino, pentylamino and the like. Preferred are lower straight, branched or cyclic alkyl substituted amino groups containing from 1 to 4 carbon atoms.
“环烷基”指3至8元全碳单环、全碳5元/6元或6元/6元稠和环或多环稠和环(“稠和”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个 或多个环具有完全连接的π电子系统，环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷或环庚三烯。环烷基为可取代的和未取代的。当被取代时，取代基优选为一个或多个各自选自以下的基团，包括：氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。"Cycloalkyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6-membered fused or polycyclic fused ring ("thickened" ring means each in the system The ring shares an adjacent pair of carbon atoms) with other rings in the system, one of which Or a plurality of rings having a fully connected π-electron system, examples of which are not limited to cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, Cycloheptane or cycloheptatriene. Cycloalkyl groups are substitutable and unsubstituted. When substituted, the substituent is preferably one or more groups each selected from the group consisting of hydrogen, hydroxy, thiol, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkane , lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, Amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, Alkylcarbonylamino, arylcarbonylamino.
“芳基”表示6至14个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。“芳基”包括："Aryl" means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a fully conjugated pi-electron system. "Aryl" includes:
六元的碳芳香环，如，苯；a six-membered carbon aromatic ring, such as benzene;
双环，其中至少有一个环是碳芳香环，如，萘，茚或1,2,3,4-四氢喹啉；以及a bicyclic ring in which at least one ring is a carbon aromatic ring such as naphthalene, anthracene or 1,2,3,4-tetrahydroquinoline;
三环，其中至少有一个环是碳芳香环，如，芴。A tricyclic ring in which at least one ring is a carbon aromatic ring, such as hydrazine.
例如，芳基包括含六元的碳芳香环并一个六元杂环，这个杂环包含一个或多个选自氮、氧和硫的杂原子，条件是连接点在碳芳香环上。但是，芳基不包含、也不通过任何方式与下面分别定义的杂环芳基重叠。因此，在此定义，如果一个或多个碳芳香环与一个杂芳香环并环，由此产生的环系统是杂芳基，而不是芳基。芳基的非限制性实例有苯基、萘基。芳基可以是取代的或未取代的。当被取代时，优选的基团为：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。For example, an aryl group includes a six-membered carbon aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbon aromatic ring. However, the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbon aromatic rings are ring bonded to a heteroaromatic ring, the resulting ring system is a heteroaryl group rather than an aryl group. Non-limiting examples of aryl groups are phenyl, naphthyl. The aryl group can be substituted or unsubstituted. When substituted, preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkane Sulfur, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkyl Sulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonyl Amino group.
“杂芳基”表示5至14个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。杂芳基指的是： "Heteroaryl" means a monocyclic or fused ring radical of 5 to 14 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C In addition, it has a fully conjugated π-electron system. Heteroaryl refers to:
5-8元的单环芳烃，含一个或多个选自N、O和S的杂原子，如1-4个杂原子，在一些实施方案中，1-3个杂原子，环上其他原子是碳原子；a 5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring. Is a carbon atom;
8-12元的双环芳烃，含一个或多个选自N、O和S的杂原子，如1-4个杂原子，在一些实施方案中，1-3个杂原子，环上其他原子是碳原子；其中至少有一个环是芳香环；以及An 8-12 membered bicyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, the other atoms on the ring are a carbon atom; at least one of which is an aromatic ring;
11-14元的三环芳烃，含一个或多个选自N、O和S的杂原子，如1-4个杂原子，在一些实施方案中，1-3个杂原子，环上其他原子是碳原子；其中至少有一个环是芳香环。A 11-14 membered tricyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring. It is a carbon atom; at least one of the rings is an aromatic ring.
例如，杂芳基包括一个5-6元的杂芳香环并一个5-6元的环烷基。对于这样的双环并起来的杂芳基，其中只有一个环含有一个或多个杂原子，连接位点在杂芳香环上。For example, a heteroaryl group includes a 5-6 membered heteroaromatic ring and a 5-6 membered cycloalkyl group. For such heteroaryl groups which are bicyclic, one of the rings contains one or more heteroatoms and the attachment sites are on the heteroaromatic ring.
当杂芳基上的硫原子和氧原子总数超过1时，这些杂原子不会一一相邻。在一些实施方案中，硫原子和氧原子在杂芳基中的总数不超过2。在一些实施方案中，硫原子和氧原子在杂芳基中的总数不超过1。When the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed one.
杂芳基的例子，包括但不限于，吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、三氮唑、嘧啶、吡啶、吡啶酮、咪啶、吡嗪、哒嗪、吲哚、氮杂吲哚、苯并咪唑、苯并三氮唑、吲哚啉、吲哚酮、喹啉、异喹啉、喹唑啉、噻吩并吡啶、噻吩并嘧啶等。此类基团的优选实施例为苯环、吡啶、嘧啶、哒嗪、吡嗪、喹啉、异喹啉、吡咯、吡唑、咪唑、噻吩、噻唑、呋喃或噁唑。杂芳基中的一个或全部氢原子可被下列基团取代：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, imidate, pyrazine, pyridazine, anthracene, Azaindene, benzimidazole, benzotriazole, porphyrin, anthrone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like. Preferred examples of such groups are benzene rings, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, pyrrole, pyrazole, imidazole, thiophene, thiazole, furan or oxazole. One or all of the hydrogen atoms in the heteroaryl group may be substituted with hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, Lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, Alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkyl Carbonylamino, arylcarbonylamino.
“杂环烷基”表示由一个或多个环，优选1至2个环(包括螺环系统)组成的一价饱和环状基团，每个环3至8个原子，其结合有一个或多个环杂原子(选自N，O或S(O)0-2)，并且其可以任选独立地被一个或多个，优选1个或2个取代基取代，所述的取代基选自:氢、羟基、巯基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂环烷基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂环烷基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨 基羰基、烷基羰基氨基、芳基羰基氨基。除非另外指出。"Heterocycloalkyl" means a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings, including a spiro ring system, each ring having 3 to 8 atoms in combination with one or a plurality of ring heteroatoms (selected from N, O or S(O) 0-2 ), and which may be optionally substituted independently by one or more, preferably one or two substituents, said substituents being selected From: hydrogen, hydroxy, mercapto, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl , lower cycloalkylalkylene, lower heterocycloalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl , arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino. Unless otherwise stated.
杂环烷基的实例包括但不限于氧杂环丙烷，氮杂环丙烷，吡啶，吗啉-3-酮，硫代吗啉1,1-二氧化物，吗啉基，哌嗪基，哌啶基，氮杂环丁烷基，吡咯烷基，六氢氮杂草基，氧杂环丁烷基，四氢呋喃基，四氢噻吩基，噁唑烷基，噻唑烷基，异噁唑烷基，四氢-2H-吡喃基，硫代吗琳基，奎宁环基和咪唑啉基，优选
Figure PCTCN2017087263-appb-000030
Figure PCTCN2017087263-appb-000031
Figure PCTCN2017087263-appb-000032
W选自O、S或NR12，各基团如前所述，实例还可以是双环的，诸如，例如，3，8-二氮杂-双环[3.2.1]辛烷、2，5-二氮杂双环[2.2.2]辛烷或八氢-吡嗪并[2，1-c][1,4]噁嗪；优选氧杂环丙烷、氧杂环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丙烷、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；其杂环烷基(和衍生物)包括其离子形式。Examples of heterocycloalkyl groups include, but are not limited to, oxirane, aziridine, pyridine, morpholin-3-one, thiomorpholine 1,1-dioxide, morpholinyl, piperazinyl, piperidine Pyridyl, azetidinyl, pyrrolidinyl, hexahydroazain, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl , tetrahydro-2H-pyranyl, thio-allinyl, quinuclidinyl and imidazolinyl, preferably
Figure PCTCN2017087263-appb-000030
Figure PCTCN2017087263-appb-000031
Figure PCTCN2017087263-appb-000032
W is selected from O, S or NR 12 , and each group is as described above, and the examples may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5- Diazabicyclo[2.2.2]octane or octahydro-pyrazino[2,1-c][1,4]oxazine; preferably oxirane, oxetane, tetrahydrofuran, tetrahydro- 2H-pyran, aziridine, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; The base (and derivative) includes its ionic form.
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。"Alkoxy" means -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
“芳氧基”表示-O-芳基和-O-杂芳基。代表性实例包括但不限于苯氧基、吡啶氧基、呋喃氧基、噻吩氧基、嘧啶氧基、吡嗪氧基等及其衍生物。"Aryloxy" means -O-aryl and -O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
“芳基亚烷基”表示烷基，优选如上所定义的低级烷基，它被如上所述的芳基取代，例如-CH2苯基、-(CH2)2苯基、-(CH2)3苯基、CH3CH(CH3)CH2苯基及其衍生物。"Arylalkylene" means an alkyl group, preferably a lower alkyl group as defined above, which is substituted by an aryl group as described above, for example -CH 2 phenyl, -(CH 2 ) 2 phenyl, -(CH 2 3 phenyl, CH 3 CH(CH 3 )CH 2 phenyl and its derivatives.
“杂芳基亚烷基”表示烷基，优选如上所定义的低级烷基，它被如上所述的杂芳基取代，例如-CH2吡啶基、-(CH2)2嘧啶基、-(CH2)3咪唑基等及其衍生物。"Heteroaryl alkylene" denotes a lower alkyl, preferably as defined above, heteroaryl which is substituted as described above, for example, -CH 2 pyridinyl, - (CH 2) 2 pyrimidinyl, - ( CH 2 ) 3 imidazolyl and the like and derivatives thereof.
“氧代基”表示＝O基团。"Oxo" means a =O group.
“羟基”表示-OH基团。"Hydroxy" means an -OH group.
“巯基”表示-SH基团。"Indenyl" means a -SH group.
“卤素”表示氟、氯、溴或碘，优选为氟或氯。"Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
“卤代烷基”表示被卤素取代的烷基，优选如上所定义的低级烷基，它被一个或多个相 同或不同的卤原子取代，例如-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3等。"Haloalkyl" means an alkyl group substituted by a halogen, preferably a lower alkyl group as defined above, which is substituted by one or more of the same or different halogen atoms, for example -CH 2 Cl, -CF 3 , -CCl 3 , - CH 2 CF 3 , -CH 2 CCl 3 and the like.
“氰基”表示-CN基团。"Cyano" means a -CN group.
“氨基”表示-NH2基团。"Amino" means a -NH 2 group.
“硝基”表示-NO2基团。"Nitro" means a -NO 2 group.
“四氢-2H-吡喃”表示
Figure PCTCN2017087263-appb-000033
"tetrahydro-2H-pyran" means
Figure PCTCN2017087263-appb-000033
“烷基磺酰基”表示-S(O2)C1-C6烷基，其中烷基定义如上。"Alkylsulfonyl" means a -S(O 2 )C 1 -C 6 alkyl group wherein alkyl is as defined above.
“环烷基氧基”表示-OH基团中的H被环烷基取代，其中环烷基的定义如上。"Cycloalkyloxy" means that H in the -OH group is substituted by a cycloalkyl group, wherein cycloalkyl is as defined above.
“任意取代的”包括一个或多个取代基取代的情况和未取代的情况，如任意取代的烷基包括未取代的烷基和被一个或多个取代基取代的烷基。"Optionally substituted" includes both substituted and substituted unsubstituted ones, such as an optionally substituted alkyl group including an unsubstituted alkyl group and an alkyl group substituted with one or more substituents.
所谓“任选地”的意思是指后续描述的事件或情形可能会也可能不会发生，并且该描述包括事物或情形可能会也可能不会发生，并且该描述包括事物或情形发生和不发生两种情况。By "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description may or may not occur, and that the description includes or does not occur. Two situations.
在一些实施方案中，“被一个或多个基团取代”是指在指定的原子或基团中的一个、两个、三个或四个氢原子分别被指定范围的基团中选出的相同或不同的基团替换。In some embodiments, "substituted by one or more groups" means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.
波浪线表示连接位点；A wavy line indicates a connection site;
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括："Pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。(1) a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid, and the inorganic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc. Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, ortho-benzene Formic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid .
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。(2) a salt formed by replacing an acidic proton in a parent compound with a metal ion or by complexing with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与一种或多种药学上可接受的辅料的组合。其中“辅料”通常选择本发明所述化合物之外的别的化学成分，例如药学上可接受的药用载体、或其他具有药物效果 的化合物等的混合。药物组合物的目的可以是促进给药给动物的过程，也可以是药物协同作用。"Pharmaceutical composition" refers to a combination of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with one or more pharmaceutically acceptable excipients. Wherein "auxiliary" is generally selected from other chemical components other than the compounds described herein, such as pharmaceutically acceptable pharmaceutically acceptable carriers, or other pharmaceutical effects. Mixing of compounds and the like. The purpose of the pharmaceutical composition may be to facilitate the administration to the animal or to synergistic effects of the drug.
“药用载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。"Pharmaceutically acceptable carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, various Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, B Glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil and the like.
前述的药物组合物中，除了包括药学上可接受的载体等外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。The pharmaceutical composition of the foregoing may include, in addition to a pharmaceutically acceptable carrier and the like, an adjuvant commonly used in medicine, such as an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, A toner, a solubilizer, a thickener, a surfactant, a complexing agent, a protein, an amino acid, a fat, a saccharide, a vitamin, a mineral, a trace element, a sweetener, a coloring matter, a flavor, or a combination thereof.
本发明所述的式(I)化合物对RORγt有明显的抑制作用，而RORγt在炎性、代谢性和自身免疫性疾病中有非常重要的作用，抑制RORγt将使得这些疾病得到缓解或有效治疗。The compounds of formula (I) according to the invention have a significant inhibitory effect on RORγt, while RORγt plays a very important role in inflammatory, metabolic and autoimmune diseases, and inhibition of RORγt will result in the alleviation or effective treatment of these diseases.
具体实施方式detailed description
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。实施例1：N-(4-乙基苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 1的制备The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. Example 1: N-(4-ethylphenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide compound EXP Preparation of 1
Figure PCTCN2017087263-appb-000034
Figure PCTCN2017087263-appb-000034
1)化合物2的合成 1) Synthesis of Compound 2
Figure PCTCN2017087263-appb-000035
Figure PCTCN2017087263-appb-000035
将化合物1(10.0g,73.5mmol,1.0eq)在室温下溶于MeCN(200mL)中，加入K2CO3(32.0g,220.5mmol,3.0eq)，室温搅拌三十分钟，再加入MeI(21.0g，147.0mmol，2.0eq)，室温搅拌16小时。LCMS检测反应完全。将溶剂旋干，硅胶拌样，过柱(PE:EA＝40:1),得到化合物2(2.8g,收率：25％)。Compound 1 (10.0g, 73.5mmol, 1.0eq) was dissolved at room temperature MeCN (200mL) was added K 2 CO 3 (32.0g, 220.5mmol , 3.0eq), stirred for thirty minutes at room temperature, was added MeI ( 21.0 g, 147.0 mmol, 2.0 eq), stirred at room temperature for 16 h. LCMS detected complete reaction. The solvent was spin-dried, and the mixture was applied to silica gel, and the column was passed (PE: EA = 40:1) to give Compound 2 (2.8 g, yield: 25%).
TLC:PE/EA＝10:1,UV 254nmTLC: PE/EA=10:1, UV 254nm
Rf(Compound 1)＝0.6R f (Compound 1)=0.6
Rf(Compound 2)＝0.5R f (Compound 2)=0.5
2)化合物3的合成2) Synthesis of Compound 3
Figure PCTCN2017087263-appb-000036
Figure PCTCN2017087263-appb-000036
在单口瓶中加入ClSO3H(30mL,0.46mol,24.6eq),冷却到0℃，再加入化合物2(2.8g，18.7mmol，1.0eq)，搅拌二十分钟，撤去冰水浴，室温反应16小时。TLC点板显示反应完全，有新点生成。将反应液倒入搅拌中的冰水中淬灭，加二氯甲烷萃取，无水硫酸钠干燥，旋干有机相，过柱(PE/EA＝20:1-10:1)，得白色固体化合物3(3.6g，收率：78％)。Add ClSO 3 H (30 mL, 0.46 mol, 24.6 eq) to a single-necked flask, cool to 0 ° C, then add compound 2 (2.8 g, 18.7 mmol, 1.0 eq), stir for twenty minutes, remove the ice water bath, and react at room temperature 16 hour. The TLC dot plate shows complete reaction and new points are generated. The reaction solution was poured into ice water with stirring, and the mixture was extracted with methylene chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness. 3 (3.6 g, yield: 78%).
TLC:PE/EA＝3:1,UV 254nmTLC: PE/EA=3:1, UV 254nm
Rf(Compound 2)＝0.8R f (Compound 2)=0.8
Rf(Compound 3)＝0.4R f (Compound 3)=0.4
3)化合物5的合成3) Synthesis of Compound 5
Figure PCTCN2017087263-appb-000037
Figure PCTCN2017087263-appb-000037
将化合物3(1.0g，4.32mmol，1.0eq)，化合物4(0.78g，4.44mmol，1.1eq)室温下加入20mL吡啶中，室温下搅拌两小时，TLC显示反应完全。将吡啶旋干，过柱(PE:EA＝20:1-15:1)得到化合物5(1.4g，收率：89％)。Compound 3 (1.0 g, 4.32 mmol, 1.0 eq), Compound 4 (0.78 g, 4.44 mmol, 1.1 eq) was added to 20 mL of pyridine at room temperature and stirred at room temperature for two hours. The pyridine was spin-dried and passed through a column (PE: EA = 20:1 - 15:1) to give compound 5 (1.4 g, yield: 89%).
TLC:PE/EA＝3:1,UV 254nmTLC: PE/EA=3:1, UV 254nm
Rf(Compound 3)＝0.4R f (Compound 3)=0.4
Rf(Compound 5)＝0.5R f (Compound 5)=0.5
4)化合物6的合成4) Synthesis of Compound 6
Figure PCTCN2017087263-appb-000038
Figure PCTCN2017087263-appb-000038
将化合物5(0.97g，2.48mmol，1.0eq)溶解于100mL DCM中,冷却到0℃.缓慢滴加BBr3(7.3mL，0.68M in DCM,5.0mmol，2.0eq)。0℃下反应1h.旋干溶剂，过柱(PE:EA＝20:1)得到化合物6(0.33g，收率：33％)。Compound 5 (0.97g, 2.48mmol, 1.0eq) dissolved in 100mL DCM cooled to 0 ℃. Was slowly added dropwise BBr 3 (7.3mL, 0.68M in DCM , 5.0mmol, 2.0eq). The reaction was carried out at 0 ° C for 1 h. The solvent was evaporated to dryness (yield: PE: EA = 20:1) to afford compound 6 (0.33 g, yield: 33%).
TLC:PE/EA＝3:1,UV 254nmTLC: PE/EA=3:1, UV 254nm
Rf(Compound 5)＝0.5R f (Compound 5)=0.5
Rf(Compound 6)＝0.7R f (Compound 6)=0.7
5)Exp 1的合成5) Synthesis of Exp 1
Figure PCTCN2017087263-appb-000039
Figure PCTCN2017087263-appb-000039
室温下，将化合物6(170mg，0.45mmol，1.0eq)溶解在MeOH(10mL)中，加入化合物7(62mg，0.54mmol，1.2eq)，吡咯烷(40mg，0.54mmol，1.2eq),80℃下搅拌3小时。TLC显示反应完全，旋干溶剂，prep-HPLC分离制备得到固体化合物 Compound 6 (170 mg, 0.45 mmol, 1.0 eq) was dissolved in MeOH (10 mL) EtOAc (EtOAc (EtOAc) Stir under 3 hours. TLC showed the reaction was complete, the solvent was dried, and the solid compound was isolated by prep-HPLC.
Exp1(70mg,收率:33％).Exp1 (70 mg, yield: 33%).
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 6)＝0.7R f (Compound 6)=0.7
Rf(Compound Exp1)＝0.1R f (Compound Exp1)=0.1
LC-MS:[M+1]＝472.2LC-MS: [M+1]=472.2
1H NMR(400MHz,CDCl3)δ8.13(d,J＝2.0Hz,1H),7.48(dd,J＝8.8,2.4Hz,1H),7.05(d,J＝8.0Hz,2H),6.92(d,J＝8.8Hz,1H),6.89(d,J＝8.4Hz,2H),4.26-4.22(m,1H),4.02-3.98(m,2H),3.41-3.33(m,2H),3.22(d,J＝7.2Hz,2H),2.69(d,J＝7.6Hz,2H),2.57(q,J＝7.6Hz,2H),1.96-1.93(m,1H),1.84-1.80(m,1H),1.55-1.52(m,7H),1.16(t,J＝7.2Hz,3H),0.83(d,J＝6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.13 (d, J = 2.0Hz, 1H), 7.48 (dd, J = 8.8,2.4Hz, 1H), 7.05 (d, J = 8.0Hz, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 4.26 - 4.22 (m, 1H), 4.02-3.98 (m, 2H), 3.41-3.33 (m, 2H), 3.22 (d, J = 7.2 Hz, 2H), 2.69 (d, J = 7.6 Hz, 2H), 2.57 (q, J = 7.6 Hz, 2H), 1.96-1.93 (m, 1H), 1.84-1.80 (m) , 1H), 1.55-1.52 (m, 7H), 1.16 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 6.8 Hz, 6H).
实施例2：N-(4-乙基苯基)-4羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 2的制备Example 2: N-(4-ethylphenyl)-4hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide compound EXP 2 preparation
Figure PCTCN2017087263-appb-000040
Figure PCTCN2017087263-appb-000040
室温下，将Exp1(40mg，0.09mmol，1.0eq)溶解在MeOH(5mL)中，加入化合物NaBH4(10mg，0.25mmol，3.0eq),室温下搅拌2小时。TLC显示反应完全，旋干溶剂，prep-HPLC分离制备得到固体化合物Exp 2(21mg,收率:52％).At room temperature, the Exp1 (40mg, 0.09mmol, 1.0eq) was dissolved in MeOH (5mL), was added the compound NaBH 4 (10mg, 0.25mmol, 3.0eq ), stirred at room temperature for 2 hours. TLC showed the reaction was complete, the solvent was evaporated, and the solid compound Exp 2 (21 mg, yield: 52%) was obtained by prep-HPLC separation.
TLC:PE/EA＝3:1,UV 254nmTLC: PE/EA=3:1, UV 254nm
Rf(Compound Exp1)＝0.3R f (Compound Exp1)=0.3
Rf(Compound Exp 2)＝0.1R f (Compound Exp 2)=0.1
LC-MS:[M+1]＝474.2LC-MS: [M+1]=474.2
1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.27(dd,J＝8.0,2.0Hz,1H),7.05(d,J＝8.0Hz,2H),6.91(d,J＝8.0Hz,2H),6.72(d,J＝8.4Hz,1H),4.84-4.80(m,1H),3.99-3.90(m,3H),3.39-3.33(m,2H),3.22-3.15(m,2H),2.56(q,J＝7.6Hz,2H),2.28-2.23(m,1H),1.91-1.66(m,4H),1.49-1.40(m,4H),1.16(t,J＝7.6Hz,3H),0.84-0.81(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.27 (dd, J = 8.0, 2.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.4 Hz, 1H), 4.84 - 4.80 (m, 1H), 3.99 - 3.90 (m, 3H), 3.39 - 3.33 (m, 2H), 3.22-3.15 (m , 2H), 2.56 (q, J = 7.6 Hz, 2H), 2.28-2.23 (m, 1H), 1.91-1.66 (m, 4H), 1.49-1.40 (m, 4H), 1.16 (t, J = 7.6) Hz, 3H), 0.84-0.81 (m, 6H).
实施例3：N-(4-乙基苯基)-4羟基-N-异丁基-4-甲基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 3的制备Example 3: N-(4-ethylphenyl)-4hydroxy-N-isobutyl-4-methyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonate Preparation of amide compound EXP 3
Figure PCTCN2017087263-appb-000041
Figure PCTCN2017087263-appb-000041
将化合物Exp 1(50mg，0.67mmol，1.0eq)在室温下溶于四氢呋喃(3mL)中，在0℃时，缓慢滴加MeMgBr(1.0ml,1.6mmol,2.5eq),常温搅拌1小时。TLC点板显示反应完全，有新点生成。用饱和氯化铵水溶液(5mL)淬灭，用乙酸乙酯(30mL)萃取三次，合并有机相，用无水硫酸钠干燥，过滤，浓缩得粗品。经prep-HPLC制备分离(流动相：0.1％TFA/CH3CN/H2O)得到白色固体化合物Exp 3(11mg，收率：12％)。The compound Exp 1 (50 mg, 0.67 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL) at room temperature, and then, at 0 ° C, MeMgBr (1.0 ml, 1.6 mmol, 2.5 eq) was slowly added dropwise and stirred at room temperature for 1 hour. The TLC dot plate shows complete reaction and new points are generated. It was quenched with aq. EtOAc (EtOAc) Separation by prep-HPLC (mobile phase: 0.1% TFA / CH 3 CN / H 2 O) afforded white solid compound Exp 3 (11 mg, yield: 12%).
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Exp 1)＝0.40R f (Exp 1)=0.40
Rf(Exp 3)＝0.20R f (Exp 3)=0.20
LC-MS:[M+1]＝488LC-MS: [M+1]=488
1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.41(dd,J＝8.0,2.4Hz,1H),7.11(d,J＝8.4Hz,2H),6.95(d,J＝8.0Hz,2H),6.82(d,J＝8.4Hz,1H),4.09-4.05(m,2H),3.98-3.94(m,1H),3.43-3.40(m,2H),3.33-3.27(m,1H),3.23-3.17(m,1H),2.63(q,J＝7.6Hz,2H),2.10-2.06(m,1H),1.95-1.85(m,5H),1.50(s,3H),1.25(s,2H),1.22(t,J＝7.6Hz,3H),0.92-0.88(m, 1 H NMR (400MHz, CDCl 3 ) δ7.58 (s, 1H), 7.41 (dd, J = 8.0,2.4Hz, 1H), 7.11 (d, J = 8.4Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 4.09-4.05 (m, 2H), 3.98-3.94 (m, 1H), 3.43-3.40 (m, 2H), 3.33-3.27 (m) , 1H), 3.23-3.17 (m, 1H), 2.63 (q, J = 7.6 Hz, 2H), 2.10-2.06 (m, 1H), 1.95-1.85 (m, 5H), 1.50 (s, 3H), 1.25 (s, 2H), 1.22 (t, J = 7.6 Hz, 3H), 0.92-0.88 (m,
6H).6H).
实施例4：N-(4-乙基苯基)-N-异丁基-4-甲基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 4的制备Example 4: N-(4-ethylphenyl)-N-isobutyl-4-methyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide compound EXP Preparation of 4
Figure PCTCN2017087263-appb-000042
Figure PCTCN2017087263-appb-000042
将化合物Exp 3(110mg，0.23mmol，1.0eq)在室温下溶于DCM(5mL)中，加 入Et3SH(1mL，2.3mmol，10.0eq)，在0℃时，滴加BF3乙醚溶液(1mL,2.3mmol,10.0eq),常温搅拌1小时。LCMS显示原料反应完，有产物生成。用饱和氯化铵水溶液(5mL)淬灭，用乙酸乙酯(30mL)萃取三次，合并有机相，用无水硫酸钠干燥，过滤，浓缩得粗品。经机器分离(0.1％TFA/CH3CN/H2O)得到白色固体化合物Exp 4(12mg，收率：11％)。Compound Exp 3 (110mg, 0.23mmol, 1.0eq ) was dissolved at room temperature, DCM (5mL), the added Et 3 SH (1mL, 2.3mmol, 10.0eq), at 0 deg.] C, was added dropwise a solution of BF 3 in ether ( 1 mL, 2.3 mmol, 10.0 eq), stirred at room temperature for 1 hour. LCMS showed that the starting material was reacted and product was formed. It was quenched with aq. EtOAc (EtOAc) Machine was isolated (0.1% TFA / CH 3 CN / H 2 O) to give a white solid Compound Exp 4 (12mg, yield: 11%).
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Exp 3)＝0.2R f (Exp 3)=0.2
Rf(Exp 4)＝0.4R f (Exp 4)=0.4
LC-MS:[M+1]＝472LC-MS: [M+1]=472
1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.4Hz,1H),7.29(s,1H),7.11(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.80(d,J＝8.4Hz,1H),4.06-4.02(m,2H),3.90-3.83(m,2H),3.46-3.40(m,2H),3.28-3.33(m,2H),3.21-3.16(m,1H),2.94-2.89(m,1H),2.62(q,J＝7.6Hz,2H),2.07-2.01(m,1H),1.89-1.86(m,2H),1.62-1.60(m,2H),1.46-1.39(m,2H),1.24(s,1H),1.21(d,J＝7.6Hz,6H),0.90-0.86(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz) , 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.06-4.02 (m, 2H), 3.90-3.83 (m, 2H), 3.46-3.40 (m, 2H), 3.28-3.33 (m, 2H) ), 3.21-3.16 (m, 1H), 2.94-2.89 (m, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.07-2.01 (m, 1H), 1.89-1.86 (m, 2H), 1.62-1.60 (m, 2H), 1.46-1.39 (m, 2H), 1.24 (s, 1H), 1.21 (d, J = 7.6 Hz, 6H), 0.90-0.86 (m, 6H).
实施例5：4-胺基-N-(4-乙基苯基)-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺三氟醋酸盐EXP 5的制备Example 5: 4-Amino-N-(4-ethylphenyl)-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide trifluoro Preparation of acetate EXP 5
Figure PCTCN2017087263-appb-000043
Figure PCTCN2017087263-appb-000043
1)化合物2的制备1) Preparation of Compound 2
将盐酸羟胺(20mg，0.29mmol，2.7eq)溶于5mL的无水乙醇中，室温下加入醋酸钠(50mg，0.61mmol，5.7eq)，室温下搅拌15分钟，然后将Exp 1(50mg，0.11mmol，1.0eq)溶于1.0mL无水乙醇并加入反应液中。室温下搅拌过夜，TLC显示约有30％的原料剩余。补加盐酸羟胺(20mg，0.29mmol，2.7eq)和醋酸钠(50mg，0.61mmol，5.7eq)加入反应液中并在30℃下搅拌5小时，TLC显示原料反应完毕。将反应液旋干后溶于10mL的乙酸乙酯中，用浓度为0.5N的5mL的碳酸钠水溶液洗，再用饱和食盐水洗，无水硫酸钠干燥，旋干后得到白色固体化合物2(50mg，0.10mmol，收率：91％)Hydroxylamine hydrochloride (20 mg, 0.29 mmol, 2.7 eq) was dissolved in 5 mL of dry ethanol, sodium acetate (50 mg, 0.61 mmol, 5.7 eq) was added at room temperature, stirred at room temperature for 15 min, then Exp 1 (50 mg, 0.11) Methyl, 1.0 eq) was dissolved in 1.0 mL of absolute ethanol and added to the reaction mixture. Stir overnight at room temperature and TLC showed approximately 30% of the starting material remained. Hydroxylamine hydrochloride (20 mg, 0.29 mmol, 2.7 eq) and sodium acetate (50 mg, 0.61 mmol, 5.7 eq) were added to the reaction mixture and stirred at 30 ° C for 5 hr. The reaction solution was dried and dissolved in 10 mL of ethyl acetate, washed with 5 mL of sodium carbonate aqueous solution of 0.5N, washed with saturated brine, dried over anhydrous sodium sulfate and dried to give white solid compound 2 (50 mg) , 0.10 mmol, yield: 91%)
TLC:PE/EA＝2:1,UV 254nm TLC: PE/EA=2:1, UV 254nm
Rf(Exp 1)＝0.3R f (Exp 1)=0.3
Rf(Compound 2)＝0.6R f (Compound 2)=0.6
2)Exp 5的制备2) Preparation of Exp 5
将化合物2(45mg，0.09mmol，1.0eq)溶于5mL甲醇中，然后加入Raney-Ni(20mg),反应瓶用氮气置换两次后用氢气置换三次。在室温下用氢气球反应过夜。过滤，滤液旋干后用DMSO溶解，然后prep-HPLC制备(流动相：乙腈+水+0.1％三氟乙酸)纯化得到白色固体化合物Exp 5(35mg，0.054mmol,收率：82％)Compound 2 (45 mg, 0.09 mmol, 1.0 eq) was dissolved in 5 mL of methanol, then Raney-Ni (20 mg) was added, and the reaction flask was replaced with nitrogen twice and then replaced with hydrogen three times. The reaction was carried out overnight with a hydrogen balloon at room temperature. Filtration, the filtrate was spun dry, dissolved in DMSO, and then purified by prep-HPLC (mobile phase: acetonitrile + water + 0.1% trifluoroacetic acid) to obtain white solid compound Exp 5 (35 mg, 0.054 mmol, yield: 82%)
LC-MS:[M-16]＝456.3LC-MS: [M-16]=456.3
1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.36(s,1H),7.95(s,0.5H),7.85(s,0.5H),7.35(d,J＝8.8Hz,0.5H),7.28(d,J＝6.8Hz,0.5H),7.19(d,J＝8.0Hz,2H),7.07-6.87(m,3H),4.71-4.57(m,1H),4.15-4.10(m,1H),3.93(d,J＝8.0Hz,2H),3.25-3.11(m,2H),2.69-2.54(m,3H),2.38-2.32(m,2H),2.05-1.72(m,3H),1.54(br s,1H),1.50-1.31(m,3H),1.17(t,J＝7.6Hz,3H),0.87-0.84(m,6H). 1 H NMR (400MHz, DMSO- d 6) δ8.53 (s, 1H), 8.36 (s, 1H), 7.95 (s, 0.5H), 7.85 (s, 0.5H), 7.35 (d, J = 8.8 Hz, 0.5H), 7.28 (d, J = 6.8 Hz, 0.5H), 7.19 (d, J = 8.0 Hz, 2H), 7.07-6.87 (m, 3H), 4.71-4.57 (m, 1H), 4.15 -4.10 (m, 1H), 3.93 (d, J = 8.0 Hz, 2H), 3.25-3.11 (m, 2H), 2.69-2.54 (m, 3H), 2.38-2.32 (m, 2H), 2.05-1.72 (m, 3H), 1.54 (br s, 1H), 1.50-1.31 (m, 3H), 1.17 (t, J = 7.6 Hz, 3H), 0.87-0.84 (m, 6H).
实施例6：N-(4-乙基苯基)-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 6的制备Example 6: Preparation of N-(4-ethylphenyl)-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 6
Figure PCTCN2017087263-appb-000044
Figure PCTCN2017087263-appb-000044
将化合物Exp 1(53mg，0.11mmol，1.0eq)加到6mL乙醚中，然后加入2mL浓盐酸，冷却到零度后加入锌粉(588mg，8.99mmol,80eq)。升到室温后在室温下搅拌3小时。过滤，滤液旋干后得到粗品产物。粗品产物用prep-HPLC(流动相：乙腈+水+0.1％三氟乙酸)纯化得到白色固体化合物Exp 6(4mg，0.054mmol,收率：8％)Compound Exp 1 (53 mg, 0.11 mmol, 1.0 eq) was added to 6 mL of diethyl ether, then 2 mL of concentrated hydrochloric acid was added, and after cooling to zero, zinc powder (588 mg, 8.99 mmol, 80 eq) was added. After warming to room temperature, it was stirred at room temperature for 3 hours. Filtration and spinning off the filtrate gave the crude product. The crude product was purified by prep-HPLC (mobile phase: EtOAc: EtOAc (EtOAc) EtOAc)
LC-MS:[M+1]＝458.3LC-MS: [M+1]=458.3
1H NMR(400MHz,MeOD)δ7.23-7.21(m,2H),7.16(d,J＝8.4Hz,2H),6.95(d,J＝8.4Hz,2H),6.82(d,J＝9.2Hz,1H),4.00(d,J＝8.0Hz,2H),3.89-3.85(m,1H),3.47-3.45(m,2H),3.30-3.28(m,2H),2.86-2.71(m,2H),2.64(q,J＝6.8Hz,2H),2.07-2.04(m,1H),1.91-1.88(m,2H),1.78-1.61(m,2H),1.55-1.50(m,3H),1.22(t,J＝7.2Hz,3H),0.89(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, MeOD) δ 7.23 - 7.21 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 9.2 Hz, 1H), 4.00 (d, J = 8.0 Hz, 2H), 3.89-3.85 (m, 1H), 3.47-3.45 (m, 2H), 3.30-3.28 (m, 2H), 2.86-2.71 (m, 2H), 2.64 (q, J = 6.8 Hz, 2H), 2.07-2.04 (m, 1H), 1.91-1.88 (m, 2H), 1.78-1.61 (m, 2H), 1.55-1.50 (m, 3H) , 1.22 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H).
实施例7：N-(4-乙基苯基)-N-异丁基-4-甲氧基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 7的制备Example 7: N-(4-ethylphenyl)-N-isobutyl-4-methoxy-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP Preparation of 7
Figure PCTCN2017087263-appb-000045
Figure PCTCN2017087263-appb-000045
室温下，将Exp 2(80mg，0.17mmol，1.0eq)溶解在THF(5mL)中，加入化合物NaH(13mg，60％in mineral oil,0.34mmol，2.0eq),室温下搅拌0.5小时后再滴加MeI(100mg,0.7mmol,4eq),室温搅拌1.5小时。TLC显示已经反应完全，旋干溶剂,prep-HPLC制备分离(流动相：0.1％TFA/CH3CN/H2O体系)得到固体化合物Exp 7(31mg,收率:37％).Exp 2 (80 mg, 0.17 mmol, 1.0 eq) was dissolved in THF (5 mL) at room temperature. Compound NaH (13 mg, 60% in mineral oil, 0.34 mmol, 2.0 eq) was added and stirred at room temperature for 0.5 hour. MeI (100 mg, 0.7 mmol, 4 eq) was added and stirred at room temperature for 1.5 h. TLC showed that the reaction had been completed, the solvent was evaporated, and purified by prep-HPLC (mobile phase: 0.1% TFA/CH 3 CN/H 2 O system) to give solid compound Exp 7 (31 mg, yield: 37%).
TLC:PE/EA＝1:1,UV 254nmTLC: PE/EA=1:1, UV 254nm
Rf(Exp 2)＝0.7R f (Exp 2)=0.7
Rf(Exp 7)＝0.9R f (Exp 7)=0.9
LC-MS:[M+1]＝488.2LC-MS: [M+1]=488.2
1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.23(dd,J＝8.6,2.0Hz,1H),7.05(d,J＝8.0Hz,2H),6.91(d,J＝8.0Hz,2H),6.71(d,J＝8.4Hz,1H),4.45-4.41(m,1H),3.99(d,J＝10.8Hz,2H),3.97-3.87(m,1H),3.40-3.35(m,5H),3.21-3.18(m,2H),2.56(q,J＝7.2Hz,2H),2.30-2.25(m,1H),1.86-1.71(m,7H),1.56-1.46(m,4H),1.16(t,J＝7.6Hz,3H),0.83(d,J＝6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.60 (s, 1H), 7.23 (dd, J = 8.6,2.0Hz, 1H), 7.05 (d, J = 8.0Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 4.45-4.41 (m, 1H), 3.99 (d, J = 10.8 Hz, 2H), 3.97-3.87 (m, 1H), 3.40- 3.35 (m, 5H), 3.21-3.18 (m, 2H), 2.56 (q, J = 7.2 Hz, 2H), 2.30-2.25 (m, 1H), 1.86-1.71 (m, 7H), 1.56-1.46 ( m, 4H), 1.16 (t, J = 7.6 Hz, 3H), 0.83 (d, J = 6.8 Hz, 6H).
实施例8：N-(2,4-二甲基苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP8的制备Example 8: N-(2,4-dimethylphenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonate Preparation of amide EXP8
Figure PCTCN2017087263-appb-000046
Figure PCTCN2017087263-appb-000046
1)化合物3的制备 1) Preparation of Compound 3
Figure PCTCN2017087263-appb-000047
Figure PCTCN2017087263-appb-000047
将化合物1(5.0g，41.3mmol，1.0eq)在室温下溶于THF(100mL)中,加入2(2.9g，41.3mmol，1.0eq),室温搅拌1h,在0℃缓慢加入NaBH(OAc)3(12.2g，57.8mmol，1.4eq)，室温搅拌16小时。LCMS检测反应完全。将溶剂旋干，硅胶拌样，过柱(PE:EA＝50:1),得到化合物3(5.0g,收率：68％)。Compound 1 (5.0 g, 41.3 mmol, 1.0 eq) was dissolved in THF (100 mL), EtOAc (EtOAc (EtOAc) 3 (12.2 g, 57.8 mmol, 1.4 eq), stirred at room temperature for 16 h. LCMS detected complete reaction. The solvent was spin-dried, and the mixture was applied to silica gel, and was applied to a column (PE: EA = 50:1) to give Compound 3 (5.0 g, yield: 68%).
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 1)＝0.3R f (Compound 1)=0.3
Rf(Compound 3)＝0.7R f (Compound 3)=0.7
2)EXP 8的制备2) Preparation of EXP 8
Figure PCTCN2017087263-appb-000048
Figure PCTCN2017087263-appb-000048
将化合物4(400mg,1.21mmol,1.0eq)在室温下溶于15mL DCM和3mL MeCN中,再加入化合物3(236mg，1.33mmol，1.1eq)，加入1mL吡啶，室温反应2小时。TLC点板显示反应完全，有新点生成。旋干，加二氯甲烷和水萃取，无水硫酸钠干燥，旋干有机相，刮板(PE/EA＝2:1)，得白色固体化合物5(194mg，收率：34％)。Compound 4 (400 mg, 1.21 mmol, 1.0 eq) was dissolved in 15 mL of DCM and 3 mL of MeCN at room temperature, then compound 3 (236 mg, 1.33 mmol, 1.1 eq) was added, and 1 liter of pyridine was added and reacted at room temperature for 2 hours. The TLC dot plate shows complete reaction and new points are generated. The mixture was dried with EtOAc (EtOAc m.).
TLC:PE/EA＝3:1,UV 254nmTLC: PE/EA=3:1, UV 254nm
Rf(Compound 3)＝0.8R f (Compound 3) = 0.8
Rf(Compound 4)＝0.3R f (Compound 4)=0.3
Rf(EXP 8)＝0.4R f (EXP 8)=0.4
LC-MS:[M+1]＝472.6。LC-MS: [M+1] = 472.6.
实施例9：N-(2,4-二甲基苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP9的制备 Example 9: N-(2,4-Dimethylphenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide Preparation of EXP9
Figure PCTCN2017087263-appb-000049
Figure PCTCN2017087263-appb-000049
将化合物EXP 8(130mg，0.27mmol，1.0eq)，化合物NaBH4(31.3mg，0.81mmol，3.0eq)室温下加入20mL MeOH中，室温下搅拌两小时，TLC显示反应完全。将MeOH旋干，刮板(PE:EA＝2:1)得到固体化合物EXP 9(63mg，收率：49％)。Compound EXP 8 (130mg, 0.27mmol, 1.0eq ), the compound of NaBH 4 (31.3mg, 0.81mmol, 3.0eq ) in 20mL MeOH was added at room temperature, stirred at room temperature for two hours, TLC indicated complete reaction. The MeOH was spin-dried and squeegee (PE: EA = 2:1) to give the solid compound EXP 9 (63 mg, yield: 49%).
TLC:PE/EA＝2:1,UV 254nmTLC: PE/EA=2:1, UV 254nm
Rf(EXP 8)＝0.6R f (EXP 8)=0.6
Rf(EXP 9)＝0.3R f (EXP 9)=0.3
1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.01(s,1H),6.78-6.74(m,2H),6.45(t,J＝8.4Hz,1H),4.84(br s,1H),4.07-3.88(m,3H),3.44-3.27(m,3H),2.95-2.94(m,1H),2.30-2.27(m,3H),2.22(s,3H),1.97-1.68(m,5H),0.96-0.91(m,3H),0.81-0.78(m,2H),0.73-0.72(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.67 (d, J = 8.0Hz, 1H), 7.34 (d, J = 8.4Hz, 1H), 7.01 (s, 1H), 6.78-6.74 (m, 2H) , 6.45 (t, J = 8.4 Hz, 1H), 4.84 (br s, 1H), 4.07-3.88 (m, 3H), 3.44 - 3.27 (m, 3H), 2.95-2.94 (m, 1H), 2.30- 2.27 (m, 3H), 2.22 (s, 3H), 1.97-1.68 (m, 5H), 0.96-0.91 (m, 3H), 0.81-0.78 (m, 2H), 0.73-0.72 (m, 3H).
实施例10：N-(4-乙基苯基)-N-异丁基-2-(1-甲基哌啶-4-基)-4-氧代-2,3-二氢苯并吡喃-4-酮-6-磺酰胺EXP 10的制备Example 10: N-(4-ethylphenyl)-N-isobutyl-2-(1-methylpiperidin-4-yl)-4-oxo-2,3-dihydrobenzopyrazole Preparation of pyran-4-one-6-sulfonamide EXP 10
Figure PCTCN2017087263-appb-000050
Figure PCTCN2017087263-appb-000050
参照实施例1的方法，制备获得化合物EXP 10，LC-MS:[M+H]＝485.4。Preparation of Compound EXP 10, LC-MS: [M+H] = 485.4.
实施例11：N-(4-乙基苯基)-4-羟基-N-异丁基-2-(1-甲基哌啶-4-基)2,3-二氢苯并吡喃-4-酮-6-磺酰胺EXP 11的制备 Example 11: N-(4-ethylphenyl)-4-hydroxy-N-isobutyl-2-(1-methylpiperidin-4-yl)2,3-dihydrobenzopyran- Preparation of 4-keto-6-sulfonamide EXP 11
Figure PCTCN2017087263-appb-000051
Figure PCTCN2017087263-appb-000051
参照实施例2的方法，制备获得化合物EXP 11，LC-MS:[M+H]＝487.3，1H NMR(400MHz,DMSO-d6)δ9.18(br s,1H),7.67(s,1H),7.24(d,J＝8.4Hz,1H),7.18(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.83(d,J＝8.4Hz,1H),5.75(d,J＝6.4Hz,1H),4.74-4.82(m,1H),4.12-4.20(m,1H),3.43-3.51(m,2H),3.27-3.23(m,2H),3.00-2.89(m,2H),2.77(s,3H),2.60(q,J＝7.6Hz,2H),2.22-2.14(m,1H),2.11-2.03(m,1H),1.93-1.81(m,2H),1.69-1.50(m,3H),1.44-1.36(m,1H),1.17(t,J＝7.6Hz,3H),0.83(d,J＝6.4Hz,6H).Preparation of the compound EXP 11 , LC-MS: [M+H]=487.3, 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.18 (br s, 1H), 7.67 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H) , 5.75 (d, J = 6.4 Hz, 1H), 4.74 - 4.82 (m, 1H), 4.12-4.20 (m, 1H), 3.43 - 3.51 (m, 2H), 3.27-3.23 (m, 2H), 3.00 -2.89(m,2H), 2.77(s,3H), 2.60(q,J=7.6Hz,2H),2.22-2.14(m,1H),2.11-2.03(m,1H),1.93-1.81(m , 2H), 1.69-1.50 (m, 3H), 1.44-1.36 (m, 1H), 1.17 (t, J = 7.6 Hz, 3H), 0.83 (d, J = 6.4 Hz, 6H).
实施例12：N-(4-氟苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 12的制备Example 12: N-(4-Fluorophenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 12 preparation
Figure PCTCN2017087263-appb-000052
Figure PCTCN2017087263-appb-000052
参照实施例1的方法，制备获得化合物EXP 12，LC-MS:[M+1]＝462.5。Preparation of Compound EXP 12, LC-MS: [M+1] = 462.5.
实施例13：N-(4-氟苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 13的制备Example 13: Preparation of N-(4-fluorophenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 13
Figure PCTCN2017087263-appb-000053
Figure PCTCN2017087263-appb-000053
参照实施例2的方法，制备获得化合物EXP 13，LC-MS:[M+1]＝464.2Prepared to obtain the compound EXP 13, LC-MS by the method of Example 2: [M+1] = 464.2
1H NMR(400MHz,CDCl3)δ7.69(d,J＝1.2Hz,1H),7.32(dd,J＝8.4Hz,J＝2.0Hz,1H),7.06-6.97(m,4H),6.80(d,J＝8.8Hz,1H),4.93-4.89(m,1H),4.08-3.98(m,3H),3.46-3.40(m, 2H),3.30-3.26(m,2H),2.36-2.32(m,1H),1.92-1.741(m,3H),1.63-1.48(m,3H),0.92-0.89(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.69 (d, J = 1.2Hz, 1H), 7.32 (dd, J = 8.4Hz, J = 2.0Hz, 1H), 7.06-6.97 (m, 4H), 6.80 (d, J = 8.8 Hz, 1H), 4.93-4.89 (m, 1H), 4.08-3.98 (m, 3H), 3.46-3.40 (m, 2H), 3.30-3.26 (m, 2H), 2.36-2.32 (m, 1H), 1.92-1.741 (m, 3H), 1.63-1.48 (m, 3H), 0.92-0.89 (m, 6H).
实施例14：N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)-N-(2-(三氟甲基)苄基)色满-6-磺酰胺EXP 14的制备Example 14: N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)benzyl)chroman-6- Preparation of Sulfonamide EXP 14
Figure PCTCN2017087263-appb-000054
Figure PCTCN2017087263-appb-000054
参照实施例8的方法，制备了Exp14，LC-MS:[M+1]＝525.6.Referring to the method of Example 8, Exp14 was prepared, LC-MS: [M+1]=525.6.
实施例15：4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)-N-((2-(三氟甲基)苄基)色满-6-磺酰胺EXP 15的制备Example 15: 4-Hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)-N-((2-(trifluoromethyl)benzyl)chroman-6- Preparation of sulfonamide EXP 15
Figure PCTCN2017087263-appb-000055
Figure PCTCN2017087263-appb-000055
参照实施例9，制备了Exp 15，LC-MS:[M+1]＝528.2Referring to Example 9, Exp 15, LC-MS was prepared: [M+1]=528.2
1H NMR(400MHz,CDCl3)δ7.98(d,J＝1.2Hz,1H),7.92(d,J＝7.6Hz,1H),7.65-7.55(m,3H),7.37(t,J＝7.6Hz,1H),6.90(d,J＝8.4Hz,1H),4.99-4.95(m,1H),4.46(s,2H),4.08-4.01(m,2H),3.47-3.41(m,2H),2.94(d,J＝7.2Hz,2H),2.38-2.34(m,1H),1.63-1.46(m,6H),1.50-1.45(m,1H),0.75(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.65-7.55 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.99-4.95 (m, 1H), 4.46 (s, 2H), 4.08-4.01 (m, 2H), 3.47-3.41 (m, 2H) ), 2.94 (d, J = 7.2 Hz, 2H), 2.38-2.34 (m, 1H), 1.63-1.46 (m, 6H), 1.50-1.45 (m, 1H), 0.75 (d, J = 6.8 Hz, 6H).
实施例16：N-环丁基-N-(4-乙基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP16的制备Example 16: N-cyclobutyl-N-(4-ethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP16 preparation
Figure PCTCN2017087263-appb-000056
Figure PCTCN2017087263-appb-000056
参照实施例8的方法，制备了Exp16.LC-MS:[M+1]＝470.3 Referring to the method of Example 8, Exp16.LC-MS was prepared: [M+1]=470.3
1H NMR(400MHz,CDCl3)δ8.24(d,J＝2.0Hz,1H),7.62(dd,J＝8.8,2.4Hz,1H),7.12(d,J＝8.0Hz,2H),7.00(d,J＝8.8Hz,1H),6.85(d,J＝8.0Hz,2H),4.40-4.37(m,2H),4.07(d,J＝11.6Hz,2H),3.46-3.43(m,2H),2.77(d,J＝1.6Hz,2H),2.62(q,J＝7.6Hz,2H),1.91-1.86(m,6H),1.63-1.57(m,2H),1.55-1.50(m,2H)，1.24(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.24 (d, J = 2.0Hz, 1H), 7.62 (dd, J = 8.8,2.4Hz, 1H), 7.12 (d, J = 8.0Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 4.40 - 4.37 (m, 2H), 4.07 (d, J = 11.6 Hz, 2H), 3.46 - 3.43 (m, 2H), 2.77 (d, J = 1.6 Hz, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.91-1.86 (m, 6H), 1.63-1.57 (m, 2H), 1.55-1.50 (m , 2H), 1.24 (t, J = 7.6 Hz, 3H).
实施例17：N-环丁基-N-(4-乙基苯基)-4-羟基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP17的制备Example 17: Preparation of N-cyclobutyl-N-(4-ethylphenyl)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP17
Figure PCTCN2017087263-appb-000057
Figure PCTCN2017087263-appb-000057
参照实施例9，制备了Exp 17，LC-MS:[M+1]＝472.3Referring to Example 9, Exp 17, LC-MS was prepared: [M+1] = 472.3
1H NMR(400MHz,CDCl3)δ7.72(d,J＝1.2Hz,1H),7.39(dd,J＝8.8,2.0Hz,1H),7.12(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,2H),6.80(d,J＝8.4Hz,1H),4.93-4.87(m,1H),4.37-4.31(m,1H),4.07-3.98(m,2H),3.46-3.40(m,2H),2.67-2.61(q,J＝7.6Hz,2H),2.33-2.30(m,1H),1.96-1.74(m,2H),1.65-1.58(m,2H)，1.54-1.50(m,2H)，1.23(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.72 (d, J = 1.2Hz, 1H), 7.39 (dd, J = 8.8,2.0Hz, 1H), 7.12 (d, J = 8.4Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.93-4.87 (m, 1H), 4.37 - 4.31 (m, 1H), 4.07 - 3.98 (m, 2H), 3.46-3.40 (m, 2H), 2.67-2.61 (q, J = 7.6 Hz, 2H), 2.33-2.30 (m, 1H), 1.96-1.74 (m, 2H), 1.65-1.58 (m, 2H), 1.54-1.50 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H).
实施例18：N-(4-乙基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)-N-(2,2,2-三氟乙基)色满-6-磺酰胺EXP 18的制备Example 18: N-(4-ethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoroethyl) Preparation of chroman-6-sulfonamide EXP 18
Figure PCTCN2017087263-appb-000058
Figure PCTCN2017087263-appb-000058
参照实施例8的方法，制备了Exp18，LC-MS:[M+1]＝498.5Referring to the method of Example 8, Exp18 was prepared, LC-MS: [M+1]=498.5
实施例19：N-(4-乙基苯基)-4-羟基-2-(四氢-2H-吡喃-4-基)-N-(2,2,2-三氟乙基)色满-6-磺酰胺EXP 19的制备 Example 19: N-(4-ethylphenyl)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoroethyl) Preparation of Man-6-sulfonamide EXP 19
Figure PCTCN2017087263-appb-000059
Figure PCTCN2017087263-appb-000059
参照实施例9的方法，制备了Exp19.Referring to the method of Example 9, Exp19 was prepared.
1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.37(d,J＝8.4Hz,1H),7.14(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),6.81(d,J＝8.8Hz,1H),5.35(br s,1H),4.91-4.87(m,1H),4.18-3.99(m,5H),3.46-3.40(m,2H),2.64(d,J＝8.0Hz,2H),2.36-2.31(m,1H),2.21(d,J＝7.7Hz,1H),2.03-1.73(m,4H),1.24(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.74 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.14 (d, J = 8.0Hz, 2H), 6.98 (d, J = 8.0Hz , 2H), 6.81 (d, J = 8.8 Hz, 1H), 5.35 (br s, 1H), 4.91-4.87 (m, 1H), 4.18-3.99 (m, 5H), 3.46-3.40 (m, 2H) , 2.64 (d, J = 8.0 Hz, 2H), 2.36-2.31 (m, 1H), 2.21 (d, J = 7.7 Hz, 1H), 2.03-1.73 (m, 4H), 1.24 (t, J = 7.6) Hz, 3H).
实施例20：N-(4-乙基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 20的制备Example 20: Preparation of N-(4-ethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 20
Figure PCTCN2017087263-appb-000060
Figure PCTCN2017087263-appb-000060
参照实施例8的方法，制备了Exp20，LC-MS:[M+1]＝416.5.Referring to the method of Example 8, Exp20 was prepared, LC-MS: [M+1]=416.5.
实施例21：N-(4-乙基苯基)-4-羟基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 21的制备Example 21: Preparation of N-(4-ethylphenyl)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 21
Figure PCTCN2017087263-appb-000061
Figure PCTCN2017087263-appb-000061
参照实施例9的方法，制备了Exp21.Referring to the method of Example 9, Exp21.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.46(d,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),6.74(d,J＝8.8Hz,1H),4.88-4.86(m,1H),4.09-3.93(m,4H),3.42-3.37(m,2H),2.84(br s,1H),2.55(q,J＝7.6Hz,2H),2.26-2.30(m,1H),1.85-1.75(m,2H),1.54-1.43(m,2H),1.26(s,2H),1.17(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz) , 2H), 6.74 (d, J = 8.8 Hz, 1H), 4.88-4.86 (m, 1H), 4.09-3.93 (m, 4H), 3.42-3.37 (m, 2H), 2.84 (br s, 1H) , 2.55 (q, J = 7.6 Hz, 2H), 2.26-2.30 (m, 1H), 1.85-1.75 (m, 2H), 1.54-1.43 (m, 2H), 1.26 (s, 2H), 1.17 (t , J = 7.6 Hz, 3H).
实施例22：N-(2-氟苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP22的制备 Example 22: Preparation of N-(2-fluorophenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP22
Figure PCTCN2017087263-appb-000062
Figure PCTCN2017087263-appb-000062
参照实施例8的方法，制备了Exp22.Referring to the method of Example 8, Exp22 was prepared.
1H NMR(400MHz,CDCl3)δ8.16(d,J＝2.0Hz,1H),7.60(dd,J＝8.4,2.4Hz,1H),7.27-7.22(m,2H),7.09-7.05(m,1H),6.95-6.91(m,2H),4.28-4.24(m,1H),4.01(d,J＝12.2Hz,2H),3.28(d,J＝7.6Hz,2H),2.69(d,J＝7.6Hz,2H),1.96-1.92(m,1H),1.82(d,J＝14.0Hz,1H),1.64(br s,2H),1.54-1.49(m,2H),0.85(d,J＝6.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.16 (d, J = 2.0Hz, 1H), 7.60 (dd, J = 8.4,2.4Hz, 1H), 7.27-7.22 (m, 2H), 7.09-7.05 ( m,1H), 6.95-6.91 (m, 2H), 4.28-4.24 (m, 1H), 4.01 (d, J = 12.2 Hz, 2H), 3.28 (d, J = 7.6 Hz, 2H), 2.69 (d) , J=7.6Hz, 2H), 1.96-1.92(m,1H), 1.82(d,J=14.0Hz,1H),1.64(br s,2H),1.54-1.49(m,2H),0.85(d , J = 6.4 Hz, 6H).
实施例23：N-(2-氟苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP23的制备Example 23: Preparation of N-(2-fluorophenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP23
Figure PCTCN2017087263-appb-000063
Figure PCTCN2017087263-appb-000063
参照实施例9的方法，制备了Exp23.Referring to the method of Example 9, Exp23 was prepared.
1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.36(dd,J＝8.4,2.4Hz,1H),7.22-7.19(m,2H),7.05(t,J＝7.6Hz,1H),6.96(t,J＝9.6Hz,1H),6.74(d,J＝8.8Hz,1H),4.86-4.81(m,1H),4.00-3.91(m,3H),3.39-3.36(m,2H),3.30-3.22(m,2H),2.29-2.24(m,1H),1.88-1.66(m,4H),1.55-1.45(m,4H),0.85-0.83(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.71 (s, 1H), 7.36 (dd, J = 8.4,2.4Hz, 1H), 7.22-7.19 (m, 2H), 7.05 (t, J = 7.6Hz, 1H), 6.96 (t, J = 9.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.86 - 4.81 (m, 1H), 4.00 - 3.91 (m, 3H), 3.39 - 3.36 (m , 2H), 3.30-3.22 (m, 2H), 2.29-2.24 (m, 1H), 1.88-1.66 (m, 4H), 1.55-1.45 (m, 4H), 0.85-0.83 (m, 6H).
实施例24：N-(4-氰基-苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 24的制备Example 24: N-(4-cyano-phenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP Preparation of 24
Figure PCTCN2017087263-appb-000064
Figure PCTCN2017087263-appb-000064
参照实施例8的方法，制备了Exp24. Referring to the method of Example 8, Exp24 was prepared.
1H NMR(400MHz,CDCl3)δ8.16(d,J＝2.0Hz,1H),7.62(d,J＝8.8Hz,2H),7.51(dd,J＝8.8,2.4Hz,1H),7.23(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,1H),4.33-4.30(m,1H),4.08(d,J＝12.4Hz,2H),3.46-3.41(m,2H),3.36(d,J＝7.2Hz,2H),2.76(d,J＝7.6Hz,2H),2.04-2.00(m,2H),1.98-1.90(m,2H),1.62-1.55(m,2H),0.90(d,J＝6.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.16 (d, J = 2.0Hz, 1H), 7.62 (d, J = 8.8Hz, 2H), 7.51 (dd, J = 8.8,2.4Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 4.33-4.30 (m, 1H), 4.08 (d, J = 12.4 Hz, 2H), 3.46 - 3.41 (m, 2H), 3.36 (d, J = 7.2 Hz, 2H), 2.76 (d, J = 7.6 Hz, 2H), 2.04-2.00 (m, 2H), 1.98-1.90 (m, 2H), 1.62-1.55 (m , 2H), 0.90 (d, J = 6.4 Hz, 6H).
实施例25：N-(4-氰基-苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 25的制备Example 25: N-(4-cyano-phenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 25 Preparation
Figure PCTCN2017087263-appb-000065
Figure PCTCN2017087263-appb-000065
参照实施例9的方法，制备了Exp25.Referring to the method of Example 9, Exp25 was prepared.
1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.54(d,J＝8.4Hz,2H),7.22-7.7.16(m,3H),6.73(d,J＝8.8Hz,1H),4.85-4.80(m,1H),3.99-3.91(m,3H),3.39-3.35(m,2H),3.26-3.22(m,2H),2.28-2.23(m,1H),2.00(br s,2H),1.89-1.64(m,3H),1.51-1.43(m,2H),0.84-0.82(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.60 (s, 1H), 7.54 (d, J = 8.4Hz, 2H), 7.22-7.7.16 (m, 3H), 6.73 (d, J = 8.8Hz, 1H), 4.85-4.80 (m, 1H), 3.99-3.91 (m, 3H), 3.39-3.35 (m, 2H), 3.26-3.22 (m, 2H), 2.28-2.23 (m, 1H), 2.00 ( Br s, 2H), 1.89-1.64 (m, 3H), 1.51-1.43 (m, 2H), 0.84-0.82 (m, 6H).
实施例26：N-((5-(乙基磺酰基)吡啶-2-基)亚甲基)-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 26的制备Example 26: N-((5-(ethylsulfonyl)pyridin-2-yl)methylene)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman- Preparation of 6-sulfonamide EXP 26
Figure PCTCN2017087263-appb-000066
Figure PCTCN2017087263-appb-000066
参照实施例8的方法，制备了Exp26.Referring to the method of Example 8, Exp26 was prepared.
LC-MS:[M+1]＝495.1LC-MS: [M+1]=495.1
1H NMR(400MHz,CD3OD)δ8.76(d,J＝1.6Hz,1H),8.10(dd,J＝8.0,2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.86(dd,J＝8.4,2.0Hz,1H),7.53(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),4.36(s,3H),4.03-4.00(m,2H),3.47-3.45(m,2H),3.23(q,J＝7.4Hz,2H),2.89-2.80(m,1H),2.70-2.68(m,1H),2.03(br s,1H),1.90(d,J＝11.2Hz,1H),1.68-1.47(m,3H),1.18(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CD 3 OD) δ8.76 (d, J = 1.6Hz, 1H), 8.10 (dd, J = 8.0,2.0Hz, 1H), 8.06 (d, J = 2.0Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.36 (s, 3H), 4.03-4.00 (m) , 2H), 3.47-3.45 (m, 2H), 3.23 (q, J = 7.4 Hz, 2H), 2.89-2.80 (m, 1H), 2.70-2.68 (m, 1H), 2.03 (br s, 1H) , 1.90 (d, J = 11.2 Hz, 1H), 1.68-1.47 (m, 3H), 1.18 (t, J = 7.6 Hz, 3H).
实施例27：N-((5-(乙基磺酰基)吡啶-2-基)亚甲基)-4-羟基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 27的制备Example 27: N-((5-(ethylsulfonyl)pyridin-2-yl)methylene)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)chroman-6 - Preparation of sulfonamide EXP 27
Figure PCTCN2017087263-appb-000067
Figure PCTCN2017087263-appb-000067
参照实施例9的方法，制备了Exp27.Referring to the method of Example 9, Exp27 was prepared.
LC-MS:[M+1]＝497.2LC-MS: [M+1]=497.2
1H NMR(400MHz,DMSO)δ8.85(d,J＝1.6Hz,1H),8.29(t,J＝6.4Hz,1H),8.20(dd,J＝8.4,2.4Hz,1H),7.82(d,J＝1.2Hz,1H),7.61(d,J＝8.0Hz,1H),7.47(dd,J＝8.4,2.0Hz,1H),6.80(d,J＝8.4Hz,1H),4.76-4.72(m,1H),4.19(d,J＝6.4Hz,2H),4.09-4.05(m,1H),3.92-3.88(m,2H),3.39-3.25(m,4H),2.20-2.16(m,1H),1.84(br s,1H),1.76(d,J＝13.2Hz,1H),1.60-1.58(m,2H),1.49-1.22(m,3H),1.11(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO) δ 8.85 (d, J = 1.6 Hz, 1H), 8.29 (t, J = 6.4 Hz, 1H), 8.20 (dd, J = 8.4, 2.4 Hz, 1H), 7.82 ( d, J = 1.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.76- 4.72 (m, 1H), 4.19 (d, J = 6.4 Hz, 2H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 2H), 3.39-3.25 (m, 4H), 2.20-2.16 ( m,1H), 1.84 (br s,1H), 1.76 (d, J = 13.2 Hz, 1H), 1.60-1.58 (m, 2H), 1.49-1.22 (m, 3H), 1.11 (t, J = 7.2) Hz, 3H).
实施例28：N-(4-乙基苯基)–N-异丁基-4-氧代-2-((四氢-2H-吡喃-4-基)亚甲基)色满-6-磺酰胺EXP 28的制备Example 28: N-(4-ethylphenyl)-N-isobutyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)methylene)chroman-6 - Preparation of sulfonamide EXP 28
Figure PCTCN2017087263-appb-000068
Figure PCTCN2017087263-appb-000068
参照实施例1的方法，制备了Exp28.Referring to the method of Example 1, Exp28 was prepared.
LC-MS:[M+H]＝486.4LC-MS: [M+H]=486.4
1H NMR(400MHz,CDCl3)δ8.20(d,J＝2.0Hz,1H),7.55(d,J＝11.2Hz,1H),7.13(d,J＝8.4Hz,2H),7.00-6.95(m,3H),4.70-4.60(m,1H),3.99(d,J＝14.0Hz,2H),3.43(t,J＝12.0Hz,2H),3.29(d,J＝7.6Hz,2H),2.79-2.70(m,2H),2.64(q,J＝7.6Hz,2H),1.98-1.83(m,2H),1.74-1.61(m,3H),1.46-1.34(m,3H),1.23(t,J＝7.6Hz,3H),0.91(d,J＝6.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.20 (d, J = 2.0Hz, 1H), 7.55 (d, J = 11.2Hz, 1H), 7.13 (d, J = 8.4Hz, 2H), 7.00-6.95 (m, 3H), 4.70-4.60 (m, 1H), 3.99 (d, J = 14.0 Hz, 2H), 3.43 (t, J = 12.0 Hz, 2H), 3.29 (d, J = 7.6 Hz, 2H) , 2.79-2.70 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.98-1.83 (m, 2H), 1.74-1.61 (m, 3H), 1.46-1.34 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H), 0.91 (d, J = 6.4 Hz, 6H).
实施例29：N-(4-乙基苯基)-4-羟基-N-异丁基-2-((四氢-2H-吡喃-4-基)亚甲基)色满-6-磺酰胺EXP 29的制备 Example 29: N-(4-ethylphenyl)-4-hydroxy-N-isobutyl-2-((tetrahydro-2H-pyran-4-yl)methylene)chroman-6- Preparation of Sulfonamide EXP 29
Figure PCTCN2017087263-appb-000069
Figure PCTCN2017087263-appb-000069
参照实施例2的方法，制备了Exp29.Referring to the method of Example 2, Exp29 was prepared.
LC-MS:[M+H]＝488.4LC-MS: [M+H]=488.4
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.34(dd,J＝8.5,2.0Hz,1H),7.12(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.80(d,J＝8.8Hz,1H),4.91-4.87(m,1H),4.33-4.28(m,1H),3.98(d,J＝13.6Hz,2H),3.47-3.41(m,2H),3.35-3.16(m,2H),2.63(q,J＝7.6Hz,2H),2.32-2.27(m,1H),1.81-1.28(m,10H),1.23(t,J＝7.6Hz,3H),0.92-0.88(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.67 (s, 1H), 7.34 (dd, J = 8.5,2.0Hz, 1H), 7.12 (d, J = 8.0Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.8 Hz, 1H), 4.91-4.87 (m, 1H), 4.33-4.28 (m, 1H), 3.98 (d, J = 13.6 Hz, 2H), 3.47- 3.41 (m, 2H), 3.35-3.16 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.32 - 2.27 (m, 1H), 1.81-1.28 (m, 10H), 1.23 (t, J = 7.6 Hz, 3H), 0.92-0.88 (m, 6H).
实施例30：N-(3-氟苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺EXP 30的制备Example 30: Preparation of N-(3-fluorophenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide EXP 30
Figure PCTCN2017087263-appb-000070
Figure PCTCN2017087263-appb-000070
参照实施例2的方法，制备了Exp30.Referring to the method of Example 2, Exp30 was prepared.
LC-MS:[M+1]＝464.3LC-MS: [M+1]=464.3
1H NMR(400MHz,CDCl3)δ7.62(d,J＝1.2Hz,1H),7.26-7.21(m,2H),7.22-7.16(m,1H),6.94-6.90(m,1H),6.85(d,J＝7.6Hz,1H),6.73(d,J＝8.8Hz,2H),4.84-4.79(m,1H),3.99-3.91(m,3H),3.39-3.32(m,2H),3.22-3.18(m,2H),2.28-2.23(m,1H),1.85-1.65(m,3H),1.59-1.40(m,4H),0.84-0.82(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J = 1.2 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.22 - 7.16 (m, 1H), 6.94 - 6.90 (m, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 4.84 - 4.79 (m, 1H), 3.99 - 3.91 (m, 3H), 3.39 - 3.32 (m, 2H) , 3.22-3.18 (m, 2H), 2.28-2.23 (m, 1H), 1.85-1.65 (m, 3H), 1.59-1.40 (m, 4H), 0.84-0.82 (m, 6H).
实施例31：N-(4-乙基苯基)-N-异丁基-2-(1-(甲基磺酰基)哌啶-4-基)-4-氧代色满-6-磺酰胺EXP 31的制备 Example 31: N-(4-ethylphenyl)-N-isobutyl-2-(1-(methylsulfonyl)piperidin-4-yl)-4-oxochroman-6-sulfonate Preparation of amide EXP 31
Figure PCTCN2017087263-appb-000071
Figure PCTCN2017087263-appb-000071
参照实施例1的方法，制备了Exp31.Referring to the method of Example 1, Exp31 was prepared.
LC-MS:[M+H]＝449.4LC-MS: [M+H]=449.4
1H NMR(400MHz,CDCl3)δ8.20(d,J＝2.4Hz,1H),7.56(dd,J＝8.4,2.0Hz,1H),7.13(d,J＝8.0Hz,2H),7.00(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,2H),4.38-4.35(m,1H),3.94(d,J＝11.2Hz,2H),3.29(d,J＝7.6Hz,2H),2.81(s,3H),2.78-2.61(m,6H),2.10(d,J＝12.9Hz,1H),1.86(d,J＝12.1Hz,2H),1.71-1.58(m,3H),1.23(t,J＝7.6Hz,3H),0.91(d,J＝6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.20 (d, J = 2.4Hz, 1H), 7.56 (dd, J = 8.4,2.0Hz, 1H), 7.13 (d, J = 8.0Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 4.38-4.35 (m, 1H), 3.94 (d, J = 11.2 Hz, 2H), 3.29 (d, J = 7.6 Hz, 2H), 2.81 (s, 3H), 2.78-2.61 (m, 6H), 2.10 (d, J = 12.9 Hz, 1H), 1.86 (d, J = 12.1 Hz, 2H), 1.71-1.58 ( m, 3H), 1.23 (t, J = 7.6 Hz, 3H), 0.91 (d, J = 6.8 Hz, 6H).
实施例32：N-(4-乙基苯基)-4-羟基-N-异丁基-2-(1-(甲基磺酰基)哌啶-4-基)色满-6-磺酰胺EXP 32的制备Example 32: N-(4-ethylphenyl)-4-hydroxy-N-isobutyl-2-(1-(methylsulfonyl)piperidin-4-yl)chroman-6-sulfonamide Preparation of EXP 32
Figure PCTCN2017087263-appb-000072
Figure PCTCN2017087263-appb-000072
参照实施例2的方法，制备了Exp32.Referring to the method of Example 2, Exp32 was prepared.
LC-MS:[M+H]＝551.2LC-MS: [M+H]=551.2
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.35(dd,J＝8.4,2.0Hz,1H),7.12(d,J＝8.0Hz,2H),6.97(d,J＝8.4Hz,2H),6.80(d,J＝8.4Hz,1H),4.94-4.85(m,1H),4.08-4.01(m,1H),3.92(d,J＝11.4Hz,2H),3.33-3.18(m,2H),2.80(s,3H),2.71-2.59(m,4H),2.36-2.27(m,1H),2.07(d,J＝11.7Hz,1H),1.90-1.75(m,4H),1.68-1.57(m,2H),1.23(t,J＝7.6Hz,3H),0.92-0.88(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.67 (s, 1H), 7.35 (dd, J = 8.4,2.0Hz, 1H), 7.12 (d, J = 8.0Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 4.94-4.85 (m, 1H), 4.08-4.01 (m, 1H), 3.92 (d, J = 11.4 Hz, 2H), 3.33 3.18(m,2H), 2.80(s,3H),2.71-2.59(m,4H), 2.36-2.27(m,1H),2.07(d,J=11.7Hz,1H),1.90-1.75(m, 4H), 1.68-1.57 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.92-0.88 (m, 6H).
实施例33：N-(4-乙基苯基)-4-羟基-N-异丁基-2-(哌啶-4-基)色满-6-磺酰胺EXP 33的制备 Example 33: Preparation of N-(4-ethylphenyl)-4-hydroxy-N-isobutyl-2-(piperidin-4-yl)chroman-6-sulfonamide EXP 33
Figure PCTCN2017087263-appb-000073
Figure PCTCN2017087263-appb-000073
参照实施例2的方法，制备了Exp33.Referring to the method of Example 2, Exp33 was prepared.
LC-MS:[M+H]＝473.4LC-MS: [M+H]=473.4
1H NMR(400MHz,CDCl3)δ9.53(br s,1H),8.97(br s,1H),7.69(s,1H),7.32(d,J＝8.8Hz,1H),7.13(d,J＝8.4Hz,2H),6.97(d,J＝8.0Hz,2H),6.78(d,J＝8.4Hz,1H),4.95-4.81(m,1H),4.09-3.98(m,1H),3.56-3.38(m,2H),3.32-3.19(m,2H),2.9-2.81(m,2H),2.63(q,J＝7.2Hz,2H),2.33-2.18(m,2H),2.12(d,J＝15.0Hz,2H),1.98-1.88(m,3H),1.61-1.48(m,1H),1.23(t,J＝7.6Hz,3H),0.92-0.88(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ9.53 (br s, 1H), 8.97 (br s, 1H), 7.69 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 6.78 (d, J=8.4 Hz, 1H), 4.95-4.81 (m, 1H), 4.09-3.98 (m, 1H), 3.56-3.38 (m, 2H), 3.32-3.19 (m, 2H), 2.9-2.81 (m, 2H), 2.63 (q, J = 7.2 Hz, 2H), 2.33-2.18 (m, 2H), 2.12 ( d, J = 15.0 Hz, 2H), 1.98-1.88 (m, 3H), 1.61-1.48 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 0.92-0.88 (m, 6H).
实施例34：N-(4-乙基苯基)-4氟-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 34的制备Example 34: N-(4-ethylphenyl)-4fluoro-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide compound EXP 34 preparation
Figure PCTCN2017087263-appb-000074
Figure PCTCN2017087263-appb-000074
参照实施例2的方法，制备了Exp34.Referring to the method of Example 2, Exp34 was prepared.
LC-MS:[M+1]＝476.2LC-MS: [M+1]=476.2
1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.47(d,J＝8.8Hz,1H),7.13(d,J＝8.0Hz,2H),6.98(d,J＝5.2Hz,2H),6.92(d,J＝8.8Hz,1H),5.5(m,1H),4.08-4.03(m,3H),3.49-3.41(m,2H),3.26(d,J＝7.6Hz,2H),2.66(q,J＝8.0Hz,2H),2.3(m,1H),1.94-1.81(m,3H),1.66-1.51(m,4H),1.23(t,J＝7.6Hz,3H),0.91-0.84(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 5.2 Hz) , 2H), 6.92 (d, J = 8.8 Hz, 1H), 5.5 (m, 1H), 4.08-4.03 (m, 3H), 3.49-3.41 (m, 2H), 3.26 (d, J = 7.6 Hz, 2H), 2.66 (q, J = 8.0 Hz, 2H), 2.3 (m, 1H), 1.94-1.81 (m, 3H), 1.66-1.51 (m, 4H), 1.23 (t, J = 7.6 Hz, 3H) ), 0.91-0.84 (m, 6H).
实施例35：(四氢-2H-吡喃-4-基)-N-(2-(三氟甲基)苯基)苯并二氢吡喃-6-磺酰胺化合物EXP 35的制备 Example 35: Preparation of (tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethyl)phenyl)chroman-6-sulfonamide compound EXP 35
Figure PCTCN2017087263-appb-000075
Figure PCTCN2017087263-appb-000075
参照实施例2的方法，制备了Exp35.Referring to the method of Example 2, Exp35 was prepared.
LC-MS:[M+Na]+＝536.2LC-MS: [M+Na] + =536.2
1H NMR(400MHz,CDCl3)δ7.83(dd,J＝14.0,2.0Hz,1H),7.72(d,J＝7.6Hz,1H),7.51-7.45(m,3H),7.17-7.13(m,1H),6.85(dd,J＝8.6,1.2Hz,1H),4.94-4.92(m,1H),4.11(d,J＝11.4Hz,2H),4.07-3.97(m,1H),3.50-3.44(m,2H),3.35-3.30(m,1H),3.28-3.02(m,5H),2.35-2.30(m,1H),1.99-1.75(m,3H),1.60-1.53(m,1H),0.90-0.86(m,3H),0.79-0.77(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (dd, J = 14.0, 2.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.17 - 7.13 ( m,1H), 6.85 (dd, J=8.6, 1.2 Hz, 1H), 4.94-4.92 (m, 1H), 4.11 (d, J = 11.4 Hz, 2H), 4.07-3.97 (m, 1H), 3.50 -3.44 (m, 2H), 3.35-3.30 (m, 1H), 3.28-3.02 (m, 5H), 2.35-2.30 (m, 1H), 1.99-1.75 (m, 3H), 1.60-1.53 (m, 1H), 0.90-0.86 (m, 3H), 0.79-0.77 (m, 3H).
实施例36：2-(3,5-二甲基异恶唑-4-基)-N-(4-乙基苯基)-N-异丁基-4-氧代辛烷-6-磺酰胺化合物EXP 36的制备Example 36: 2-(3,5-Dimethylisoxazol-4-yl)-N-(4-ethylphenyl)-N-isobutyl-4-oxooctane-6-sulfonate Preparation of amide compound EXP 36
Figure PCTCN2017087263-appb-000076
Figure PCTCN2017087263-appb-000076
参照实施例1的方法，制备了Exp36Referring to the method of Example 1, Exp36 was prepared.
LC-MS:[M+1]＝483.3LC-MS: [M+1]=483.3
1H NMR(400MHz,CDCl3)δ13.15(s,1H),7.87(d,J＝2.0Hz,1H),7.76-7.70(m,2H),7.13-7.60(m,3H),7.02-6.97(m,3H),3.29(d,J＝7.2Hz,2H),2.64-2.50(m,5H),2.37(s,3H),1.29-1.27(m,1H),1.16(t,J＝7.6Hz,3H),0.91(d,J＝6.6Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 13.15 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.76-7.70 (m, 2H), 7.13-7.60 (m, 3H), 7.02- 6.97 (m, 3H), 3.29 (d, J = 7.2 Hz, 2H), 2.64 - 2.50 (m, 5H), 2.37 (s, 3H), 1.29-1.27 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 6H).
实施例37：N-(2,4-二氟苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 37的制备Example 37: N-(2,4-difluorophenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chromanol- Preparation of 6-sulfonamide compound EXP 37
Figure PCTCN2017087263-appb-000077
Figure PCTCN2017087263-appb-000077
参照实施例1的方法，制备了Exp37 Referring to the method of Example 1, Exp37 was prepared.
LC-MS:[M+1]＝480.16LC-MS: [M+1]=480.16
1H NMR(400MHz,DMSO)δ7.88(d,J＝1.2Hz,1H),7.75(dd,J＝8.4,2.0Hz,1H),7.41-7.35(m,1H),7.27(d,J＝8.8Hz,1H),7.25-7.18(m,1H),7.13-7.10(m,1H),4.54-4.50(m,1H),3.94-3.90(m,2H),3.26(d,J＝7.2Hz,4H),2.98-2.88(m,1H),2.77-2.67(m,1H),1.99(br s,1H),1.82(d,J＝12.4Hz,1H),1.58(d,J＝12.4Hz,1H),1.51-1.37(m,3H),0.88(d,J＝6.4Hz,6H). 1 H NMR (400 MHz, DMSO) δ 7.88 (d, J = 1.2 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.27 (d, J) = 8.8 Hz, 1H), 7.25-7.18 (m, 1H), 7.13-7.10 (m, 1H), 4.54-4.50 (m, 1H), 3.94-3.90 (m, 2H), 3.26 (d, J = 7.2) Hz, 4H), 2.98-2.88 (m, 1H), 2.77-2.67 (m, 1H), 1.99 (br s, 1H), 1.82 (d, J = 12.4 Hz, 1H), 1.58 (d, J = 12.4) Hz, 1H), 1.51-1.37 (m, 3H), 0.88 (d, J = 6.4 Hz, 6H).
实施例38：2-(1-(环戊基磺酰基)哌啶-4-基)-N-(4-乙基苯基)-N-异丁基-4-氧代辛烷-6-磺酰胺化合物EXP 38的制备Example 38: 2-(1-(Cyclopentylsulfonyl)piperidin-4-yl)-N-(4-ethylphenyl)-N-isobutyl-4-oxooctane-6- Preparation of Sulfonamide Compound EXP 38
Figure PCTCN2017087263-appb-000078
Figure PCTCN2017087263-appb-000078
参照实施例1的方法，制备了Exp38Referring to the method of Example 1, Exp38 was prepared.
1H NMR(400MHz,CD3Cl)δ8.19(d,J＝2.0Hz,1H),7.54(dd,J＝8.4,2.0Hz,1H),7.12(d,J＝8.0Hz,2H),7.01-6.94(m,3H),4.37-4.31(m,1H),3.95(d,J＝12.0Hz,2H),3.44-3.42(m,1H),3.29(d,J＝7.6Hz,1H),2.86-2.74(m,4H),2.64(q,J＝7.2Hz,2H),2.01-1.97(m,5H),1.81-1.75(m,4H),1.64-1.53(m,5H),1.23(t,J＝7.2Hz,1H),0.90(d,J＝6.4Hz,6H). 1 H NMR (400 MHz, CD 3 Cl) δ 8.19 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.1. , 2.86-2.74 (m, 4H), 2.64 (q, J = 7.2 Hz, 2H), 2.01-1.97 (m, 5H), 1.81-1.75 (m, 4H), 1.64-1.53 (m, 5H), 1.23 (t, J = 7.2 Hz, 1H), 0.90 (d, J = 6.4 Hz, 6H).
实施例39：N-环丁基-N-(2,4-二甲基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 39的制备Example 39: N-cyclobutyl-N-(2,4-dimethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman Preparation of -6-sulfonamide compound EXP 39
Figure PCTCN2017087263-appb-000079
Figure PCTCN2017087263-appb-000079
参照实施例1的方法，制备了Exp39Referring to the method of Example 1, Exp39 was prepared.
LC-MS:[M+1]＝470.19LC-MS: [M+1]=470.19
1H NMR(400MHz,DMSO)δ7.92(dd,J＝8.4,2.4Hz,1H),7.80-7.74(m,1H),7.27(dd,J＝ 8.8,2.0Hz,1H),7.18(s,1H),6.92(d,J＝7.2Hz,1H),6.38-6.36(m,1H),4.59-4.40(m,2H),3.98-3.85(m,2H),3.01-2.88(m,1H),2.74(d,J＝15.0Hz,1H),2.28(s,3H),2.22(s,3H),2.00-1.96(m,1H),1.86-1.83(m,2H),1.74-1.66(m,1H),1.62-1.55(m,3H),1.54-1.37(m,4H),0.94(d,J＝6.8Hz,1H). 1 H NMR (400 MHz, DMSO) δ 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.80-7.74 (m, 1H), 7.27 (dd, J = 8.8, 2.0 Hz, 1H), 7.18 (s) , 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.38-6.36 (m, 1H), 4.59-4.40 (m, 2H), 3.98-3.85 (m, 2H), 3.01-2.88 (m, 1H) ), 2.74 (d, J = 15.0 Hz, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00-1.96 (m, 1H), 1.86-1.83 (m, 2H), 1.74-1.66 ( m, 1H), 1.62-1.55 (m, 3H), 1.54-1.37 (m, 4H), 0.94 (d, J = 6.8 Hz, 1H).
实施例40：N-(4-(二甲基氨基)苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 40的制备Example 40: N-(4-(Dimethylamino)phenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)benzodihydropyrrol Preparation of quaternary-6-sulfonamide compound EXP 40
Figure PCTCN2017087263-appb-000080
Figure PCTCN2017087263-appb-000080
参照实施例1的方法，制备了Exp40Referring to the method of Example 1, an Exp40 was prepared.
1H NMR(400MHz,CD3Cl)δ8.15(d,J＝2.0Hz,1H),7.50(dd,J＝8.4,2.0Hz,1H),6.91(d,J＝8.4Hz,1H),6.82(d,J＝8.8Hz,2H),6.55(d,J＝9.2Hz,2H),4.27-4.23(m,1H),4.00(d,J＝11.8Hz,2H),3.42-3.32(m,2H),3.19(d,J＝7.2Hz,2H),2.89(s,6H),2.74-2.57(m,2H),1.98-1.91(m,1H),1.87-1.73(m,1H),1.55-1.45(m,4H),0.84(d,J＝6.4,6H). 1 H NMR (400 MHz, CD 3 Cl) δ 8.15 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 9.2 Hz, 2H), 4.27 - 4.23 (m, 1H), 4.00 (d, J = 11.8 Hz, 2H), 3.42-3.32 (m) , 2H), 3.19 (d, J = 7.2 Hz, 2H), 2.89 (s, 6H), 2.74-2.57 (m, 2H), 1.98-1.91 (m, 1H), 1.87-1.73 (m, 1H), 1.55-1.45 (m, 4H), 0.84 (d, J = 6.4, 6H).
实施例41：2-(1-(环戊烷羰基)哌啶-4-基)-N-(4-乙基苯基)-N-异丁基-4-氧代辛烷-6-磺酰胺化合物EXP 41的制备Example 41: 2-(1-(Cyclopentanecarbonyl)piperidin-4-yl)-N-(4-ethylphenyl)-N-isobutyl-4-oxooctane-6-sulfonate Preparation of amide compound EXP 41
Figure PCTCN2017087263-appb-000081
Figure PCTCN2017087263-appb-000081
参照实施例1的方法，制备了Exp41Referring to the method of Example 1, Exp41 was prepared.
1H NMR(400MHz,CDCl3)δ8.19(d,J＝2.4 1H),7.54(dd,J＝2.4,8.8Hz 1H),7.12(d,J＝8.0,Hz,2H),6.69(m,3H),4.79(br s,1H),4.33(br s,1H),4.11(br s,1H),3.28(d,J＝7.8,2H), 3.11(br s,1H),2.93(br s,1H),2.91-2.55(m,5H),2.02(m,2H),1.76(m,7H),1.61(m,3H),1.42(m,2H),1.23(t,J＝7.6Hz,3H),0.90-0.84(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 2.4 1H), 7.54 (dd, J = 2.4, 8.8 Hz 1H), 7.12 (d, J = 8.0, Hz, 2H), 6.69 (m) , 3H), 4.79 (br s, 1H), 4.33 (br s, 1H), 4.11 (br s, 1H), 3.28 (d, J = 7.8, 2H), 3.11 (br s, 1H), 2.93 (br s, 1H), 2.91-2.55 (m, 5H), 2.02 (m, 2H), 1.76 (m, 7H), 1.61 (m, 3H), 1.42 (m, 2H), 1.23 (t, J = 7.6 Hz) , 3H), 0.90-0.84 (m, 6H).
实施例42：N-异丁基-N-(2-甲基-6-吗啉代吡啶-3-基)-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 42的制备Example 42: N-Isobutyl-N-(2-methyl-6-morpholinopyridin-3-yl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl) Preparation of benzodihydropyran-6-sulfonamide compound EXP 42
Figure PCTCN2017087263-appb-000082
Figure PCTCN2017087263-appb-000082
参照实施例1的方法，制备了Exp42Referring to the method of Example 1, Exp42 was prepared.
1H NMR(400MHz,CDCl3)δ8.11(dd,J＝6.0,2.4Hz,1H),7.71-7.59(m,1H),7.25(dd,J＝9.4,2.4Hz,1H),7.02(d,J＝8.8Hz,1H),6.53(d,J＝8.8Hz,1H),4.38-4.20(m,1H),4.01(d,J＝11.9Hz,2H),3.78(t,J＝4.8Hz,4H),3.64-3.60(m,4H),3.37-3.30(m,2H),3.27-3.07(m,2H),2.75-2.71(m,2H),2.20(d,J＝4.5Hz,3H),1.99-1.95(m,1H),1.83(d,J＝13.3Hz,1H),1.61-1.43(m,4H),0.86-0.82(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (dd, J = 6.0, 2.4 Hz, 1H), 7.71-7.59 (m, 1H), 7.25 (dd, J = 9.4, 2.4 Hz, 1H), 7.02 ( d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.38-4.20 (m, 1H), 4.01 (d, J = 11.9 Hz, 2H), 3.78 (t, J = 4.8) Hz, 4H), 3.64-3.60 (m, 4H), 3.37-3.30 (m, 2H), 3.27-3.07 (m, 2H), 2.75-2.71 (m, 2H), 2.20 (d, J = 4.5 Hz, 3H), 1.99-1.95 (m, 1H), 1.83 (d, J = 13.3 Hz, 1H), 1.61-1.43 (m, 4H), 0.86-0.82 (m, 6H).
实施例43：N-(环丁基甲基)-N-(4-乙基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 43的制备Example 43: N-(cyclobutylmethyl)-N-(4-ethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chromanol- Preparation of 6-sulfonamide compound EXP 43
Figure PCTCN2017087263-appb-000083
Figure PCTCN2017087263-appb-000083
参照实施例1的方法，制备了Exp43Referring to the method of Example 1, Exp43 was prepared.
1H NMR(400MHz,CDCl3)δ8.25(d,J＝2.0Hz,1H),7.61(dd,J＝8.0,2.4Hz,1H),7.13(d,J＝8.4Hz,2H),7.02(d,J＝8.8Hz,1H),6.93(d,J＝8.4Hz,2H),4.39-4.29(m,1H),4.10d,J＝12.8Hz,2H),3.55(d,J＝7.6Hz,2H),3.51-3.40(m,2H),2.79(d,J＝7.2Hz,2H),2.66(q,J＝7.6Hz,2H),2.37-2.27(m,1H),2.10-1.98(m,1H),1.97-1.87(m,3H),1.87-1.76(m,2H), 1.75-1.63(m,5H),1.25(t,J＝7.6Hz,3H). 1H NMR (400MHz, CDCl 3) δ8.25 (d, J = 2.0Hz, 1H), 7.61 (dd, J = 8.0,2.4Hz, 1H), 7.13 (d, J = 8.4Hz, 2H), 7.02 ( d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 4.39-4.29 (m, 1H), 4.10d, J = 12.8 Hz, 2H), 3.55 (d, J = 7.6 Hz) , 2H), 3.51-3.40 (m, 2H), 2.79 (d, J = 7.2 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 2.37-2.27 (m, 1H), 2.10 - 1.98 ( m, 1H), 1.97-1.87 (m, 3H), 1.87-1.76 (m, 2H), 1.75-1.63 (m, 5H), 1.25 (t, J = 7.6 Hz, 3H).
实施例44：N-(4-乙基苯基)-N-异丁基-2-(4-甲基四氢-2H-吡喃-4-基)-4-氧代辛烷-6-磺酰胺化合物EXP 44的制备Example 44: N-(4-ethylphenyl)-N-isobutyl-2-(4-methyltetrahydro-2H-pyran-4-yl)-4-oxooctane-6- Preparation of Sulfonamide Compound EXP 44
Figure PCTCN2017087263-appb-000084
Figure PCTCN2017087263-appb-000084
参照实施例1的方法，制备了Exp44Referring to the method of Example 1, Exp44 was prepared.
1H NMR(400MHz,CDCl3)δ8.13(d,J＝2.0Hz,1H),7.48(dd,J＝8.8,2.0Hz,1H),7.06(d,J＝8.4Hz,2H),6.95-6.88(m,3H),4.13-4.11(m,1H),3.80-3.77(m,2H),3.58(t,J＝11.7Hz,2H),3.22(d,J＝7.2Hz,2H),2.74-2.62(m,1H),2.57(q,J＝7.2Hz,2H),1.80-1.60(m,1H),1.57-1.46(m,4H),1.16(t,J＝7.6Hz,3H),1.07(s,3H),0.84(d,J＝6.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.13 (d, J = 2.0Hz, 1H), 7.48 (dd, J = 8.8,2.0Hz, 1H), 7.06 (d, J = 8.4Hz, 2H), 6.95 -6.88 (m, 3H), 4.13-4.11 (m, 1H), 3.80-3.77 (m, 2H), 3.58 (t, J = 11.7 Hz, 2H), 3.22 (d, J = 7.2 Hz, 2H), 2.74-2.62 (m, 1H), 2.57 (q, J = 7.2 Hz, 2H), 1.80-1.60 (m, 1H), 1.57-1.46 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H) , 1.07 (s, 3H), 0.84 (d, J = 6.4 Hz, 6H).
实施例45：N-(4-(叔丁基)苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 45的制备Example 45: N-(4-(tert-butyl)phenyl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonate Preparation of amide compound EXP 45
Figure PCTCN2017087263-appb-000085
Figure PCTCN2017087263-appb-000085
参照实施例1的方法，制备了Exp45Referring to the method of Example 1, Exp45 was prepared.
1H NMR(400MHz,CDCl3)δ8.12(d,J＝2.4Hz,1H),7.48(dd,J＝8.8,2.4Hz,1H),7.23(d,J＝8.4Hz,2H),6.94-6.89(m,1H),4.28-4.22(m,1H),4.08(d,J＝12.1Hz,2H),3.43-3.33(m,2H),3.22(d,J＝7.6Hz,2H),2.69(d,J＝7.6Hz,2H),1.98-1.92(m,2H),1.84(d,J＝13.6Hz,2H),1.56-1.27(m,4H),1.23(s,9H),0.77(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.94 -6.89 (m, 1H), 4.28-4.22 (m, 1H), 4.08 (d, J = 12.1 Hz, 2H), 3.43-3.33 (m, 2H), 3.22 (d, J = 7.6 Hz, 2H), 2.69 (d, J = 7.6 Hz, 2H), 1.98-1.92 (m, 2H), 1.84 (d, J = 13.6 Hz, 2H), 1.56-1.27 (m, 4H), 1.23 (s, 9H), 0.77 (d, J = 6.8 Hz, 6H).
实施例46：N-(4-乙基苯基)-2-(1-((S)-2-羟基丙酰基)哌啶-4-基)-N-异丁基-4-氧代辛烷-6-磺酰胺化合物EXP 46的制备 Example 46: N-(4-ethylphenyl)-2-(1-((S)-2-hydroxypropanoyl)piperidin-4-yl)-N-isobutyl-4-oxoxin Preparation of alkane-6-sulfonamide compound EXP 46
Figure PCTCN2017087263-appb-000086
Figure PCTCN2017087263-appb-000086
参照实施例1的方法，制备了Exp46Referring to the method of Example 1, Exp46 was prepared.
1H NMR(400MHz,CD3Cl)δ8.19(d,J＝1.2Hz,1H),7.55(d,J＝8.4Hz,1H),7.12(d,J＝8.0Hz,2H),7.01-6.94(m,3H),4.75(br s,1H),4.49(br s,1H),4.36-4.33(m,1H),3.84(d,J＝10.4Hz,1H),3.29(d,J＝7.2Hz,2H),3.12-3.07(m,1H),2.78-2.61(m,5H),2.43(br s,3H),2.17(br s,2H),1.84-1.81(m,1H),1.61-1.57(m,1H),1.52-1.46(m,1H),1.35(br s,3H),1.25(t,J＝7.6Hz,3H),0.90(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, CD 3 Cl) δ 8.19 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.01 6.94 (m, 3H), 4.75 (br s, 1H), 4.49 (br s, 1H), 4.36-4.33 (m, 1H), 3.84 (d, J = 10.4 Hz, 1H), 3.29 (d, J = 7.2 Hz, 2H), 3.12-3.07 (m, 1H), 2.78-2.61 (m, 5H), 2.43 (br s, 3H), 2.17 (br s, 2H), 1.84-1.81 (m, 1H), 1.61 -1.57 (m, 1H), 1.52-1.46 (m, 1H), 1.35 (br s, 3H), 1.25 (t, J = 7.6 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H).
实施例47：N-苄基-N-(4-乙基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 47的制备Example 47: N-Benzyl-N-(4-ethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonate Preparation of amide compound EXP 47
Figure PCTCN2017087263-appb-000087
Figure PCTCN2017087263-appb-000087
参照实施例1的方法，制备了Exp47Referring to the method of Example 1, Exp47 was prepared.
1H NMR(400MHz,CDCl3)δ8.22(d,J＝2.4Hz,1H),7.59-7.54(m,1H),7.15-7.12(m,5H),6.96(d,J＝8.4Hz,3H),6.82(d,J＝8.4Hz,2H),4.65(s,2H),4.29-4.23(m,1H),4.01(d,J＝10.9Hz,2H),3.42-3.33(m,2H),2.70(d,J＝7.2Hz,2H),2.50(q,J＝7.6Hz,2H),1.84(d,J＝13.0Hz,1H),1.10(t,J＝7.6Hz,3H).1H NMR (400MHz, CDCl 3 ) δ 8.22 (d, J = 2.4Hz, 1H), 7.59-7.54 (m, 1H), 7.15-7.12 (m, 5H), 6.96 (d, J = 8.4 Hz, 3H ), 6.82 (d, J = 8.4 Hz, 2H), 4.65 (s, 2H), 4.29 - 4.23 (m, 1H), 4.01 (d, J = 10.9 Hz, 2H), 3.42-3.33 (m, 2H) , 2.70 (d, J = 7.2 Hz, 2H), 2.50 (q, J = 7.6 Hz, 2H), 1.84 (d, J = 13.0 Hz, 1H), 1.10 (t, J = 7.6 Hz, 3H).
实施例48：N-(4-乙基苯基)-N-异丁基-2-(氧杂环丁烷-3-基)-4-氧代辛烷-6-磺酰胺化合物EXP 48的制备 Example 48: N-(4-ethylphenyl)-N-isobutyl-2-(oxetan-3-yl)-4-oxooctane-6-sulfonamide compound EXP 48 Preparation
Figure PCTCN2017087263-appb-000088
Figure PCTCN2017087263-appb-000088
参照实施例1的方法，制备了Exp48Referring to the method of Example 1, Exp48 was prepared.
LC-MS:[M+1]＝444LC-MS: [M+1]=444
1H NMR(400MHz,CDCl3)δ8.15(d,J＝2.0Hz,1H),7.51(dd,J＝8.4,2.4Hz,1H),7.06(d,J＝8.4Hz,2H),6.98(d,J＝8.8Hz,1H),6.89(d,J＝8.4Hz,2H),4.89-4.4.83(m,2H),4.78-4.4.73(m,2H),4.57(t,J＝6.4Hz,1H),3.36-3.31(m,2H),3.23(d,J＝7.6Hz,2H),2.62-2.54(m,3H),1.55-1.47(m,1H),1.16(t,J＝7.6Hz,3H),0.84(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.4, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 4.89-4.4.83 (m, 2H), 4.78-4.4.73 (m, 2H), 4.57 (t, J = 6.4 Hz, 1H), 3.36-3.31 (m, 2H), 3.23 (d, J = 7.6 Hz, 2H), 2.62-2.54 (m, 3H), 1.55-1.47 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 0.84 (d, J = 6.8 Hz, 6H).
实施例49：N-(4-氟苄基)-4-氧代-2-(四氢-2H-吡喃-4-基)-N-((5-(三氟甲基)呋喃-2-基)甲基)色满-6-磺酰胺化合物EXP 49的制备Example 49: N-(4-Fluorobenzyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-((5-(trifluoromethyl)furan-2 -Methyl)methane-6-sulfonamide compound EXP 49
Figure PCTCN2017087263-appb-000089
Figure PCTCN2017087263-appb-000089
参照实施例1的方法，制备了Exp49Referring to the method of Example 1, Exp49 was prepared.
LC-MS:[M-19]＝548.1LC-MS: [M-19]=548.1
1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.4Hz,1H),7.80(dd,J＝8.8,2.4Hz,1H),7.23-7.21(m,2H),7.00-6.94(m,3H),6.52(d,J＝2.0Hz,1H),6.13(d,J＝3.2Hz,1H),4.27-4.19(m,6H),4.03-3.99(m,2H),3.42-3.34(m,2H),2.69-2.66(m,2H),1.97-1.94(m,1H),1.84(d,J＝12.8Hz,1H),1.57-1.53(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.17 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 8.8,2.4Hz, 1H), 7.23-7.21 (m, 2H), 7.00-6.94 ( m,3H), 6.52 (d, J=2.0 Hz, 1H), 6.13 (d, J=3.2 Hz, 1H), 4.27-4.19 (m, 6H), 4.03-3.99 (m, 2H), 3.42-3.34 (m, 2H), 2.69-2.66 (m, 2H), 1.97-1.94 (m, 1H), 1.84 (d, J = 12.8 Hz, 1H), 1.57-1.53 (m, 2H).
实施例50：N-(环丙基甲基)-N-(4-乙基苯基)-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 50的制备 Example 50: N-(cyclopropylmethyl)-N-(4-ethylphenyl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)benzodihydropyrrol Preparation of quaternary-6-sulfonamide compound EXP 50
Figure PCTCN2017087263-appb-000090
Figure PCTCN2017087263-appb-000090
参照实施例1的方法，制备了Exp50Referring to the method of Example 1, Exp50 was prepared.
1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.0Hz,1H),7.55(dd,J＝8.8,2.0Hz,1H),7.06(d,J＝8.4Hz,2H),6.94-6.92(m,3H),4.27-4.22(m,1H),4.00(d,J＝12.0Hz,2H),3.42-3.31(m,4H),2.69(d,J＝7.2Hz,2H),2.58(q,J＝7.6Hz,2H),1.96-1.92(m,1H),1.82(J＝13.2Hz,1H),1.56-1.42(m,4H),1.16(t,J＝7.6Hz,3H),0.85-0.72(m,2H),0.38-0.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.17 (d, J = 2.0Hz, 1H), 7.55 (dd, J = 8.8,2.0Hz, 1H), 7.06 (d, J = 8.4Hz, 2H), 6.94 - 6.92 (m, 3H), 4.27-4.22 (m, 1H), 4.00 (d, J = 12.0 Hz, 2H), 3.42-3.31 (m, 4H), 2.69 (d, J = 7.2 Hz, 2H), 2.58 (q, J = 7.6 Hz, 2H), 1.96-1.92 (m, 1H), 1.82 (J = 13.2 Hz, 1H), 1.56-1.42 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H) ), 0.85-0.72 (m, 2H), 0.38-0.30 (m, 2H).
实施例51：N-(4-(1,1,1,3,3,3-六氟-2-羟基丙-2-基)-2-甲基苯基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 51的制备Example 51: N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)-N-isobutyl-4 -Oxo-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide compound EXP 51
Figure PCTCN2017087263-appb-000091
Figure PCTCN2017087263-appb-000091
参照实施例1的方法，制备了Exp51Referring to the method of Example 1, Exp51 was prepared.
LC-MS:[M+1]＝624.2LC-MS: [M+1]=624.2
1H NMR(400MHz,CDCl3)δ8.23-8.21(m,1H),7.63-7.52(m,2H),7.40-7.36(m,1H),7.04-7.02(m,1H),6.73(d,J＝9.4Hz,,1H),4.35-4.32(m,1H),4.10-4.06(m,3H),3.48-3.41(m,3H),3.11-3.06(m,1H),2.78(d,J＝8.4Hz,2H),2.465(d,J＝4.1Hz,3H),2.07-2.00(m,2H),1.92-1.89(m,1H),1.66-1.60(m,2H),1.03-1.01(m,3H),0.83(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.23-8.21 (m, 1H), 7.63-7.52 (m, 2H), 7.40-7.36 (m, 1H), 7.04-7.02 (m, 1H), 6.73 (d , J=9.4 Hz,, 1H), 4.35-4.32 (m, 1H), 4.10-4.06 (m, 3H), 3.48-3.41 (m, 3H), 3.11-3.06 (m, 1H), 2.78 (d, J=8.4 Hz, 2H), 2.465 (d, J=4.1 Hz, 3H), 2.07-2.00 (m, 2H), 1.92-1.89 (m, 1H), 1.66-1.60 (m, 2H), 1.03-1.01 (m, 3H), 0.83 (d, J = 6.6 Hz, 3H).
实施例52：2-(1-(环戊烷羰基)哌啶-4-基)-N-(4-乙基苯基)-N-异丁基-4-氧代辛烷-6-磺酰胺化合物EXP 52的制备 Example 52: 2-(1-(Cyclopentanecarbonyl)piperidin-4-yl)-N-(4-ethylphenyl)-N-isobutyl-4-oxooctane-6-sulfonate Preparation of amide compound EXP 52
Figure PCTCN2017087263-appb-000092
Figure PCTCN2017087263-appb-000092
参照实施例1的方法，制备了Exp52Referring to the method of Example 1, Exp52 was prepared.
1H NMR(400MHz,CD3Cl)δ8.19(d,J＝2.0Hz,1H),7.55(dd,J＝8.4,2.0Hz,1H),7.12(d,J＝8.4Hz,2H),7.00-6.94(m,3H),4.78(d,J＝12.8Hz,1H),4.35-4.31(m,1H),4.11(d,J＝12.8Hz,1H),3.29(d,J＝7.6Hz,1H),3.10-3.03(m,1H),2.92-2.90(m,1H),2.77-2.75(m,2H),2.66-2.55(m,3H),2.00(br s,3H),1.82(br s,5H),1.62-1.53(m,3H),1.43-1.38(m,2H),1.22(t,J＝7.6Hz,4H),0.90(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, CD 3 Cl) δ 8.19 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.00-6.94 (m, 3H), 4.78 (d, J = 12.8 Hz, 1H), 4.35 - 4.31 (m, 1H), 4.11 (d, J = 12.8 Hz, 1H), 3.29 (d, J = 7.6 Hz) , 1H), 3.10-3.03 (m, 1H), 2.92-2.90 (m, 1H), 2.77-2.75 (m, 2H), 2.66-2.55 (m, 3H), 2.00 (br s, 3H), 1.82 ( Br s, 5H), 1.62-1.53 (m, 3H), 1.43-1.38 (m, 2H), 1.22 (t, J = 7.6 Hz, 4H), 0.90 (d, J = 6.8 Hz, 6H).
实施例53：N-(苯并[b]噻吩-2-基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 53的制备Example 53: N-(Benzo[b]thiophen-2-yl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl)benzodihydropyr Preparation of quaternary-6-sulfonamide compound EXP 53
Figure PCTCN2017087263-appb-000093
Figure PCTCN2017087263-appb-000093
参照实施例1的方法，制备了Exp53Referring to the method of Example 1, Exp53 was prepared.
LC-MS:[M+1]＝500.2LC-MS: [M+1]=500.2
1H NMR(400MHz,CDCl3)δ8.23(d,J＝2.4Hz,1H),7.65-7.59(m,3H),7.28-7.23(m,2H),7.12(s,1H),6.93(d,J＝8.8Hz,1H),4.26-4.23(m,1H),4.02-3.99(m,2H),3.41-3.32(m,3H),2.69(d,J＝8.0Hz,1H),1.97-1.92(m,1H),1.83-1.74(m,2H),1.61-1.44(m,4H),0.90(d,J＝6.4Hz,6H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 2.4 Hz, 1H), 7.65-7.59 (m, 3H), 7.28-7.23 (m, 2H), 7.12 (s, 1H), 6.93 ( d, J = 8.8 Hz, 1H), 4.26 - 4.23 (m, 1H), 4.02-3.99 (m, 2H), 3.41-3.32 (m, 3H), 2.69 (d, J = 8.0 Hz, 1H), 1.97 -1.92 (m, 1H), 1.83-1.74 (m, 2H), 1.61-1.44 (m, 4H), 0.90 (d, J = 6.4 Hz, 6H)
实施例54：N-环丁基-N-(2,4-二甲基苯基)-4-氧代-2-((四氢-2H-吡喃-4-基)甲基)色满-6-磺酰胺化合物EXP 54的制备 Example 54: N-cyclobutyl-N-(2,4-dimethylphenyl)-4-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl) Preparation of -6-sulfonamide compound EXP 54
Figure PCTCN2017087263-appb-000094
Figure PCTCN2017087263-appb-000094
参照实施例1的方法，制备了Exp54Referring to the method of Example 1, Exp54 was prepared.
1H NMR(400MHz,CD3Cl)δ8.31-8.29(m,1H),7.73-7.71(m,1H),7.12(s,1H),7.03(dd,J＝8.0,2.8Hz,1H),6.85(d,J＝7.2Hz,1H),6.40-6.38(m,1H),4.68(br s,1H),4.56-4.53(m,1H),4.01-3.97(m,2H),3.43(t,J＝11.6Hz,2H),2.75(d,J＝7.6Hz,2H),2.31(s,3H),2.29(s,3H),2.25-2.22(m,1H),1.92-1.84(m,7H),1.48-1.40(m,4H). 1 H NMR (400 MHz, CD 3 Cl) δ 8.31 - 8.29 (m, 1H), 7.73 - 7.71 (m, 1H), 7.12 (s, 1H), 7.03 (dd, J = 8.0, 2.8 Hz, 1H) , 6.85 (d, J = 7.2 Hz, 1H), 6.40-6.38 (m, 1H), 4.68 (br s, 1H), 4.56-4.53 (m, 1H), 4.01-3.97 (m, 2H), 3.43 ( t, J = 11.6 Hz, 2H), 2.75 (d, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.25 - 2.22 (m, 1H), 1.92-1.84 (m , 7H), 1.48-1.40 (m, 4H).
实施例55：N-(4-乙基苯基)-2-(3-羟基环丁基)-N-异丁基-4-氧代辛烷-6-磺酰胺化合物EXP 55的制备Example 55: Preparation of N-(4-ethylphenyl)-2-(3-hydroxycyclobutyl)-N-isobutyl-4-oxooctane-6-sulfonamide compound EXP 55
Figure PCTCN2017087263-appb-000095
Figure PCTCN2017087263-appb-000095
参照实施例1的方法，制备了Exp55Referring to the method of Example 1, Exp55 was prepared.
1H NMR(400MHz,CDCl3)δ7.82(d,J＝2.0Hz,1H),7.60(dd,J＝8.4Hz,1.6Hz,1H),7.08(d,J＝8.4Hz,2H),6.99(d,J＝8.8Hz,1H),6.91(d,J＝8.4Hz,2H),6.63(d,J＝14.8Hz,1H),4.24-4.20(m,1H),3.22(d,J＝7.2Hz,2H),2.60-2.51(m,4H),1.88-1.66(m,5H),1.62-1.48(m,2H),1.15(t,J＝7.6Hz,3H),0.85(d,J＝6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.82 (d, J = 2.0Hz, 1H), 7.60 (dd, J = 8.4Hz, 1.6Hz, 1H), 7.08 (d, J = 8.4Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 14.8 Hz, 1H), 4.24 - 4.20 (m, 1H), 3.22 (d, J) = 7.2 Hz, 2H), 2.60-2.51 (m, 4H), 1.88-1.66 (m, 5H), 1.62-1.48 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H), 0.85 (d, J=6.8Hz, 6H).
实施例56：N-(4-乙基苯基)-N-异丁基-4-氧代-2-(1-(四氢-2H-吡喃-4-基)乙基)色满-6-磺酰胺化合物EXP 56的制备 Example 56: N-(4-ethylphenyl)-N-isobutyl-4-oxo-2-(1-(tetrahydro-2H-pyran-4-yl)ethyl)chroman- Preparation of 6-sulfonamide compound EXP 56
Figure PCTCN2017087263-appb-000096
Figure PCTCN2017087263-appb-000096
参照实施例1的方法，制备了Exp56Referring to the method of Example 1, Exp56 was prepared.
LC-MS:[M+H]＝500.3LC-MS: [M+H]=500.3
1H NMR(400MHz,CDCl3)δ8.20(d,J＝2.4Hz,1H),7.55-7.52(m,1H),7.13(d,J＝8.4Hz,2H),7.03-6.93(m,3H),4.64-4.60(m,1H),4.06-3.96(m,2H),3.41(t,J＝10.9Hz,2H),3.29(d,J＝7.3Hz,2H),2.97-2.87(m,1H),2.74-2.64(m,3H),1.70–1.57(m,3H),1.53-1.39(m,2H),1.23(t,J＝7.6Hz,3H),1.11(d,J＝6.9Hz,2H),1.00(t,J＝6.7Hz,1H),0.91(d,J＝6.6Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J = 2.4 Hz, 1H), 7.55-7.52 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.03-6.93 (m, 3H), 4.64-4.60 (m, 1H), 4.06-3.96 (m, 2H), 3.41 (t, J = 10.9 Hz, 2H), 3.29 (d, J = 7.3 Hz, 2H), 2.97 - 2.87 (m) , 1H), 2.74 - 2.64 (m, 3H), 1.70 - 1.57 (m, 3H), 1.53-1.39 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 1.11 (d, J = 6.9) Hz, 2H), 1.00 (t, J = 6.7 Hz, 1H), 0.91 (d, J = 6.6 Hz, 6H).
实施例57：(2-(1-(环戊烷羰基)哌啶-4-基)-N-(4-乙基苯基)-4-羟基-N-异丁基苯并二氢吡喃-6-磺酰胺化合物EXP 57的制备Example 57: (2-(1-(Cyclopentanecarbonyl)piperidin-4-yl)-N-(4-ethylphenyl)-4-hydroxy-N-isobutylchroman Preparation of -6-sulfonamide compound EXP 57
Figure PCTCN2017087263-appb-000097
Figure PCTCN2017087263-appb-000097
参照实施例2的方法，制备了Exp57.Referring to the method of Example 2, Exp57 was prepared.
LC-MS:[M+1]＝569.3LC-MS: [M+1]=569.3
1H NMR(400MHz,CDCl3)δ7.66(d,J＝1.6Hz 1H),7.34(dd,J＝8.0,1.2Hz,1H),7.12(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.79(d,J＝8.4Hz,1H),4.89(br s,1H),4.42(br s,1H),4.02(br s,1H),3.35-3.17(m,2H),2.92(br s,1H),2.81(br s,1H),2.63(q,J＝7.2Hz,2H),2.30(br s,1H),2.01(s,3H),1.79-1.75(m,8H),1.57-1.54(m,5H),1.36(br s,2H),1.23(t,J＝7.6Hz,3H),0.90-0.88(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.66 (d, J = 1.6Hz 1H), 7.34 (dd, J = 8.0,1.2Hz, 1H), 7.12 (d, J = 8.0Hz, 2H), 6.97 ( d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 4.89 (br s, 1H), 4.42 (br s, 1H), 4.02 (br s, 1H), 3.35-3.17 ( m, 2H), 2.92 (br s, 1H), 2.81 (br s, 1H), 2.63 (q, J = 7.2 Hz, 2H), 2.30 (br s, 1H), 2.01 (s, 3H), 1.79- 1.75 (m, 8H), 1.57-1.54 (m, 5H), 1.36 (br s, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.90-0.88 (m, 6H).
实施例58：N-(4-乙基苯基)-8-(羟基甲基)-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 58的制备Example 58: N-(4-ethylphenyl)-8-(hydroxymethyl)-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman Preparation of -6-sulfonamide compound EXP 58
Figure PCTCN2017087263-appb-000098
Figure PCTCN2017087263-appb-000098
1)乙酸2-溴苯酯(化合物2的制备)1) 2-bromophenyl acetate (preparation of compound 2)
Figure PCTCN2017087263-appb-000099
Figure PCTCN2017087263-appb-000099
将化合物1(10g，57.8mmol，1.0eq)溶解到100mL的二氯甲烷中，常温下加入三乙胺(12mL，86.7mmol,1.5eq)和DMAP(0.35g,2.9mmol,0.05eq)。冷却到负5度后滴加乙酰氯(36.48g，63.6mmol,1.1eq)。滴加完毕后在负5度下搅拌10分钟，然后升至室温并搅拌2小时。反应液依次用1N盐酸水溶液(200mL),饱和碳酸氢钠水溶液和饱和食盐水洗涤，无水硫酸钠干燥，旋干后柱层析纯化(纯石油醚到石油醚：乙酸乙酯＝10：1)得到无色油状化合物2(12g，55.81mmol，收率：96％)。Compound 1 (10 g, 57.8 mmol, 1.0 eq) was dissolved in 100 mL of dichloromethane, and triethylamine (12 mL, 86.7 mmol, 1.5 eq) and DMAP (0.35 g, 2.9 mmol, 0.05 eq). After cooling to minus 5 degrees, acetyl chloride (36.48 g, 63.6 mmol, 1.1 eq) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at minus 5 degrees for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was washed with aq. EtOAc EtOAc EtOAc EtOAc. The compound 2 (12 g, 55.81 mmol, yield: 96%) was obtained as colorless oil.
TLC:PE/EA＝10:1,UV 254nmTLC: PE/EA=10:1, UV 254nm
Rf(Compound 1)＝0.5R f (Compound 1)=0.5
Rf(Compound 2)＝0.7R f (Compound 2)=0.7
2)1-(3-溴-2-羟基苯基)乙-1-酮(化合物3)的制备 2) Preparation of 1-(3-bromo-2-hydroxyphenyl)ethan-1-one (Compound 3)
Figure PCTCN2017087263-appb-000100
Figure PCTCN2017087263-appb-000100
将化合物2(6.0g，27.91mmol，1.0eq)溶于60mL的1，2-二氯苯中，室温下加入三氯化铝(5.6g,41.86mmol,1.5eq)，然后升温至140度并在此温度下搅拌4小时。冷却到室温后将反应液倒入1N的盐酸水溶液(200mL)中，用乙酸乙酯(2x 50mL)萃取，有机相合并后用饱和食盐水洗，无水硫酸钠干燥后旋干。残留物柱层析纯化(石油醚：乙酸乙酯＝50：1)得到棕色油状固体化合物3(1g，4.65mmol，收率：17％)。Compound 2 (6.0 g, 27.91 mmol, 1.0 eq) was dissolved in 60 mL of 1,2-dichlorobenzene, and aluminum trichloride (5.6 g, 41.86 mmol, 1.5 eq) was added at room temperature, then warmed to 140 ° and Stir at this temperature for 4 hours. After cooling to room temperature, the reaction mixture was poured into EtOAc EtOAc (EtOAc) The residue was purified by EtOAc EtOAcjjjjjjjjj
TLC:PE/EA＝10:1,UV 254nmTLC: PE/EA=10:1, UV 254nm
Rf(Compound 2)＝0.7R f (Compound 2)=0.7
Rf(Compound 3)＝0.5R f (Compound 3)=0.5
3)8-溴-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-4-酮(化合物5)的制备3) Preparation of 8-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (Compound 5)
Figure PCTCN2017087263-appb-000101
Figure PCTCN2017087263-appb-000101
将化合物3(1.0g，4.65mmol，1.0eq)溶解到15mL的甲醇中，然后加入化合物4(0.64g,5.58mmol,1.2eq)和四氢吡咯(0.49g,6.98mmol,1.5eq)。反应液在70度下搅拌3小时。冷却到室温后将反应液旋干，残留物柱层析纯化(石油醚：乙酸乙酯＝40：1到20：1)得到化合物5(0.8g，2.57mmol，收率：55％)。Compound 3 (1.0 g, 4.65 mmol, 1.0 eq) was dissolved in 15 mL MeOH then compound 4 (0.64 g, 5.58 mmol, 1.2 eq) and tetrahydropyrrole (0.49 g, 6.98 mmol, 1.5 eq). The reaction solution was stirred at 70 °C for 3 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
TLC:PE/EA＝2:1,UV 254nmTLC: PE/EA=2:1, UV 254nm
Rf(Compound 3)＝0.9R f (Compound 3)=0.9
Rf(Compound 5)＝0.7R f (Compound 5)=0.7
4)8-溴-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-4-醇(化合物6)的制备4) Preparation of 8-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ol (Compound 6)
Figure PCTCN2017087263-appb-000102
Figure PCTCN2017087263-appb-000102
将化合物5(600mg，1.93mmol，1.0eq)溶于10mL的甲醇中，加入硼氢化钠(219mg，5.79mmol，3.0eq)后常温搅拌2小时。将反应液旋干后将残留物中加入20mL的乙酸乙酯和10mL的水，有机相用饱和食盐水洗，无水硫酸钠干燥，旋干后得到白色固体化合物6(600mg，1.91mmol，收率：99％)。Compound 5 (600 mg, 1.93 mmol, 1.0 eq) was dissolved in 10 mL of methanol, and sodium borohydride (219 mg, 5.79 mmol, 3.0 eq) was added and stirred at room temperature for 2 hr. After the reaction mixture was dried, the residue was evaporated to dryness crystals crystalssssssssssssssssss :99%).
TLC:PE/EA＝1:1,UV 254nmTLC: PE/EA=1:1, UV 254nm
Rf(Compound 5)＝0.9R f (Compound 5)=0.9
Rf(Compound 6)＝0.6R f (Compound 6)=0.6
5)8-溴-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃(化合物7)的制备5) Preparation of 8-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman (Compound 7)
Figure PCTCN2017087263-appb-000103
Figure PCTCN2017087263-appb-000103
将化合物7(600mg，1.92mmol，1.0eq)溶于10mL的二氯甲烷中，冷却到负5度后依次滴加三乙基硅烷(3mL,19.17mmol,10.0eq)和三氟化硼乙醚(2.5mL,19.17mmol,10.0eq)。在负5度下搅拌20分钟后升至室温并在室温下搅拌2小时。反应液用水洗和饱和食盐水洗，无水硫酸钠干燥，旋干后柱层析纯化(石油醚：乙酸乙酯＝5：1)得到白色固体化合物7(530mg，1.78mmol，收率：93％)。Compound 7 (600 mg, 1.92 mmol, 1.0 eq) was dissolved in 10 mL of dichloromethane. After cooling to minus 5, triethylsilane (3 mL, 19.17 mmol, 10.0 eq) and boron trifluoride diethyl ether ( 2.5 mL, 19.17 mmol, 10.0 eq). After stirring at minus 5 degrees for 20 minutes, it was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate ).
TLC:PE/EA＝2:1,UV 254nmTLC: PE/EA=2:1, UV 254nm
Rf(Compound 6)＝0.5R f (Compound 6)=0.5
Rf(Compound 7)＝0.8R f (Compound 7) = 0.8
6)2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-8-羧酸甲酯(化合物8)的制备6) Preparation of methyl 2-(tetrahydro-2H-pyran-4-yl)chroman-8-carboxylate (Compound 8)
Figure PCTCN2017087263-appb-000104
Figure PCTCN2017087263-appb-000104
将化合物7(300mg，1.0mmol，1.0eq)溶于8mL的N,N-二甲基乙酰胺中，然后室温下依次加入4mL甲醇，三乙胺(556uL,4.0mmol,4.0eq)，1,3-双(二苯基磷烷基)丙烷 (82mg，0.2mmol，0.2eq)和醋酸钯(45mg,0.2mmol,0.2eq)，反应液在1个大气压的一氧化碳气氛下升至80度下搅拌过夜。冷却到室温后反应液中加入20mL的乙酸乙酯，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，旋干后柱层析纯化(石油醚：乙酸乙酯＝2：1)得到白色固体化合物8(270mg，0.98mmol，收率：98％)。Compound 7 (300 mg, 1.0 mmol, 1.0 eq) was dissolved in 8 mL of N,N-dimethylacetamide, then 4 mL methanol, triethylamine (556 uL, 4.0 mmol, 4.0 eq), 3-bis(diphenylphosphinoalkyl)propane (82 mg, 0.2 mmol, 0.2 eq) and palladium acetate (45 mg, 0.2 mmol, 0.2 eq), and the reaction mixture was stirred at room temperature under an atmosphere of carbon monoxide at 1 atm. After cooling to room temperature, 20 mL of ethyl acetate was added to the reaction mixture, and the organic phase was washed with water, brine, dried over anhydrous sodium sulfate and dried over silica. Solid Compound 8 (270 mg, 0.98 mmol, yield: 98%).
TLC:PE/EA＝2:1,UV 254nmTLC: PE/EA=2:1, UV 254nm
Rf(Compound 6)＝0.8R f (Compound 6) = 0.8
Rf(Compound 7)＝0.7R f (Compound 7)=0.7
7)6-(氯磺酰基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-8-羧酸甲酯(化合物9)的制备7) Preparation of methyl 6-(chlorosulfonyl)-2-(tetrahydro-2H-pyran-4-yl)chroman-8-carboxylate (Compound 9)
Figure PCTCN2017087263-appb-000105
Figure PCTCN2017087263-appb-000105
将2mL的氯磺酸冷却到零度，然后加入化合物8(100mg，0.36mmol，1.0eq)，加完后升至室温并搅拌1小时。TLC显示原料8反应完毕。将反应液缓慢倒入冰水中，用10mL的乙酸乙酯萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，旋干后柱层析纯化(石油醚：乙酸乙酯＝10：1到5：1)得到白色固体化合物9(110mg，0.29mmol，收率：81％)。2 mL of chlorosulfonic acid was cooled to zero, then compound 8 (100 mg, 0.36 mmol, 1.0 eq) was added, and after the addition was completed, it was warmed to room temperature and stirred for 1 hour. TLC showed that the starting material 8 was completely reacted. The reaction mixture was poured into ice water, and extracted with 10 mL of ethyl acetate. The organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate Compound 5 (110 mg, 0.29 mmol, yield: 81%) was obtained as white solid.
TLC:PE/EA＝2:1,UV 254nmTLC: PE/EA=2:1, UV 254nm
Rf(Compound 8)＝0.7R f (Compound 8)=0.7
Rf(Compound 9)＝0.6R f (Compound 9)=0.6
8)6-(N-(4-乙基苯基)-N-异丁基氨磺酰基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-8-羧酸甲酯(化合物11)的制备8) 6-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-(tetrahydro-2H-pyran-4-yl)chroman-8- Preparation of methyl carboxylate (compound 11)
Figure PCTCN2017087263-appb-000106
Figure PCTCN2017087263-appb-000106
将化合物9(80mg，0.21mmol，1.0eq)溶解到2mL的吡啶中，加入化合物10(57mg，0.32mmol，1.5eq)后室温搅拌过夜。将20mL的乙酸乙酯加到反应液中，混合液用2N的盐酸水溶液(50mL)洗，分出有机相，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，旋干后柱层析纯化(石油醚：乙酸乙酯＝10：1到5：1)得到白色固体化合物11(70mg，0.13mmol，收率：65％)。Compound 9 (80 mg, 0.21 mmol, 1.0 eq) was dissolved in 2 mL of pyridine. Compound 10 (57 mg, 0.32 mmol, 1.5 eq. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with 2N aqueous hydrochloric acid (50 mL), and the organic phase was separated. The organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate Purification (petroleum ether: ethyl acetate = 10:1 to 5:1) gave Compound 11 (yield: 70 mg, 0.13 mmol, yield: 65%).
TLC:PE/EA＝2:1,UV 254nmTLC: PE/EA=2:1, UV 254nm
Rf(Compound 9)＝0.6R f (Compound 9)=0.6
Rf(Compound 11)＝0.7R f (Compound 11)=0.7
9)N-(4-乙基苯基)-8-(羟基甲基)-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 58的制备9) N-(4-ethylphenyl)-8-(hydroxymethyl)-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6 - Preparation of sulfonamide compound EXP 58
Figure PCTCN2017087263-appb-000107
Figure PCTCN2017087263-appb-000107
将化合物11(50mg，0.097mmol，1.0eq)溶解到3mL的THF中，加入三乙基硼氢化锂(1.0M的THF溶液，389uL，4.0eq)后室温下搅拌5小时。将20mL的乙酸乙酯加到反应液中，混合液用水洗，饱和食盐水洗，无水硫酸钠干燥，旋干后prep-HPLC(流动相：0.1％TFA/乙腈/水)纯化得到白色固体化合物EXP 58(7mg，0.014mmol，收率：15％)。Compound 11 (50 mg, 0.097 mmol, 1.0 eq) was dissolved in 3 mL of THF, and ethyl triethyl borohydride (1.0M in THF, 389 uL, 4.0 eq) was added and stirred at room temperature for 5 hours. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water, brine, dried over anhydrous sodium sulfate and dried EXP 58 (7 mg, 0.014 mmol, yield: 15%).
LC-MS:[M+23]＝510.2LC-MS: [M+23]=510.2
1H NMR(400MHz,CDCl3)δ7.35(s,1H),7.20(s,1H),7.13(d,J＝8.0Hz,2H),6.99(d,J＝8.0Hz,2H),4.73-4.59(m,1H),4.09(d,J＝11.6Hz,2H),3.96-3.85(m,1H),3.49-3.43(m,2H),3.26(d,J＝7.6Hz,2H),2.84-2.72(m,4H),2.64(q,J＝7.2Hz,2H),2.07(d,J＝13.6Hz,1H),1.89(d,J＝10.1Hz,2H),1.78-1.75(m,1H),1.63-1.53(m,3H),1.23(t,J＝7.6Hz,3H),0.90(d,J＝6.6Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.35 (s, 1H), 7.20 (s, 1H), 7.13 (d, J = 8.0Hz, 2H), 6.99 (d, J = 8.0Hz, 2H), 4.73 -4.59 (m, 1H), 4.09 (d, J = 11.6 Hz, 2H), 3.96-3.85 (m, 1H), 3.49-3.43 (m, 2H), 3.26 (d, J = 7.6 Hz, 2H), 2.84-2.72 (m, 4H), 2.64 (q, J = 7.2 Hz, 2H), 2.07 (d, J = 13.6 Hz, 1H), 1.89 (d, J = 10.1 Hz, 2H), 1.78-1.75 (m) , 1H), 1.63-1.53 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H).
实施例59：N-环丁基-N-(2,4-二甲基苯基)-4-羟基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 59的制备 Example 59: N-cyclobutyl-N-(2,4-dimethylphenyl)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)chromanol- Preparation of 6-sulfonamide compound EXP 59
Figure PCTCN2017087263-appb-000108
Figure PCTCN2017087263-appb-000108
参照实施例2的方法，制备了Exp59Referring to the method of Example 2, Exp59 was prepared.
LC-MS:[M+1]＝472.21LC-MS: [M+1]=472.21
1H NMR(400MHz,CDCl3)δ7.75(d,J＝12.8Hz,1H),7.43-7.39(m,1H),7.04(s,1H),6.77(t,J＝8.4Hz,2H),6.34(d,J＝5.6Hz,1H),4.87-4.85(m,1H),4.51-4.36(m,1H),3.99-3.90(m,3H),3.38-3.35(m,2H),2.23-2.20(m,7H),1.95-1.64(m,7H),1.46-1.43(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 12.8 Hz, 1H), 7.43-7.39 (m, 1H), 7.04 (s, 1H), 6.77 (t, J = 8.4 Hz, 2H) , 6.34 (d, J = 5.6 Hz, 1H), 4.87-4.85 (m, 1H), 4.51-4.36 (m, 1H), 3.99-3.90 (m, 3H), 3.38-3.35 (m, 2H), 2.23 -2.20 (m, 7H), 1.95-1.64 (m, 7H), 1.46-1.43 (m, 6H).
实施例60：N-(4-(二甲基氨基)苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 60的制备Example 60: N-(4-(Dimethylamino)phenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman Preparation of -6-sulfonamide compound EXP 60
Figure PCTCN2017087263-appb-000109
Figure PCTCN2017087263-appb-000109
参照实施例2的方法，制备了Exp60Referring to the method of Example 2, Exp60 was prepared.
1H NMR(400MHz,CD3Cl)δ7.44(d,J＝10.0Hz,1H),7.31(s,1H),7.22(d,J＝8.8Hz,2H),7.12(d,J＝8.4Hz,2H),6.82(d,J＝8.8Hz,1H),4.74-4.69(m,1H),4.05(d,J＝11.2Hz,2H),3.95-3.86(m,1H),3.46-3.34(m,6H),3.18-3.13(m,2H),3.12(s,6H),2.31-2.25(m,1H),1.81-1.64(m,2H),1.52-1.42(m,2H),0.87-0.81(m,6H). 1 H NMR (400 MHz, CD 3 Cl) δ 7.44 (d, J = 10.0 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 1H), 4.74 - 4.69 (m, 1H), 4.05 (d, J = 11.2 Hz, 2H), 3.95-3.86 (m, 1H), 3.46-3.34 (m, 6H), 3.18-3.13 (m, 2H), 3.12 (s, 6H), 2.31-2.25 (m, 1H), 1.81-1.64 (m, 2H), 1.52-1.42 (m, 2H), 0.87 -0.81 (m, 6H).
实施例61：N-(环丁基甲基)-N-(4-乙基苯基)-4-羟基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 61的制备 Example 61: N-(cyclobutylmethyl)-N-(4-ethylphenyl)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)chroman-6 - Preparation of sulfonamide compound EXP 61
Figure PCTCN2017087263-appb-000110
Figure PCTCN2017087263-appb-000110
参照实施例2的方法，制备了Exp61Referring to the method of Example 2, Exp61 was prepared.
1H NMR(400MHz,CDCl3)δ7.64(d,J＝1.2Hz,1H),7.31(dd,J＝8.4,2.0Hz,1H),7.04(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),6.74(d,J＝8.8Hz,1H),4.87-4.80(m,1H),4.01-3.98(m,2H),3.96-3.90(m,1H),3.48-3.36(m,4H),2.56(q,J＝7.6Hz,2H),2.29-2.20(m,2H),1.96(br s,2H),1.77-1.68(m,4H),1.65-1.48(m,6H),1.16(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.64 (d, J = 1.2Hz, 1H), 7.31 (dd, J = 8.4,2.0Hz, 1H), 7.04 (d, J = 8.4Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.8 Hz, 1H), 4.87 - 4.80 (m, 1H), 4.01-3.98 (m, 2H), 3.96 - 3.90 (m, 1H), 3.48-3.36 (m, 4H), 2.56 (q, J = 7.6 Hz, 2H), 2.29-2.20 (m, 2H), 1.96 (br s, 2H), 1.77-1.68 (m, 4H), 1.65-1.48 (m, 6H), 1.16 (t, J = 7.6 Hz, 3H).
实施例62：N-(2,4-二氟苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 62的制备Example 62: N-(2,4-Difluorophenyl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6 - Preparation of sulfonamide compound EXP 62
Figure PCTCN2017087263-appb-000111
Figure PCTCN2017087263-appb-000111
参照实施例2的方法，制备了Exp62Referring to the method of Example 2, Exp62 was prepared.
LC-MS:[M+1]＝482.17LC-MS: [M+1] = 482.17
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.36(d,J＝9.2Hz,1H),6.79-6.70(m,4H),4.85-4.83(m,1H),4.01-3.94(m,3H),3.39-3.36(m,2H),3.25-3.22(m,2H),2.31-2.23(m,1H),2.10(s,1H),1.71-1.65(m,3H),1.54-1.37(m,4H),0.85-0.82(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.72 (s, 1H), 7.36 (d, J = 9.2Hz, 1H), 6.79-6.70 (m, 4H), 4.85-4.83 (m, 1H), 4.01- 3.94 (m, 3H), 3.39-3.36 (m, 2H), 3.25-3.22 (m, 2H), 2.31-2.23 (m, 1H), 2.10 (s, 1H), 1.71-1.65 (m, 3H), 1.54-1.37 (m, 4H), 0.85-0.82 (m, 6H).
实施例63：N-(4-(1,1,1,3,3,3-六氟-2-羟基丙-2-基)-2-甲基苯基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)色满-6-磺酰胺化合物EXP 63的制备 Example 63: N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-methylphenyl)-4-hydroxy-N-iso Preparation of Butyl-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide Compound EXP 63
Figure PCTCN2017087263-appb-000112
Figure PCTCN2017087263-appb-000112
参照实施例2的方法，制备了Exp63Referring to the method of Example 2, Exp63 was prepared.
LC-MS:[M+1]＝626.3LC-MS: [M+1]=626.3
实施例64：N-苄基-N-(4-乙基苯基)-4-羟基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 64的制备Example 64: N-Benzyl-N-(4-ethylphenyl)-4-hydroxy-2-(tetrahydro-2H-pyran-4-yl)chroman-6-sulfonamide Preparation of Compound EXP 64
Figure PCTCN2017087263-appb-000113
Figure PCTCN2017087263-appb-000113
参照实施例2的方法，制备了Exp64Referring to the method of Example 2, Exp64 was prepared.
1H NMR(400MHz,CDCl3)δ7.76(d,J＝1.6Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),7.24-7.18(m,5H),7.03(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),6.84(d,J＝8.4Hz,1H),4.95-4.88(m,1H),4.75-4.65(m,2H),4.06-3.98(m,3H),3.48-3.41(m,2H),2.56(q,J＝7.2Hz,2H),2.37-2.31(m,1H),1.91-1.73(m,4H),1.58-1.52(m,2H),1.17(t,J＝7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.76 (d, J = 1.6Hz, 1H), 7.43 (dd, J = 8.4,2.0Hz, 1H), 7.24-7.18 (m, 5H), 7.03 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 4.95-4.88 (m, 1H), 4.75-4.65 (m, 2H), 4.06-3.98 (m, 3H), 3.48-3.41 (m, 2H), 2.56 (q, J = 7.2 Hz, 2H), 2.37-2.31 (m, 1H), 1.91-1.73 (m, 4H), 1.58- 1.52 (m, 2H), 1.17 (t, J = 7.6 Hz, 3H).
实施例65：N-(苯并[b]噻吩-2-基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP 65的制备Example 65: N-(Benzo[b]thiophen-2-yl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)chroman Preparation of -6-sulfonamide compound EXP 65
Figure PCTCN2017087263-appb-000114
Figure PCTCN2017087263-appb-000114
参照实施例2的方法，制备了Exp65Referring to the method of Example 2, Exp65 was prepared.
LC-MS:[M+1]＝502.3LC-MS: [M+1]=502.3
1H NMR(400MHz,CDCl3)δ7.73(d,J＝2.0Hz,1H),7.64-7.59(m,2H),7.38(dd,J＝8.4,2.0Hz,1H),7.29-7.21(m,2H),7.10(s,1H),6.73(d,J＝8.4Hz,1H),4.82-4.78(m,1H),4.01-3.91(m,3H),3.41-3.24(m,4H),2.27-2.22(m,1H),1.84-1.64(m,4H),1.55-1.42(m,3H),1.19(s,1H),0.90-0.88(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 2.0 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.29 - 7.21. m, 2H), 7.10 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.82-4.78 (m, 1H), 4.01-3.91 (m, 3H), 3.41-3.24 (m, 4H) , 2.27-2.22 (m, 1H), 1.84-1.64 (m, 4H), 1.55-1.42 (m, 3H), 1.19 (s, 1H), 0.90-0.88 (m, 6H).
实施例66：N-(4-乙基苯基)-4-羟基-N-异丁基-2-(1-(四氢-2H-吡喃-4-基)乙基)色满-6-磺酰胺化合物EXP 66的制备Example 66: N-(4-ethylphenyl)-4-hydroxy-N-isobutyl-2-(1-(tetrahydro-2H-pyran-4-yl)ethyl)chroman-6 - Preparation of sulfonamide compound EXP 66
Figure PCTCN2017087263-appb-000115
Figure PCTCN2017087263-appb-000115
参照实施例2的方法，制备了Exp66Referring to the method of Example 2, Exp66 was prepared.
LC-MS:[M+H]＝502.3LC-MS: [M+H]=502.3
1H NMR(400MHz,CDCl3)δ7.68(d,J＝1.6Hz,1H),7.33(dd,J＝8.6,2.2Hz,1H),7.13(d,J＝8.2Hz,2H),6.98(dd,J＝8.4,2.1Hz,2H),6.80(dd,J＝8.6,6.8Hz,1H),4.90(br s,1H),4.32(d,J＝13.2Hz,1H),4.01(br s,2H),3.41(t,J＝11.8Hz,2H),3.33-3.20(m,2H),2.64(q,J＝7.6Hz,2H),2.30-2.17(m,1H),1.98-1.90(m,1H),1.89-1.75(m,2H),1.75-1.59(m,3H),1.57-1.47(m,3H),1.23(t,J＝7.6Hz,3H),1.03-0.96(m,3H),0.96-0.89(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 8.6, 2.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.98 (dd, J=8.4, 2.1 Hz, 2H), 6.80 (dd, J=8.6, 6.8 Hz, 1H), 4.90 (br s, 1H), 4.32 (d, J = 13.2 Hz, 1H), 4.01 (br) s, 2H), 3.41 (t, J = 11.8 Hz, 2H), 3.33-3.20 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.30-2.17 (m, 1H), 1.98-1.90 (m, 1H), 1.89-1.75 (m, 2H), 1.75-1.59 (m, 3H), 1.57-1.47 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H), 1.03-0.96 (m , 3H), 0.96-0.89 (m, 6H).
实施例67：6-((6-乙基-3-甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-4-醇化合物EXP67的制备 Example 67: 6-((6-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4 Of -benzoyldihydropyran-4-ol compound EXP67
Figure PCTCN2017087263-appb-000116
Figure PCTCN2017087263-appb-000116
1)3-氯-N-(4-乙基苯基)丙酰胺(化合物3)的制备1) Preparation of 3-chloro-N-(4-ethylphenyl)propanamide (Compound 3)
Figure PCTCN2017087263-appb-000117
Figure PCTCN2017087263-appb-000117
在一个100mL的三口烧瓶中，将化合物1(2.0g，16.5mmol，1.0eq),K2CO3(3.4g，24.7mmol，1.5eq)溶于H2O(40mL)和acetone(20mL)中，氩气保护下在0℃下搅拌30min。加入3-氯丙酰氯(2.7g,21.5mmol,1.3eq)，室温下搅拌16小时。将反应液倒入冰水中淬灭，用布氏漏斗抽滤，固体用水洗涤2次，最后用正己烷洗涤3次。用油泵抽干后得到白色固体化合物3(2.7g，收率：77％)。In a 100 mL three-necked flask, Compound 1 (2.0 g, 16.5 mmol, 1.0 eq), K 2 CO 3 (3.4 g, 24.7 mmol, 1.5 eq) was dissolved in H 2 O (40 mL) and EtOAc (20 mL) Stir at 0 ° C for 30 min under argon protection. 3-Chloropropanoyl chloride (2.7 g, 21.5 mmol, 1.3 eq) was added and stirred at room temperature for 16 h. The reaction solution was poured into ice water and quenched, suction filtered with Buchner funnel, and the solid was washed twice with water and then washed three times with n-hexane. After draining with an oil pump, a white solid compound 3 (2.7 g, yield: 77%) was obtained.
2)6-乙基-3,4-二氢喹啉-2(1H)-酮(化合物4)的制备2) Preparation of 6-ethyl-3,4-dihydroquinolin-2(1H)-one (Compound 4)
Figure PCTCN2017087263-appb-000118
Figure PCTCN2017087263-appb-000118
将化合物3(0.8g，3.8mmol，1.0eq)在120℃下搅拌融化，用氩气保护。然后少量分批加入AlCl3(0.6g，4.5mmol，1.2eq)，在此温下搅拌3h。TLC检测有新点出现。冷却到室温后加水稀释，用EA萃取，无水硫酸钠干燥，旋干过柱(PE/EA＝20:1～5:1)得到化合物4(0.1g，收率：15％)。Compound 3 (0.8 g, 3.8 mmol, 1.0 eq) was stirred and stirred at 120 ° C and protected with argon. Then a small amount of AlCl 3 (0.6 g, 4.5 mmol, 1.2 eq) was added portionwise and stirred at this temperature for 3 h. There are new points in the TLC test. After cooling to room temperature, it was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, and dried over a column (PE/EA=20:1 to 5:1) to give compound 4 (0.1 g, yield: 15%).
TLC:PE/EA＝5:1,UV 254nm TLC: PE/EA=5:1, UV 254nm
Rf(Compound 3)＝0.8R f (Compound 3) = 0.8
Rf(Compound 4)＝0.5R f (Compound 4)=0.5
3)6-乙基-1-(4-甲氧基苄基)-3,4-二氢喹啉-2(1H)-酮(化合物5)的制备3) Preparation of 6-ethyl-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one (Compound 5)
Figure PCTCN2017087263-appb-000119
Figure PCTCN2017087263-appb-000119
将化合物4(0.6g，3.4mmol，1.0eq)溶于DMF(2mL)准备待用，在0℃下将NaH(60％in mineral oil，0.176g，4.4mmol，1.3eq)加入3mL的DMF中，氩气保护下搅拌5min。加入化合物4的DMF溶液后在零度下搅拌30min。加入PMBCl(0.8g，5.1mmol，1.5eq)，然后升到室温并在室温下反应3h，TLC显示反应完毕。将反应液倒入冰水中，用乙酸乙酯萃取，无水Na2SO4干燥，过柱(PE:EA＝25：1～10：1),得到黄色固体化合物5(0.2g，收率：20％)Compound 4 (0.6 g, 3.4 mmol, 1.0 eq) was dissolved in DMF (2 mL) and was taken and taken from NaH (60% in mineral oil, 0.176 g, 4.4 mmol, 1.3 eq) in 3 mL of DMF at 0 °C Stir under argon for 5 min. After the addition of the DMF solution of Compound 4, it was stirred at zero for 30 min. PMBCl (0.8 g, 5.1 mmol, 1.5 eq) was added, then allowed to warm to room temperature and allowed to react at room temperature for 3 h. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over anhydrous Na 2 SO 4 and filtered (PE: EA=25:1 to 10:1) to give compound 5 as a yellow solid (0.2 g, yield: 20%)
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 4)＝0.5R f (Compound 4)=0.5
Rf(Compound 5)＝0.6R f (Compound 5)=0.6
4)6-乙基-1-(4-甲氧基苄基)-3-甲基-3,4-二氢喹啉-2(1H)-酮(化合物6)的制备4) Preparation of 6-ethyl-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 6)
Figure PCTCN2017087263-appb-000120
Figure PCTCN2017087263-appb-000120
将LHMDS(1M/L，0.40mL,1.1eq)加入到THF(2mL)中，氮气保护并在0℃下搅拌5min。加入化合物5(0.1g，0.34mmol，1.0eq)的3mL THF溶液后在0℃下搅拌30min，将反应液冷却至-78℃。加入CH3I(72.3mg，0.51mmol，1.5eq)，使混合物恢复至室温并搅拌过夜。TLC显示有新点出现。加水稀释，用DCM萃取，Na2SO4干燥，过柱(PE:EA＝30:1～10:1)，得到化合物6(68mg，收率：66％)LHMDS (1 M/L, 0.40 mL, 1.1 eq) was taken in THF (2 mL). After addition of a solution of compound 5 (0.1 g, 0.34 mmol, 1.0 eq) in 3 mL of THF, and stirring at 0 ° C for 30 min, the reaction mixture was cooled to -78 °C. CH 3 I (72.3 mg, 0.51 mmol, 1.5 eq) was added and the mixture was taken to room temperature and stirred overnight. The TLC shows that a new point has appeared. Diluted with water, extracted with DCM, dried over Na 2 SO 4 and then passed to a column (PE: EA = 30:1 to 10:1) to give compound 6 (68 mg, yield: 66%)
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 5)＝0.6R f (Compound 5)=0.6
Rf(Compound 6)＝0.8 R f (Compound 6) = 0.8
5)6-乙基-3-甲基-3,4-二氢喹啉-2(1H)-酮(化合物7)的制备5) Preparation of 6-ethyl-3-methyl-3,4-dihydroquinolin-2(1H)-one (Compound 7)
Figure PCTCN2017087263-appb-000121
Figure PCTCN2017087263-appb-000121
将化合物6(0.2g，0.6mmol，1.0eq)溶于TFA(5mL)中，然后在80度下搅拌3h，TLC显示没有原料剩余。加入5mL的饱和Na2CO3水溶液，乙酸乙酯萃取，干燥，浓缩，旋干后得到化合物7(0.1g，收率：87％)。Compound 6 (0.2 g, 0.6 mmol, 1.0 eq) was dissolved in EtOAc (5 mL). 5 mL of a saturated aqueous solution of Na 2 CO 3 was added, and ethyl acetate was evaporated, dried, evaporated, and evaporated to give Compound 7 (0.1 g, yield: 87%).
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 6)＝0.8R f (Compound 6) = 0.8
Rf(Compound 7)＝0.5R f (Compound 7)=0.5
6)6-乙基-3-甲基-1,2,3,4-四氢喹啉(化合物8)的制备6) Preparation of 6-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline (Compound 8)
Figure PCTCN2017087263-appb-000122
Figure PCTCN2017087263-appb-000122
将化合物7(25mg，0.13mmol，1.0eq)溶于THF(2mL)中，降温至零度后加入BH3/THF(1.0M，0.4mL，3.1eq)溶液，然后零度下搅拌30min。将体系升温至80度并搅拌3h，TLC显示没有原料剩余。加入2mL的甲醇和2mL的2N盐酸水溶液，将反应体系调节PH＝7后用EA萃取，有机相用饱和氯化钠洗，无水硫酸钠干燥。浓缩后得到化合物8(18mg，收率：79％)。Compound 7 (25mg, 0.13mmol, 1.0eq) was dissolved in THF (2mL). After cooling to zero was added BH 3 /THF(1.0M,0.4mL,3.1eq) solution, followed by stirring at zero degrees 30min. The system was warmed to 80 degrees and stirred for 3 h, and TLC showed no material remained. 2 mL of methanol and 2 mL of 2N aqueous hydrochloric acid were added, and the reaction system was adjusted to pH = 7 and extracted with EA. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After concentration, Compound 8 (18 mg, yield: 79%) was obtained.
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 7)＝0.5R f (Compound 7)=0.5
Rf(Compound 8)＝0.8R f (Compound 8) = 0.8
7)6-((6-乙基-3-甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-4-酮(化合物10)的制备 7) 6-((6-Ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl) Preparation of benzohydropyran-4-one (Compound 10)
Figure PCTCN2017087263-appb-000123
Figure PCTCN2017087263-appb-000123
将化合物8(30mg，0.17mmol，1.0eq),化合物9(61.5mg,0.19mmol,1.1eq)混合后加入2mL吡啶。室温搅拌2h，TLC显示化合物8反应完全。加入10mL EA，用2N HCl洗反应液。有机相用饱和食盐水洗，无水硫酸钠干燥，旋干后用pre-HPLC(流动相：0.1％三氟乙酸/乙腈/水)纯化得到白色固体化合物10(6mg,收率：7％)Compound 8 (30 mg, 0.17 mmol, 1.0 eq), compound 9 (61.5 mg, 0.19 mmol, 1.1 eq. After stirring at room temperature for 2 h, TLC showed that compound 8 was completely reacted. 10 mL of EA was added and the reaction was washed with 2N HCl. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
LC-MS:[M+1]＝470.3LC-MS: [M+1]=470.3
1H NMR(400MHz,CDCl3)δ8.25-8.23(m,1H),7.66-7.62(m,2H),7.05-6.91(m,2H),6.82(s,1H),4.28(q,J＝7.2Hz,1H),4.14(d,J＝13.2Hz,1H),4.05(d,J＝11.9Hz,2H),3.49-3.37(m,2H),3.12-3.00(m,1H),2.73(d,J＝8.0Hz,2H),2.65-2.51(m,3H),2.19-2.07(m,1H),2.03-1.96(m,1H),1.86(d,J＝14.0Hz,1H),1.81-1.77(m,1H),1.59-1.57(m,1H),1.56-1.52(m,1H),1.31-1.26(m,1H),1.19(t,J＝7.6Hz,3H),0.96(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.25-8.23 (m, 1H), 7.66-7.62 (m, 2H), 7.05-6.91 (m, 2H), 6.82 (s, 1H), 4.28 (q, J = 7.2 Hz, 1H), 4.14 (d, J = 13.2 Hz, 1H), 4.05 (d, J = 11.9 Hz, 2H), 3.49-3.37 (m, 2H), 3.12-3.00 (m, 1H), 2.73 (d, J = 8.0 Hz, 2H), 2.65-2.51 (m, 3H), 2.19-2.07 (m, 1H), 2.03-1.96 (m, 1H), 1.86 (d, J = 14.0 Hz, 1H), 1.81-1.77 (m, 1H), 1.59-1.57 (m, 1H), 1.56-1.52 (m, 1H), 1.31-1.26 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H), 0.96 ( d, J = 6.6 Hz, 3H).
8)6-((6-乙基-3-甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-4-醇化合物EXP67的制备8) 6-((6-ethyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-(tetrahydro-2H-pyran-4-yl) Preparation of benzodihydropyran-4-ol compound EXP67
Figure PCTCN2017087263-appb-000124
Figure PCTCN2017087263-appb-000124
将化合物10(70mg，0.19mmol，1.0eq)溶解到2mL的甲醇中,加入NaBH4(23mg，0.6mmol，3.2eq)后在室温下搅拌2h，TLC显示化合物10反应完全。pre-HPLC(流动相：流动相：0.1％三氟乙酸/乙腈/水)纯化后得到白色固体化合物Exp 67(6mg,收率：9％)After dissolving the compound 10 (70mg, 0.19mmol, 1.0eq) to 2mL of methanol was added NaBH 4 (23mg, 0.6mmol, 3.2eq ) was stirred at room temperature for 2h, TLC showed compound 10 the reaction was complete. Pre-HPLC (mobile phase: mobile phase: 0.1% trifluoroacetic acid / acetonitrile / water) afforded white solid compound Exp 67 (6 mg, yield: 9%)
LC-MS:[M+1]＝472.3LC-MS: [M+1]=472.3
1H NMR(400MHz,CDCl3)δ7.72(d,J＝11.5Hz,1H),7.67-7.64(m,1H),7.42-7.40(m,1H), 7.00(d,J＝8.4Hz,1H),6.81(s,1H),6.76(dd,J＝8.4,1.2Hz,1H),4.87-4.83(m,1H),4.17-4.02(m,3H),3.98-3.94(m,1H),3.45-3.40(m,2H),3.05-2.99(m,1H),2.56(q,J＝7.6Hz,3H),2.33-2.28(m,1H),2.15-2.02(m,1H),1.86(t,J＝11.1Hz,2H),1.79-1.69(m,2H),1.64-1.47(m,3H),1.19(t,J＝7.6Hz,3H),0.99-0.89(m,3H). 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 11.5Hz, 1H), 7.67-7.64 (m, 1H), 7.42-7.40 (m, 1H), 7.00 (d, J = 8.4Hz, 1H ), 6.81 (s, 1H), 6.76 (dd, J = 8.4, 1.2 Hz, 1H), 4.87-4.83 (m, 1H), 4.17-4.02 (m, 3H), 3.98-3.94 (m, 1H), 3.45-3.40 (m, 2H), 3.05-2.99 (m, 1H), 2.56 (q, J = 7.6 Hz, 3H), 2.33-2.28 (m, 1H), 2.15-2.02 (m, 1H), 1.86 ( t, J = 11.1 Hz, 2H), 1.79-1.69 (m, 2H), 1.64-1.47 (m, 3H), 1.19 (t, J = 7.6 Hz, 3H), 0.99-0.89 (m, 3H).
实施例68：4-(环己氧基)-N-(4-乙基苯基)-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP68的制备Example 68: 4-(Cyclohexyloxy)-N-(4-ethylphenyl)-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl)benzodihydropyrrol Preparation of quaternary-6-sulfonamide compound EXP68
Figure PCTCN2017087263-appb-000125
Figure PCTCN2017087263-appb-000125
将化合物1(40mg，0.084mmol，1.0eq)加入2mL DCM中，然后加入化合物2(84mg，0.84mmol，10.0eq)。将反应体系降温至-50℃后加入BF3.Et2O(17mg，0.12mmol，1.4eq)自然升温到室温后搅拌4h。用prep-HPLC(流动相：0.1％三氟乙酸/乙腈/水))纯化得到白色固体化合物Exp 68(6mg，收率：13％)。Compound 1 (40 mg, 0.084 mmol, 1.0 eq) was added to 2 mL DCM then compound 2 (84 mg, 0.84 mmol, 10.0 eq). The reaction system was cooled to -50 ° C, then BF 3. Et 2 O (17 mg, 0.12 mmol, 1.4 eq) was taken and warmed to room temperature and stirred for 4 h. Purification by prep-HPLC (mobile phase: 0.1% trifluoroacetic acid / acetonitrile / water) afforded white solid compound Exp 68 (6 mg, yield: 13%).
LC-MS:[M+1]＝556.3LC-MS: [M+1]=556.3
1H NMR(400MHz,CDCl3)δ7.62-7.31(m,2H),7.13(d,J＝8.0Hz,2H),6.99(d,J＝8.0Hz,2H),6.86-6.75(m,1H),4.63-4.44(m,1H),4.17-3.94(m,3H),3.49-3.44(m,4H),3.36-3.22(m,2H),2.63(q,J＝7.6Hz,2H),2.30-2.07(m,1H),1.89-1.53(m,13H),1.36-1.21(m,6H),0.89(d,J＝5.2Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.62-7.31 (m, 2H), 7.13 (d, J = 8.0Hz, 2H), 6.99 (d, J = 8.0Hz, 2H), 6.86-6.75 (m, 1H), 4.63-4.44 (m, 1H), 4.17-3.94 (m, 3H), 3.49-3.44 (m, 4H), 3.36-3.22 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H) , 2.30-2.07 (m, 1H), 1.89-1.53 (m, 13H), 1.36-1.21 (m, 6H), 0.89 (d, J = 5.2 Hz, 6H).
实施例69：N-(6-氟-2,3-二氢-1H-茚-1-基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP69的制备Example 69: N-(6-Fluoro-2,3-dihydro-1H-indol-1-yl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4- Of benzodihydropyran-6-sulfonamide compound EXP69
Figure PCTCN2017087263-appb-000126
Figure PCTCN2017087263-appb-000126
1)6-氟-N-异丁基-2,3-二氢-1H-茚-1-胺(化合物3)的制备 1) Preparation of 6-fluoro-N-isobutyl-2,3-dihydro-1H-inden-1-amine (Compound 3)
Figure PCTCN2017087263-appb-000127
Figure PCTCN2017087263-appb-000127
将化合物1(1.0g,6.67mmol,1.0eq)溶于无水甲醇(10mL)和无水四氢呋喃(30mL)中。室温下，加入化合物2(1.46g,20.0mmol,3.0eq)和NaBH(CN)3(0.837g,13.3mmol,2.0eq)。65℃加热反应16h，LCMS和TLC监测反应完毕。冷却到室温，用NaHCO3淬灭，浓缩，EA萃取，无水硫酸钠干燥，旋干过柱(石油醚：乙酸乙酯＝20:1～10:1)得到化合物3(730m g,收率:52％)Compound 1 (1.0 g, 6.67 mmol, 1.0 eq) was dissolved in anhydrous methanol (10 mL) and anhydrous tetrahydrofurane (30 mL). Compound 2 (1.46 g, 20.0 mmol, 3.0 eq) and NaBH (CN) 3 (0.837 g, 13.3 mmol, 2.0 eq) were added at room temperature. The reaction was heated at 65 ° C for 16 h, and the reaction was monitored by LCMS and TLC. Cooled to room temperature, quenched with NaHCO 3, concentrated, extracted with EA, dried over anhydrous sodium sulfate, and rotary done by column (petroleum ether: ethyl acetate = 20: 1 ~ 10: 1) to give Compound 3 (730m g, yield :52%)
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 1)＝0.8R f (Compound 1)=0.8
Rf(Compound 2)＝0.4R f (Compound 2)=0.4
2)N-(6-氟-2,3-二氢-1H-茚-1-基)-N-异丁基-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺(化合物5)的制备2) N-(6-Fluoro-2,3-dihydro-1H-indol-1-yl)-N-isobutyl-4-oxo-2-(tetrahydro-2H-pyran-4-yl) Preparation of benzodihydropyran-6-sulfonamide (Compound 5)
Figure PCTCN2017087263-appb-000128
Figure PCTCN2017087263-appb-000128
将化合物4(400mg,1.21mmol,1.0eq)和吡啶(191mg,2.42mmol,2.0eq)在室温下溶于二氯甲烷(20mL)中，加入化合物3(277mg,1.33mmol,1.1eq)。搅拌反应16小时，LCMS显示原料反应完，有产物生成。用稀盐酸(1M)洗涤，二氯甲烷萃取，干燥，浓缩，柱层析，得化合物淡黄色5(400mg,收率：67％)。Compound 4 (400 mg, 1.21 mmol, 1.0 eq) and pyridine (191 mg, 2.42 mmol, 2.0 eq) were dissolved in dichloromethane (20 mL). The reaction was stirred for 16 hours and LCMS showed the starting material was reacted and product was formed. It was washed with dilute hydrochloric acid (1M), EtOAc (EtOAc)
3)N-(6-氟-2,3-二氢-1H-茚-1-基)-4-羟基-N-异丁基-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP69的制备 3) N-(6-Fluoro-2,3-dihydro-1H-indol-1-yl)-4-hydroxy-N-isobutyl-2-(tetrahydro-2H-pyran-4-yl) Preparation of benzodihydropyran-6-sulfonamide compound EXP69
Figure PCTCN2017087263-appb-000129
Figure PCTCN2017087263-appb-000129
将化合物5(150mg，0.333mmol，1.0eq)和NaBH4(15.1mg，0.340mmol，1.2eq)在室温下溶于甲醇(10mL)中，搅拌1小时。TLC点板显示反应完全，有新点生成。加入饱和NH4Cl水溶液(5mL)淬灭反应，浓缩，乙酸乙酯萃取，分液，有机相用无水硫酸钠干燥，过滤，浓缩得粗品。Prep-HPLC(流动相：0.1％TFA/CH3CN/H2O)得白色固体化合物EXP69(50mg，收率：33％)。Compound 5 (150mg, 0.333mmol, 1.0eq) and NaBH 4 (15.1mg, 0.340mmol, 1.2eq ) at room temperature was dissolved in methanol (10 mL) and stirred for 1 hour. The TLC dot plate shows complete reaction and new points are generated. Saturated aqueous NH 4 Cl (5mL) The reaction was quenched, concentrated and extracted with ethyl acetate, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Prep-HPLC (mobile phase: 0.1% TFA / CH 3 CN / H 2 O) as a white solid compound EXP69 (50mg, yield: 33%).
TLC:PE/EA＝1:1,UV 254nmTLC: PE/EA=1:1, UV 254nm
Rf(Compound 5)＝0.40R f (Compound 5)=0.40
Rf(Compound 69)＝0.30R f (Compound 69)=0.30
LC-MS:[M+Na]＝526.2LC-MS: [M+Na]=526.2
1H NMR(400MHz,CDCl3)δ7.98(d,J＝7.6Hz,1H),7.65(d,J＝8.4Hz,1H),7.11(t,J＝8.4Hz,1H),6.90(J＝8.4Hz,2H),6.60(t,J＝8.4Hz,1H),5.41(t,J＝8.4Hz,1H)),4.98-4.97(m,1H),4.11(d,J＝5.2Hz,2H),4.04-4.00(m,1H),3.48(t,J＝8.4Hz,2H),3.35(br s,1H),2.70-2.29(m,4H),2.36-2.34(m,1H),2.27-2.19(m,1H),1.96-1.80(m,4H),1.67-1.56(m,4H),0.82-0.74(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 8.4 Hz, 1H), 6.90 (J) = 8.4 Hz, 2H), 6.60 (t, J = 8.4 Hz, 1H), 5.41 (t, J = 8.4 Hz, 1H)), 4.98 - 4.97 (m, 1H), 4.11 (d, J = 5.2 Hz, 2H), 4.04-4.00 (m, 1H), 3.48 (t, J = 8.4 Hz, 2H), 3.35 (br s, 1H), 2.70-2.29 (m, 4H), 2.36-2.34 (m, 1H), 2.27-2.19 (m, 1H), 1.96-1.80 (m, 4H), 1.67-1.56 (m, 4H), 0.82-0.74 (m, 6H).
实施例70：N-(4-乙基苯基)-4-羟基-N-(氧杂环丁烷-3-基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP70的制备Example 70: N-(4-ethylphenyl)-4-hydroxy-N-(oxetan-3-yl)-2-(tetrahydro-2H-pyran-4-yl)benzo Preparation of dihydropyran-6-sulfonamide compound EXP70
Figure PCTCN2017087263-appb-000130
Figure PCTCN2017087263-appb-000130
1)N-(4-乙基苯基)氧杂环丁烷-3-胺(化合物3)的制备 1) Preparation of N-(4-ethylphenyl)oxetan-3-amine (Compound 3)
Figure PCTCN2017087263-appb-000131
Figure PCTCN2017087263-appb-000131
将化合物1(500mg，4.13mmol，1.0eq)在室温下溶于6mL甲醇中,加入化合物2(298mg，4.13mmol，1.0eq),室温搅拌1小时,在0℃缓慢加入NaBH(OAc)3(876mg，4.13mmol，1.0eq)，室温搅拌半小时。TLC板检测反应完全。将溶剂旋干，拌样，过柱(PE:EA＝30:1),得到化合物3(110mg,收率：10％)。Compound 1 (500 mg, 4.13 mmol, 1.0 eq) was dissolved in 6 mL of MeOH at room temperature. Compound 2 (298 mg, 4.13 mmol, 1.0 eq) was added and stirred at room temperature for 1 hour. NaBH(OAc) 3 was slowly added at 0 °C ( 876 mg, 4.13 mmol, 1.0 eq), stirred at room temperature for half an hour. The TLC plate was tested for complete reaction. The solvent was spun dry, mixed, and passed through a column (PE: EA = 30:1) to give Compound 3 (110 mg, yield: 10%).
TLC:PE/EA＝5:1,UV 254nmTLC: PE/EA=5:1, UV 254nm
Rf(Compound 1)＝0.1R f (Compound 1)=0.1
Rf(Compound 3)＝0.4R f (Compound 3)=0.4
2)N-(4-乙基苯基)-N-(氧杂环丁烷-3-基)-4-氧代-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺(化合物5)的制备2) N-(4-ethylphenyl)-N-(oxetan-3-yl)-4-oxo-2-(tetrahydro-2H-pyran-4-yl)benzoic acid Preparation of Hydropyran-6-sulfonamide (Compound 5)
Figure PCTCN2017087263-appb-000132
Figure PCTCN2017087263-appb-000132
将化合物3(187mg，0.56mmol，1.0eq)在室温下溶于10mL吡啶中,加入化合物4(100mg，0.56mmol，1.0eq),室温搅拌4小时，LC-MS显示大部分是产品，然后旋干溶于DMF去制备纯化，得到化合物KFP-010-149(80mg)。(制备流动相：0.1％TFA/H2O/CH3CN)。Compound 3 (187 mg, 0.56 mmol, 1.0 eq) was dissolved in 10 mL of pyridine at room temperature. Compound 4 (100 mg, 0.56 mmol, 1.0 eq) was added and stirred at room temperature for 4 hr. The product was purified by dryness in DMF to give compound K.s. (Preparation of mobile phase: 0.1% TFA/H 2 O/CH 3 CN).
1H NMR(400MHz,CD3Cl)δ8.04(d,J＝2.4Hz,1H),7.35(dd,J＝8.4,2.4Hz,1H),7.05(d,J＝8.0Hz,2H),6.90(d,J＝8.8Hz,1H),6.76(d,J＝8.4Hz,2H),4.84-4.76(m,1H),4.58-4.51(m,4H),4.28-4.23(m,1H),4.04-3.98(m,2H),3.42-3.33(m,2H),2.69(d,J＝8.4Hz,2H),2.56(q,J＝7.2Hz,2H),1.98-1.92(m,1H),1.58-1.46(m,4H),1.16(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, CD 3 Cl) δ 8.04 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.4, 2.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 4.84 - 4.76 (m, 1H), 4.58 - 4.51 (m, 4H), 4.28 - 4.23 (m, 1H) , 4.04-3.98 (m, 2H), 3.42-3.33 (m, 2H), 2.69 (d, J = 8.4 Hz, 2H), 2.56 (q, J = 7.2 Hz, 2H), 1.98-1.92 (m, 1H) ), 1.58-1.46 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H).
3)N-(4-乙基苯基)-4-羟基-N-(氧杂环丁烷-3-基)-2-(四氢-2H-吡喃-4-基)苯并二氢吡喃-6-磺酰胺化合物EXP70的制备 3) N-(4-ethylphenyl)-4-hydroxy-N-(oxetan-3-yl)-2-(tetrahydro-2H-pyran-4-yl)benzodihydrogen Preparation of pyran-6-sulfonamide compound EXP70
Figure PCTCN2017087263-appb-000133
Figure PCTCN2017087263-appb-000133
将化合物5(70mg，0.15mmol，1.0eq)在室温下溶于10mL甲醇中,加入化合物NaBH4(12mg，0.3mmol，2.0eq),室温搅拌1小时，LC-MS显示大部分是产品，然后旋干溶于DMF去制备纯化，得到化合物EXP 70(28mg)。(制备流动相：0.1％TFA/H2O/CH3CN)。Compound 5 (70mg, 0.15mmol, 1.0eq) was dissolved in 10mL of methanol at room temperature, the compound was added NaBH 4 (12mg, 0.3mmol, 2.0eq ), stirred for RT for 1 h, LC-MS showed that most product, then Purification by spin-drying in DMF gave compound <RTI ID=0.0># </RTI><RTIgt; (Preparation of mobile phase: 0.1% TFA/H 2 O/CH 3 CN).
1H NMR(400MHz,CDCl3)δ7.59(d,J＝1.2Hz,1H),7.27-7.24(m,1H),7.14(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),6.81(d,J＝8.8Hz,1H),4.92-4.81(m,2H),4.67-4.63(m,2H),4.60(d,J＝7.2Hz,2H),4.12-4.05(m,2H),4.05-3.99(m,1H),3.49-3.41(m,2H),2.65(q,J＝7.6Hz,2H),2.40-2.32(m,1H),1.87-1.73(m,2H),1.63-1.50(m,4H),1.25(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 1.2 Hz, 1H), 7.27-7.24 (m, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 4.92-4.81 (m, 2H), 4.67-4.63 (m, 2H), 4.60 (d, J = 7.2 Hz, 2H), 4.12 4.05 (m, 2H), 4.05-3.99 (m, 1H), 3.49-3.41 (m, 2H), 2.65 (q, J = 7.6 Hz, 2H), 2.40-2.32 (m, 1H), 1.87-1.73 ( m, 2H), 1.63-1.50 (m, 4H), 1.25 (t, J = 7.6 Hz, 3H).
实施例71 RORγt抑制剂荧光素酶报告基因实验Example 71 RORγt inhibitor luciferase reporter gene assay
实验材料和仪器：Experimental materials and instruments:
Figure PCTCN2017087263-appb-000134
Figure PCTCN2017087263-appb-000134
Figure PCTCN2017087263-appb-000135
Figure PCTCN2017087263-appb-000135
其中SR1001为RORγt的反向激动剂，作为阳性参照物，其结构为：Among them, SR1001 is an inverse agonist of RORγt, and as a positive reference, its structure is:
Figure PCTCN2017087263-appb-000136
Figure PCTCN2017087263-appb-000136
实验步骤：Experimental steps:
1、第一天细胞种板。293T贴壁细胞加1mL胰酶消化5min左右，用移液器吸取已消化好的细胞，转移至15mL离心管中，1000rpm，5min离心。弃旧培养基，用新鲜培养基重悬细胞并稀释至所需密度。1. The first day of cell seed plate. The 293T adherent cells were digested with 1 mL of trypsin for about 5 minutes. The digested cells were pipetted, transferred to a 15 mL centrifuge tube, and centrifuged at 1000 rpm for 5 min. Discard the old medium, resuspend the cells in fresh medium and dilute to the desired density.
2、细胞计数。按细胞密度1.5万个/孔，配制细胞悬液。种板，每孔100μL细胞。为了防止边缘效应，96孔细胞培养板只种板中间的60个孔，四周36个孔用每孔100μL PBS补齐。37℃，5％CO2培养箱培养细胞。2. Cell count. The cell suspension was prepared at a cell density of 15,000 cells/well. Plate, 100 μL of cells per well. To prevent edge effects, 96-well cell culture plates were only plated with 60 wells in the middle of the plate, and 36 wells were filled with 100 μL of PBS per well. The cells were cultured at 37 ° C in a 5% CO 2 incubator.
3、细胞种板后24小时方做细胞瞬时转染实验。配制瞬转质粒(即Gal4-RORγ-LBD：25ng/孔；PgL4.3-luc：25ng/孔)、转染试剂(脂质体2000浓度是DNA的3倍)。3. Cell transient transfection experiments were performed 24 hours after cell seed plating. A transient plasmid (ie, Gal4-RORγ-LBD: 25 ng/well; PgL4.3-luc: 25 ng/well), transfection reagent (liposome 2000 concentration of 3 times DNA) was prepared.
4、待转染试剂稀释后孵育5min，将转染试剂和质粒混合孵育20min，然后每孔加10μL。瞬时转染5h以上即可加小分子化合物(SR1001或Exp1-Exp34的化合物)。4. After the dilution of the transfection reagent, incubate for 5 min, mix the transfection reagent and plasmid for 20 min, then add 10 μL per well. A small molecule compound (a compound of SR1001 or Exp1-Exp34) can be added by transient transfection for more than 5 hours.
5、根据需要，先将待检测化合物用含10％胎牛血清的DMEM细胞培养基3倍比稀释(100～0.195μM)，然后将细胞培养板中的已有培养基吸出，之后加入已配制好的待检测化合物及新鲜培养基。5. If necessary, firstly dilute the compound to be tested with DMEM cell culture medium containing 10% fetal bovine serum (100-0.195 μM), then aspirate the existing medium in the cell culture plate, and then add it. Good test compound and fresh medium.
6、然后放入37℃，5％CO2培养箱培养细胞。大约24h后将细胞取出，镜下观察细胞生长情况，将细胞培养板拿出细胞间。然后做荧光素酶双报告基因检测实验。6. The cells were then cultured in a 5% CO 2 incubator at 37 °C. After about 24 hours, the cells were taken out, and the growth of the cells was observed under a microscope, and the cell culture plates were taken out of the cells. Then do the luciferase double reporter gene assay.
7、首先将细胞培养基吸弃，然后加入大约100μL PBS洗残留培养基。将母液5×的细胞裂解液稀释成1×后，每孔加20μL，然后振荡大约20min将细胞裂解。7. The cell culture medium was first aspirated, and then about 100 μL of PBS was added to wash the residual medium. After the mother liquor 5× cell lysate was diluted to 1×, 20 μL was added per well, and then the cells were lysed by shaking for about 20 min.
8、将细胞转入白色不透光96孔检测板。然后使用En Spire Alpha 2390均相发光免疫检测系统测试实验结果：加已配置好的萤火虫荧光素底物检测化合物干扰后的细胞活性。8. Transfer the cells to a white opaque 96-well assay plate. The results were then tested using the En Spire Alpha 2390 homogeneous luminescence immunoassay system: the configured firefly luciferin substrate was added to detect cell viability after compound interference.
9、抑制活性的计算：9. Calculation of inhibitory activity:
Figure PCTCN2017087263-appb-000137
Figure PCTCN2017087263-appb-000137
10、实验结果：10. Experimental results:
化合物Compound RORγt活性半数抑制浓度(IC50)RORγt activity half inhibitory concentration (IC 50 )
Exp 1Exp 1 ++++
Exp 2Exp 2 ++++++++
Exp 3Exp 3 ++++++++
Exp 4Exp 4 ++++++
Exp 5Exp 5 ++
Exp 6Exp 6 ++++++
Exp 7Exp 7 ++++
Exp 8Exp 8 ++++++
Exp 9Exp 9 ++++++++
Exp 10Exp 10 ++
Exp 11Exp 11 ++
Exp 12Exp 12 ++++++++
Exp 13Exp 13 ++++++++
Exp 14Exp 14 ++++
Exp 15Exp 15 ++++++++
Exp 16Exp 16 ++++++
Exp 17Exp 17 ++++++++
Exp 18Exp 18 ++++++++
Exp 19Exp 19 ++++++
Exp 20Exp 20 ++++
Exp 21Exp 21 ++++
Exp 22Exp 22 ++
Exp 23Exp 23 ++++++
Exp 24Exp 24 ++++
Exp 25Exp 25 ++++++
Exp 26Exp 26 NANA
Exp 27Exp 27 NANA
Exp 28Exp 28 ++++++++
Exp 29Exp 29 ++++++
Exp 30Exp 30 ++++++
Exp 31Exp 31 ++++
Exp 32Exp 32 ++++++++
Exp 33Exp 33 ++
Exp 34Exp 34 NANA
Exp 35Exp 35 ++++++++
Exp 36Exp 36 ++
Exp 37Exp 37 ++++++
Exp 38Exp 38 ++
Exp 39Exp 39 ++++++++
Exp 40Exp 40 ++++++
Exp 41Exp 41 ++
Exp 42Exp 42 ++++++
Exp 43Exp 43 ++++++
Exp 44Exp 44 ++++++
Exp 45Exp 45 ++++++
Exp 46Exp 46 ++
Exp 47Exp 47 ++++++
Exp 48Exp 48 ++++
Exp 49Exp 49 ++
Exp 50Exp 50 ++++++++
Exp 51Exp 51 ++++++++
Exp 52Exp 52 ++
Exp 53Exp 53 ++++
Exp 54Exp 54 ++++
Exp 55Exp 55 ++++
Exp 56Exp 56 ++++++
Exp 57Exp 57 ++
Exp 58Exp 58 ++++++++
Exp 59Exp 59 ++++++++
Exp 60Exp 60 ++++++++
Exp 61Exp 61 ++++++++
Exp 62Exp 62 ++++++
Exp 63Exp 63 ++++++++
Exp 64Exp 64 ++++++
Exp 65Exp 65 ++++++++
Exp 66Exp 66 ++++++++
Exp 67Exp 67 NANA
Exp 68Exp 68 ++
Exp 69Exp 69 ++++++
Exp 70Exp 70 ++++
SR1001SR1001 2151021510
++++表示IC50<50nM；+++表示IC50范围为50～200nM；++表示IC50范围为200～1000nM；+表示IC50>1000nM；NA表示未检测。++++ means IC 50 <50 nM; +++ means IC 50 range is 50-200 nM; ++ means IC 50 range is 200-1000 nM; + means IC 50 >1000 nM; NA means undetected.
实施例72 RORγt结合实验Example 72 RORγt Binding Experiment
1.试剂和耗材：1. Reagents and consumables:
Figure PCTCN2017087263-appb-000138
Figure PCTCN2017087263-appb-000138
Figure PCTCN2017087263-appb-000139
Figure PCTCN2017087263-appb-000139
2.化合物管理：2. Compound management:
2.1化合物储存：将化合物溶解在DMSO中，制成10mM储液。2.1 Compound Storage: The compound was dissolved in DMSO to make a 10 mM stock solution.
2.2化合物保存：所有溶解在DMSO中的化合物，短期内储存在干燥器中，室温不超过3个月。长期则保存于-20℃。2.2 Compound storage: All compounds dissolved in DMSO were stored in a desiccator for a short period of time, no more than 3 months at room temperature. Store at -20 °C for long periods of time.
2.3准备化合物：2.3 Preparing the compound:
a)所有的化合物用DMSO进行3倍梯度稀释，10个稀释梯度，起始浓度为500uM。a) All compounds were serially diluted 3 fold with DMSO, 10 dilution gradients, starting at 500 uM.
b)阳性对照化合物用DMSO进行3倍梯度稀释，10个稀释梯度，起始浓度为25uM。b) Positive control compounds were diluted 3-fold in DMSO with 10 dilution gradients at a starting concentration of 25 uM.
c)准备50x的阳性对照(25uM的阳性对照化合物)和50x的阴性对照(100％DMSO)。c) A 50x positive control (25 uM positive control compound) and a 50x negative control (100% DMSO) were prepared.
d)将化合物板子封闭并震荡5分钟。d) The compound plate was blocked and shaken for 5 minutes.
3.实验过程：3. Experimental process:
3.1制备反应buffer：将DTT和KF溶解在1x buffer D中。终浓度：DTT 5mM，KF50mM。3.1 Preparation of reaction buffer: DTT and KF were dissolved in 1x buffer D. Final concentration: DTT 5 mM, KF 50 mM.
3.2检测化合物:3.2 Detection of compounds:
a)在buffer中准备2x梯度稀释的化合物(见步骤2.3)。a) Prepare a 2x gradient dilution of the compound in the buffer (see step 2.3).
b)在384孔的反应板子中加入10ul 2x梯度稀释的化合物(见步骤a)。b) Add 10 ul of 2x gradient dilution of compound to a 384 well reaction plate (see step a).
c)用冷冻的buffer制备2x的反应物：RORγ-LBD(40nM),SRC(100nM),anti-GST Eu(1:200)和链酶青霉素-D2(25nM)。c) Prepare 2x reactants with frozen buffer: RORγ-LBD (40 nM), SRC (100 nM), anti-GST Eu (1:200) and streptomycin-D2 (25 nM).
d)在384孔反应板子(见步骤b)中加入10ul 2x反应物(见步骤c)。d) Add 10 ul of 2x reactant to the 384-well reaction plate (see step b) (see step c).
e)将384孔反应板离心，1000g，1min。e) Centrifuge the 384-well reaction plate at 1000 g for 1 min.
f)室温避光孵育1小时。 f) Incubate for 1 hour at room temperature in the dark.
g)检测板子：波长665nm和615nm；仪器：多标记微孔板检测仪。g) Detection plate: wavelengths 665 nm and 615 nm; instrument: multi-label microplate detector.
4.数据分析4. Data analysis
4.1相对比率(RR):计算每个孔的相对比例[(665nm响应值/615nm响应值-空白背景响应值)*1000]。4.1 Relative Ratio (RR): Calculate the relative proportion of each well [(665 nm response / 615 nm response - blank background response) * 1000].
4.2百分抑制率(％Inhibition)的计算如下：4.2 Percent inhibition rate (%Inhibition) is calculated as follows:
Figure PCTCN2017087263-appb-000140
Figure PCTCN2017087263-appb-000140
4.3计算化合物的IC50和量效曲线:通过计算得到的化合物的抑制率和化合物浓度的log值，利用Graphpad 5.0，得到化合物的IC50和量效曲线。4.3 IC 50 of the compound is calculated and dose-response curve: log inhibition rate was calculated by the compounds and compound concentration using Graphpad 5.0, to obtain dose-response curve and IC50 of the compound.
4.4检查报告：4.4 Inspection report:
4.4.1一个实验员完成报告，另一个实验员再次检查报告，以确保数据的准确性。4.4.1 One tester completes the report and the other examiner checks the report again to ensure the accuracy of the data.
4.4.1.1数据从检测仪器中导出并手动进行分析。4.4.1.1 Data is exported from the instrumentation and analyzed manually.
4.4.1.2将比率转化为百分抑制率。利用Graphpad5.0软件和百分抑制率第一次计算出化合物的IC50。4.4.1.2 Convert the ratio to percent inhibition. Graphpad5.0 software using the first and the percent inhibition calculated IC 50 compound.
4.4.1.3用比率计算化合物的IC50，用本次的IC50检查数据的准确性。4.4.1.3 Calculate the IC 50 of the compound using the ratio and check the accuracy of the data with the IC 50 of this time.
4.4.2确定所有化合物的名称是否正确。4.4.2 Determine if the names of all compounds are correct.
4.5数据标准：Z factor>0.5；S/B>3；4.5 data standard: Z factor>0.5; S/B>3;
阳性对照化合物的IC50在历史平均数值的3倍范围内。3 times the historical average in the range of 50 values of the positive control compound IC.
5.数据结果:5. Data results:
化合物Compound RORγt活性半数抑制浓度(IC50)RORγt activity half inhibitory concentration (IC 50 )
Exp 1Exp 1 17nM17nM
Exp 2Exp 2 2.6nM2.6nM
Exp 6Exp 6 25nM25nM
Exp 32Exp 32 6.6nM6.6nM
Exp 35Exp 35 13nM13nM
Exp 39Exp 39 12nM12nM
Exp 50Exp 50 4.1nM4.1nM
Exp 51Exp 51 5.2nM5.2nM
Exp 58Exp 58 1.4nM1.4nM
Exp 60Exp 60 2.7nM2.7nM
Exp 61Exp 61 0.5nM0.5nM
SR1001SR1001 255nM255nM
通过上述实验结果可以看出，式(I)化合物对RORγt有明显的抑制作用，而RORγt在炎性、代谢性和自身免疫性疾病中有非常重要的作用，抑制RORγt将使得这些疾病得到缓解或有效治疗。特别是RORγt抑制剂用于治疗呼吸系统疾病(例如哮喘、COPD)、自身免疫性疾病(如类风湿性关节炎、银屑病、溃疡性结肠炎、克罗恩氏病)的用途被深入研究和认可。 It can be seen from the above experimental results that the compound of formula (I) has a significant inhibitory effect on RORγt, and RORγt plays a very important role in inflammatory, metabolic and autoimmune diseases, and inhibition of RORγt will cause these diseases to be alleviated or Effective treatment. In particular, the use of RORγt inhibitors for the treatment of respiratory diseases (such as asthma, COPD), autoimmune diseases (such as rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease) has been studied in depth. And recognition.

Claims (25)

  1. 结构如式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：A compound of the formula (I): or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
    Figure PCTCN2017087263-appb-100001
    Figure PCTCN2017087263-appb-100001
    其中，among them,
    R1、R2各自独立的选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷基胺基、C1-C6烷氧基、C3-C8环烷基氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 8 a cycloalkyloxy group, or R 1 , R 2 combined into an oxo group;
    R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C8杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C1-C6卤代烷基或C3-C8环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkyl;
    R5选自任意取代的C6-C10芳基、任意取代的-CH2C6-C10芳基、任意取代的C2-C10杂芳基或任意取代的-CH2C2-C10杂芳基，取代基选自氢、卤素、氰基、C1-C6烷基、氨基、C1-C3烷基胺基、C2-C8杂环烷基、C1-C2烷基C4-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基C1-C6卤代烷基或-S(O2)C1-C6烷基；R 5 is selected from an optionally substituted C 6 -C 10 aryl group, an optionally substituted -CH 2 C 6 -C 10 aryl group, an optionally substituted C 2 -C 10 heteroaryl group or an optionally substituted -CH 2 C 2 - a C 10 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, amino, C 1 -C 3 alkylamino, C 2 -C 8 heterocycloalkyl, C 1 - C 2 alkyl C 4 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy C 1 -C 6 haloalkyl or S(O 2 )C 1 -C 6 alkyl;
    R6选自氢、卤素、羟基、氨基、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 6 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
    R3为基团-(CHR7)s-(Y)t-(CHR8)u-R9；R 3 is a group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
    R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
    Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
    R9选自任意取代的C2-C8杂环烷基、任意取代的C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C10杂芳基，取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、羟基取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基或卤素；R 9 is selected from optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl a substituent selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy or halogen;
    m选自0、1、2；m is selected from 0, 1, 2;
    s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
    X选自O、NR10、CR10； X is selected from O, NR 10 , CR 10 ;
    R10选自氢、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基；R 10 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl;
    n选自0、1。n is selected from 0 and 1.
  2. 根据权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，所述R5选自任意取代的以下基团：苯环、吡啶环、苯并噻吩、嘧啶环、哒嗪环、吡嗪环、喹啉、异喹啉、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、呋喃环或噁唑环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基。A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein said R 5 Any one selected from the group consisting of a benzene ring, a pyridine ring, a benzothiophene, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a quinoline, an isoquinoline, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiophene ring, a thiazole ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl.
  3. 根据权利要求2中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于所述R5选自任意取代的苯环、任意取代的苯并噻吩或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基。A compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 2, characterized in that said R 5 is selected From an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl.
  4. 根据权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，所述R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基取代的C1-C6烷基、羟基或卤素。A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein said R 9 Selected from the following groups optionally substituted: oxirane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperidine, Morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O) ( CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy-substituted C 1 -C 6 alkyl, hydroxy or halogen.
  5. 根据权利要求4中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，所述R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基取代的C1-C6烷基、羟基或卤素。A compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 4, wherein said R 3 Is -CH 2 R 9 or -R 9 ; R 9 is selected from the following groups which are optionally substituted: oxirane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran , azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; substituent selected from H, C 1 -C 6 alkyl , C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 Cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy substituted C 1 - C 6 alkyl, hydroxy or halogen.
  6. 根据权利要求5中所述的式(I)化合物或其立体异构体、互变异构体或其药学上 可接受的盐或其溶剂合物或者前药，其特征在于，所述R9选自任意取代的以下基团：氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、羟基取代的C1-C6烷基、羟基或卤素。A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 5, wherein said R 9 Selected from the following groups optionally substituted: oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, morpholine, pyridine; the substituent is selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkane , -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )(CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O)(CH 2 ) m C 2 -C 8 heterocycloalkyl, hydroxy substituted C 1 -C 6 alkyl, hydroxy or halogen.
  7. 根据权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，其中X选自O、NH或CH2。A compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein X is selected from the group consisting of O, NH or CH 2 .
  8. 根据权利要求7中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，其中X为O或NH。A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 7, wherein X is O Or NH.
  9. 根据权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，R1、R2各自独立的选自氢、羟基、卤素、氨基、C1-3烷基、C1-C3烷氧基、C3-C6环烷基氧基或者R1、R2合并为氧代基。A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein R 1 , R 2 independently selected from hydrogen, hydroxy, halogen, amino, C 1-3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyloxy or R 1 , R 2 combined to form oxo base.
  10. 根据权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C6杂环烷基、任意取代的-CH2C3-C6环烷基、任意取代的C6-C10芳基或任意取代的C2-C8杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基或C3-C6环烷基。A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein R 4 is selected from Hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted -CH 2 C 3 -C 6 ring An alkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 8 heteroaryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
  11. 根据权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，R6选自氢、卤素、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；A compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein R 6 is selected from a hydrogen, a halogen, an optionally substituted C 1 -C 6 alkyl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
  12. 权利要求1中所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，其中：A compound of formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, as defined in claim 1, wherein:
    X为O；X is O;
    n为0或1；n is 0 or 1;
    R1、R2各自独立的选自氢、羟基、卤素、氨基、C1-C3烷基、C1-C3烷氧基，或者R1、R2合并为氧代基；R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or R 1 and R 2 are combined into an oxo group;
    R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C6环烷基、任意取代的C4-C8杂环烷基、任意取代的-CH2C3-C8环烷基或任意取代的C6-C10芳基，取代基选自氢、卤素、 羟基、氨基、C1-C3烷基或C3-C8环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 4 -C 8 heterocycloalkyl, optionally substituted -CH 2 C 3 a C 8 cycloalkyl group or an optionally substituted C 6 -C 10 aryl group, the substituent being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl;
    R5选自任意取代的苯环、任意取代的苯并噻吩或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3烷基胺基或-S(O2)C1-C3烷基；R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy , C 1 -C 3 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 3 alkyl;
    R6选自氢、卤素、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基；R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl;
    R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丁烷、环丁烷、四氢呋喃、四氢-2H-吡喃、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C3烷基、卤素取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C3烷基、羟基或卤素。R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the group optionally substituted: oxetane, cyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, Morpholine, pyridine; the substituent is selected from H, C 1 -C 3 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, - S(O 2 )C 1 -C 3 alkyl, hydroxy or halogen.
  13. 结构如式Ia-Ij任一结构所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：A compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, of any of the structures of Formula Ia-Ij:
    Figure PCTCN2017087263-appb-100002
    Figure PCTCN2017087263-appb-100002
    其中：R3、R4、R5、R6和n的定义如权利要求1中所述。Wherein: R 3 , R 4 , R 5 , R 6 and n are as defined in claim 1.
  14. 根据权利要求13所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，其中：The compound according to claim 13 or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein:
    R3选自基团-(CHR7)s-(Y)t-(CHR8)u-R9； R 3 is selected from the group -(CHR 7 ) s -(Y) t -(CHR 8 ) u -R 9 ;
    R7、R8独立选自氢、C1-C6烷基、羟基；R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxy;
    Y选自C1-C6烷基、NH或O；Y is selected from C 1 -C 6 alkyl, NH or O;
    s、t、u独立地选自0、1、2；s, t, u are independently selected from 0, 1, 2;
    R9选自任意取代的以下基团：氧杂环丙烷、氧杂环丁烷、环丁烷、异噁唑、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶、吗啉-3-酮或硫代吗啉1,1-二氧化物；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、-S(O2)(CH2)mC3-C8环烷基、-S(O2)(CH2)m C2-C8杂环烷基、-C(O)C1-C6烷基、-C(O)(CH2)mC3-C8环烷基、-C(O)(CH2)m C2-C8杂环烷基、C2-C10杂芳基、C6-C10芳基、羟基取代的C1-C6烷基、羟基或卤素；R 9 is selected from the group optionally substituted: oxirane, oxetane, cyclobutane, isoxazole, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, pyrrolidine, piperazine a pyridine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; the substituent is selected from H, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, -S(O 2 )(CH 2 ) m C 3 -C 8 cycloalkyl, -S(O 2 )( CH 2 ) m C 2 -C 8 heterocycloalkyl, -C(O)C 1 -C 6 alkyl, -C(O)(CH 2 ) m C 3 -C 8 cycloalkyl, -C(O (CH 2 ) m C 2 -C 8 heterocycloalkyl, C 2 -C 10 heteroaryl, C 6 -C 10 aryl, hydroxy-substituted C 1 -C 6 alkyl, hydroxy or halogen;
    R4选自氢、任意取代的C1-C6烷基、任意取代的C3-C8环烷基、任意取代的C2-C6杂环烷基、任意取代的-CH2C3-C8环烷基、任意取代的C6-C10芳基或任意取代的C2-C8杂芳基，取代基选自氢、卤素、羟基、氨基、C1-C6烷基、C3-C6环烷基或C3-C6环烷基；R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted -CH 2 C 3 a -C 8 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 2 -C 8 heteroaryl group, the substituent group being selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl;
    R5选自任意取代的以下基团：苯环、吡啶环、苯并噻吩、嘧啶环、哒嗪环、吡嗪环、喹啉、异喹啉、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、呋喃环或噁唑环；取代基选自氢、卤素、氰基、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基；R 5 is selected from the group optionally substituted: benzene ring, pyridine ring, benzothiophene, pyrimidine ring, pyridazine ring, pyrazine ring, quinoline, isoquinoline, pyrrole ring, pyrazole ring, imidazole ring, thiophene a ring, a thiazole ring, a furan ring or an oxazole ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 3 alkylamino or -S(O 2 )C 1 -C 6 alkyl;
    R6选自氢、卤素、任意取代的C1-C6烷基，取代基选自氢、卤素、羟基、氨基或C1-C6烷基。R 6 is selected from hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, and the substituent is selected from hydrogen, halogen, hydroxy, amino or C 1 -C 6 alkyl.
  15. 结构如式Ia-Ie、Ih、Ii或Ij所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：A compound of the formula Ia-Ie, Ih, Ii or Ij or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof or a solvate or prodrug thereof:
    Figure PCTCN2017087263-appb-100003
    Figure PCTCN2017087263-appb-100003
    Figure PCTCN2017087263-appb-100004
    Figure PCTCN2017087263-appb-100004
    其中，R3、R4、R5、R6和n的定义如权利要求1所述。Wherein R 3 , R 4 , R 5 , R 6 and n are as defined in claim 1.
  16. 结构如式Ia-Ie或Ij任一所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药：A compound of any of formula Ia-Ie or Ij, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof:
    Figure PCTCN2017087263-appb-100005
    Figure PCTCN2017087263-appb-100005
    其中：R3、R4、R5、R6和n的定义如权利要求14所述。Wherein: R 3 , R 4 , R 5 , R 6 and n are as defined in claim 14.
  17. 根据权利要求16所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，其中：The compound according to claim 16 or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein:
    R5选自任意取代的苯环、任意取代的苯并噻吩或任意取代的吡啶环；取代基选自氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C3烷基胺基或-S(O2)C1-C6烷基；R 5 is selected from an optionally substituted benzene ring, an optionally substituted benzothiophene or an optionally substituted pyridine ring; the substituent is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy a C 1 -C 6 haloalkyl group, a C 1 -C 3 alkylamino group or a -S(O 2 )C 1 -C 6 alkyl group;
    R3为-CH2R9或-R9；R9选自任意取代的以下基团：氧杂环丁烷、环丁烷、四氢呋喃、四氢-2H-吡喃、氮杂环丁烷、吡咯烷、哌啶、吗啉、吡啶；取代基选自H、C1-C6烷基、卤素取代的C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、羟基或卤素。R 3 is -CH 2 R 9 or -R 9 ; R 9 is selected from the group optionally substituted: oxetane, cyclobutane, tetrahydrofuran, tetrahydro-2H-pyran, azetidine, Pyrrolidine, piperidine, morpholine, pyridine; substituents selected from H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 2 -C 8 heterocycloalkyl, C 3 -C 8 -cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
  18. 根据权利要求17所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，其中：R9选自任意取代的四氢-2H-吡喃、任意取代的哌啶、任意取代的氧杂环丁烷或任意取代的环丁烷；取代基选自H、C1-C6烷基、C2-C8杂环烷基、C3-C8环烷基、-S(O2)C1-C6烷基、羟基或卤素。The compound according to claim 17 or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein R 9 is selected from the group consisting of Tetrahydro-2H-pyran, optionally substituted piperidine, optionally substituted oxetane or optionally substituted cyclobutane; substituents selected from H, C 1 -C 6 alkyl, C 2 -C 8 Cycloalkyl, C 3 -C 8 cycloalkyl, -S(O 2 )C 1 -C 6 alkyl, hydroxy or halogen.
  19. 根据权利要求1所述的式(I)化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其特征在于，所述化合物选自： The compound of the formula (I), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to claim 1, wherein the compound is selected from the group consisting of :
    Figure PCTCN2017087263-appb-100006
    Figure PCTCN2017087263-appb-100006
    Figure PCTCN2017087263-appb-100007
    Figure PCTCN2017087263-appb-100007
    Figure PCTCN2017087263-appb-100008
    Figure PCTCN2017087263-appb-100008
  20. 权利要求1所述式(I)化合物的制备方法，其特征在于，所述方法选自路线1、路线2或路线3：Process for the preparation of a compound of formula (I) according to claim 1, characterized in that the process is selected from route 1, route 2 or route 3:
    路线1：Route 1:
    Figure PCTCN2017087263-appb-100009
    Figure PCTCN2017087263-appb-100009
    路线2：Route 2:
    Figure PCTCN2017087263-appb-100010
    Figure PCTCN2017087263-appb-100010
    路线3：Route 3:
    Figure PCTCN2017087263-appb-100011
    Figure PCTCN2017087263-appb-100011
    其中，R1、R2、R3、R4、R5、R6、X和n的定义如权利要求1中所述。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and n are as defined in claim 1.
  21. 一种药物组合物，其特征在于，其包括一种或多种权利要求1-19中任一项所述化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，和一种或多种药学上可接受的辅料。A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a solvate or prodrug thereof, and one or more pharmaceutically acceptable excipients.
  22. 权利要求1-19中任一项所述的化合物或立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，其在用于制备治疗RORγ介导的疾病的药物中的应 用。The compound or stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, according to any one of claims 1 to 19, for use in the preparation of a therapeutic RORγ-mediated The disease of the drug should use.
  23. 根据权利要求22所述的应用，其特征在于所述疾病为炎性、代谢性或自身免疫性疾病。The use according to claim 22, characterized in that the disease is an inflammatory, metabolic or autoimmune disease.
  24. 权利要求23所述的应用，其特征在于所述炎性、代谢性或自身免疫性疾病为哮喘、慢性阻塞性肺病、支气管炎、过敏性鼻炎、异位性皮肤炎、囊性纤维化、肺同种异体移植排斥、多发性硬化症、类风湿性关节炎、青少年类风湿性关节炎、骨关节炎、强直性脊柱炎、系统性红斑狼疮、银屑病、桥本氏病、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、克罗恩氏病、炎性肠病、炎性肠综合征、斯耶格伦氏综合征、视神经炎、I型糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合征、银屑病关节炎、格雷氏病或巩膜炎。The use according to claim 23, characterized in that the inflammatory, metabolic or autoimmune diseases are asthma, chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung Allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, Autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, inflammatory bowel syndrome, Sjogren's syndrome, optic neuritis, type I diabetes, optic neuromyelitis , myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriatic arthritis, Gracies or scleritis.
  25. 如权利要求24所述的应用，其特征在于，所述疾病为哮喘、类风湿性关节炎、银屑病、溃疡性结肠炎或克罗恩氏病。 The use according to claim 24, wherein the disease is asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or Crohn's disease.
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