Bicyclic ring-containing compound that is TYK2 inhibitor (variants), pharmaceutical composition containing it, their use, and treatment method

Abstract

FIELD: chemical industry.SUBSTANCE: invention relates to a compound of formula I, wherein X is selected from the group consisting of N and CH; each R1 is independently selected from halogen; q is 0; each R2 is independently selected from the group consisting of halogen, hydroxy, amino, cyano and nitro; n is 0; each of T1, T2, T3, T4 and T5 is independently selected from the group consisting of CH and N, with the proviso that at least one of them is selected from CH; ring A is selected from 4-6-membered heterocyclyl and 5-6-membered heteroaryl; each R3 is independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, C1-8alkyl and C3cycloalkyl, where C1-8alkyl is optionally substituted with one or more Ra; m is selected from the group consisting of 0, 1, 2 and 3; each Ra is halogen; wherein the heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from N and O. The invention also relates to a compound selected from the group of compounds indicated in the claims. The invention also relates to a pharmaceutical composition for inhibiting TYK2, comprising an effective amount of a compound of formula I or a compound selected from the group of compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; to the use of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament intended for use in the treatment of a TYK2-associated disease; and to a method of treating a TYK2-associated disease comprising administering to a mammal in need of treatment a therapeutically or prophylactically effective amount of a compound of formula I or a compound selected from the group of compounds, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.EFFECT: compounds exhibiting inhibitory activity against TYK2.22 cl, 9 tbl, 66 ex

Description

[0001] CROSS-REFERENCE NATIONAL APPLICATIONS

[0002] This application claims the benefit and priority of Chinese Patent Application No. 202110165856.4 filed with the National Intellectual Property Administration of the People's Republic of China on February 6, 2021, Chinese Patent Application No. 202110935764.X filed with the National Intellectual Property Administration of the People's Republic of China on August 16, 2021, Chinese Patent Application No. 202111063960.9 filed with the National Intellectual Property Administration of the People's Republic of China on September 10, 2021, and Chinese Patent Application No. 202210056272.8 filed with the National Intellectual Property Administration of the People's Republic of China on January 18, 2022, the contents of each of which are hereby incorporated by reference in their entirety.

[0003] FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0004] The present invention relates to the field of pharmaceutical chemistry. It provides a bicyclic ring-containing compound that is a TYK2 inhibitor, a method for producing the same, and its use in the preparation of a medicinal product for use in the treatment or prevention of TYK2-related diseases.

[0005] TECHNICAL LEVEL

[0006] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to be critical in regulating downstream signaling cascades from the IL-12, IL-23, and type I interferon receptors in both mice and humans. TYK2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, which is an important signal leading to the dimerization of STAT proteins and the transcription of STAT-dependent proinflammatory genes. TYK2-deficient mice serve as experimental models that are susceptible to colitis, psoriasis, and multiple sclerosis, demonstrating the importance of TYK2-mediated signaling in autoimmune reactions and related disorders. In humans, individuals who express an inactive variant of TYK2 are protected from the effects of multiple sclerosis and potentially other autoimmune disorders.

[0007] Given that disorders that may benefit from therapies involving cytokine and / or interferon modulation, TYK2 inhibitor compounds that are capable of modulating cytokines and / or interferons such as IL-12, IL-23 and / or IFNα, as well as methods of using such compounds, may provide significant therapeutic effects for numerous patients in need thereof.

[0008] SUMMARY OF THE INVENTION

[0009] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0010] ,

[0011] where

[0012] X is selected from the group consisting of N and CH;

[0013] each R 1 independently selected from halogen;

[0014] q is selected from the group consisting of 0, 1 and 2;

[0015] each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0016] n is selected from the group consisting of 0, 1 and 2;

[0017] each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH;

[0018] Ring A is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl;

[0019] each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-8 alkyl and C 1-8 alkoxy, where C 1-8 alkyl or C 1-8 alkoxy optionally substituted by one or more R a ;

[0020] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0021] each R a independently selected from the group consisting of halogen, hydroxy, amino, and cyano.

[0022] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0023] ,

[0024] where

[0025] X is selected from the group consisting of N and CH;

[0026] each R 1 independently selected from halogen;

[0027] q is selected from the group consisting of 0, 1, and 2;

[0028] each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0029] n is selected from the group consisting of 0, 1 and 2;

[0030] each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH;

[0031] Ring A is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl;

[0032] each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-8 alkyl, C 3-10cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C 6-10 aryl and C 1-8 alkoxy, where C 1-8 alkyl, C 3-10 cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C 6-10 aryl or C 1-8 alkoxy optionally substituted by one or more R a ;

[0033] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0034] each R a independently selected from the group consisting of halogen, hydroxy, amino, and cyano.

[0035] In another aspect, the present invention further provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof described herein above. In some embodiments, the pharmaceutical composition disclosed herein further comprises a pharmaceutically acceptable excipient.

[0036] In another aspect, the present invention further provides a method for treating or preventing various diseases associated with TYK2, comprising administering to a mammal, preferably a human, in need of treatment, a therapeutically or prophylactically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition based on it, described herein above.

[0037] In another aspect, the present invention further provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein above, in the preparation of a medicament for use in the treatment or prevention of various diseases associated with TYK2.

[0038] In another aspect, the present invention further provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition based on it, described herein above, in the treatment or prevention of various diseases associated with TYK2.

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0041] ,

[0042] where

[0043] X is selected from the group consisting of N and CH;

[0044] each R 1 independently selected from halogen;

[0045] q is selected from the group consisting of 0, 1, and 2;

[0046] each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0047] n is selected from the group consisting of 0, 1 and 2;

[0048] each of T 1 , T 2 , T 3 , T 4 and T5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH;

[0049] Ring A is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl;

[0050] each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-8 alkyl and C 1-8 alkoxy, where C 1-8 alkyl or C 1-8 alkoxy optionally substituted by one or more R a ;

[0051] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0052] each R a independently selected from the group consisting of halogen, hydroxy, amino, and cyano.

[0053] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0054] ,

[0055] where

[0056] X is selected from the group consisting of N and CH;

[0057] every R 1independently selected from halogen;

[0058] q is selected from the group consisting of 0, 1, and 2;

[0059] every R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0060] n is selected from the group consisting of 0, 1 and 2;

[0061] each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH;

[0062] Ring A is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl;

[0063] each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-8 alkyl, C 3-10 cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C 6-10 aryl and C 1-8 alkoxy, where C 1-8 alkyl, C 3-10cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C 6-10 aryl or C 1-8 alkoxy optionally substituted by one or more R a ;

[0064] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0065] each R a independently selected from the group consisting of halogen, hydroxy, amino, and cyano.

[0066] In some embodiments, ring A is selected from the group consisting of C 5-10 cycloalkyl, C 6-10 aryl, 3-10-membered heterocycloalkenyl and 5-10-membered heteroaryl, provided that the structural unit does not represent ;

[0067] as an alternative selected from the group consisting of pyrrolidinyl, 3-hydroxypyrrolidin-1-yl-, 3-oxopyrrolidin-1-yl-, 3-methyl-2-oxopyrrolidin-1-yl-, 4,4-dimethyl-2-oxopyrrolidin-1-yl-, 3,3-dimethyl-2-oxopyrrolidin-1-yl-, oxetanyl, azetidinyl, 3-oxoazetidin-1-yl- and 3-hydroxyazetidin-1-yl-.

[0068] In some embodiments, ring A is selected from the group consisting of C 5-6 cycloalkyl, C 6-10 aryl, 3-8-membered heterocycloalkenyl and 5-8-membered heteroaryl, provided that the structural unit does not represent ;

[0069] as an alternative to a structural unit selected from the group consisting of , , , , , , , , And .

[0070] In some embodiments, ring A is selected from the group consisting of C 5-6 cycloalkyl, C 6-10 aryl, 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl, provided that the structural unit does not represent ;

[0071] as an alternative to a structural unit selected from the group consisting of , , , , , , , , And .

[0072] In some embodiments, ring A is selected from the group consisting of 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, provided that the structural unit does not represent ;

[0073] as an alternative structural unit selected from the group consisting of , , , , , , , , And .

[0074] In some embodiments, the structural unit does not represent , , , , , , , , , or .

[0075] In some embodiments, X is N. In some embodiments, X is CH.

[0076] In some embodiments, each R 1 is independently selected from the group consisting of fluorine and chlorine. In some embodiments, each R 1 independently represents fluorine.

[0077] In some embodiments, q is selected from the group consisting of 0 and 1. In some embodiments, q is 0.

[0078] In some embodiments, q is 1, and R 1 is fluorine.

[0079] In some embodiments, each R 2 is independently selected from the group consisting of fluorine, chlorine, and bromine. In some embodiments, each R 2 is independently selected from the group consisting of fluorine and chlorine. In some embodiments, each R 2 independently represents fluorine.

[0080] In some embodiments, n is selected from the group consisting of 0 and 1. In some embodiments, n is 0.

[0081] In some embodiments, each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein three of them are selected from N and two of them are selected from CH.

[0082] In some embodiments, each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein two of them are selected from N and three of them are selected from CH.

[0083] In some embodiments, both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0084] In some embodiments, each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein one of them is selected from N and four of them are selected from CH.

[0085] In some embodiments, T 1 , T 3 and T5 selected from N, and T 2 and T 4 selected from CH.

[0086] In some embodiments, T 1 and T 3 selected from N, and T 2 , T 4 and T 5 selected from CH.

[0087] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH.

[0088] In some embodiments, T 2 and T 4 selected from N, and T 1 , T 3 and T 5 selected from CH.

[0089] In some embodiments, T 1 and T 2 selected from N, and T 3 , T 4 and T 5 selected from CH.

[0090] In some embodiments, T 2 and T 3 selected from N, and T 1 , T 4 and T 5 selected from CH.

[0091] In some embodiments, T 1 and T 4 selected from N, and T 2 , T3 and T 5 selected from CH.

[0092] In some embodiments, T 1 selected from N, and T 2 , T 3 , T 4 and T 5 selected from CH.

[0093] In some embodiments, T 2 selected from N, and T 1 , T 3 , T 4 and T 5 selected from CH.

[0094] In some embodiments, T 3 selected from N, and T 1 , T 2 , T 4 and T 5 selected from CH.

[0095] In some embodiments, ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl and 5-8-membered heteroaryl.

[0096] In some embodiments, ring A is selected from the group consisting of C 3-6 cycloalkyl, 4-6-membered heterocyclyl, C 6-10 aryl and 5-6-membered heteroaryl.

[0097] In some embodiments, ring A is selected from the group consisting of C 3-6 cycloalkyl, 4-6-membered heterocyclyl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, C 6-10 aryl and 5-6-membered heteroaryl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0098] In some embodiments, ring A is selected from the group consisting of C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, 3-8-membered heterocycloalkenyl, C 6-10 aryl and 5-8-membered heteroaryl.

[0099] In some embodiments, ring A is selected from the group consisting of C 3-8 cycloalkyl, 4-6-membered heterocycloalkyl, 4-6-membered heterocycloalkenyl, C 6-10 aryl and 5-8-membered heteroaryl.

[0100] In some embodiments, ring A is selected from the group consisting of C 3-6cycloalkyl, 4-6-membered heterocycloalkyl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, 4-6-membered heterocycloalkenyl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, C 6-10 aryl and 5-6-membered heteroaryl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0101] In some embodiments, ring A is selected from the group consisting of 4-6-membered heterocycloalkyl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, 4-6-membered heterocycloalkenyl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, and 5-6-membered heteroaryl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0102] In some embodiments, ring A is selected from the group consisting of 3-8-membered heterocycloalkenyl and 5-8-membered heteroaryl.

[0103] In some embodiments, ring A is selected from the group consisting of 4-6-membered heterocycloalkenyl and 5-8-membered heteroaryl.

[0104] In some embodiments, ring A is selected from the group consisting of 4-6-membered heterocycloalkenyl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, and 5-6-membered heteroaryl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0105] In some embodiments, ring A is selected from a 5-6 membered heteroaryl containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0106] In some embodiments, ring A is selected from a 5-membered heteroaryl containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S.

[0107] In some embodiments, ring A is selected from a 5-membered heteroaryl containing 1, 2, or 3 atoms selected from the group consisting of N and O.

[0108] In some embodiments, ring A is selected from a 6-membered heteroaryl containing 1, 2, or 3 atoms selected from the group consisting of N and O.

[0109] In some embodiments, ring A is selected from a 5-membered heteroaryl containing 1, 2, or 3 atoms selected from N.

[0110] In some embodiments, ring A is selected from 6-membered heteroaryl containing 1, 2, or 3 atoms selected from N.

[0111] In some embodiments, ring A is selected from a 5-membered heteroaryl containing 1 or 2 atoms selected from N.

[0112] In some embodiments, ring A is selected from 6-membered heteroaryl containing 1 or 2 atoms selected from N.

[0113] In some embodiments, ring A is selected from a 5-membered heteroaryl containing 2 nitrogen atoms.

[0114] In some embodiments, ring A is selected from a 6-membered heteroaryl containing 2 nitrogen atoms.

[0115] In some embodiments, ring A is selected from the group consisting of oxetanyl, azetidinyl, morpholinyl, dioxanyl, dihydropyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, tetrahydropyrrolyl, triazolyl, tetrazolyl, pyrazolyl, furanyl, thienyl, dihydropyrimidinyl, oxazolyl, isoxazolyl and imidazolyl.

[0116] In some embodiments, ring A is selected from the group consisting of dihydropyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, tetrazolyl, pyrazolyl, furanyl, thienyl, dihydropyrimidinyl, oxazolyl, isoxazolyl, and imidazolyl.

[0117] In some embodiments, ring A is selected from the group consisting of tetrazolyl, pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, and imidazolyl.

[0118] In some embodiments, ring A is selected from the group consisting of tetrazolyl, pyrazolyl, and imidazolyl.

[0119] In some embodiments, ring A is selected from pyrazolyl.

[0120] In some embodiments, ring A is selected from the group consisting of C 5-10 cycloalkyl, C 6-10 aryl, 4-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-10-membered heteroaryl, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0121] In some embodiments, ring A is selected from the group consisting of C 5-6 cycloalkyl, C 6-10 aryl, 4-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0122] In some embodiments, ring A is selected from the group consisting of 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0123] In some embodiments, ring A is selected from the group consisting of dihydropyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, furanyl, thienyl, dihydropyrimidinyl, oxazolyl, isoxazolyl, and imidazolyl, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0124] In some embodiments, ring A is selected from the group consisting of triazolyl, tetrazolyl, pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, and imidazolyl, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0125] In some embodiments, ring A is selected from the group consisting of triazolyl, tetrazolyl, pyrazolyl, and imidazolyl, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N.

[0126] In some embodiments, T 1 and T 5selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from the group consisting of 4-6-membered heterocycloalkenyl and 5-6-membered heteroaryl.

[0127] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from the group consisting of 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl.

[0128] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from 5-6-membered heteroaryl.

[0129] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from 6-membered heteroaryl.

[0130] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4selected from CH; ring A is selected from 6-membered heteroaryl containing 1 or 2 nitrogen atoms.

[0131] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from 6-membered heteroaryl containing 2 nitrogen atoms.

[0132] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from 5-membered heteroaryl.

[0133] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from 5-membered heteroaryl containing 1 or 2 nitrogen atoms.

[0134] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; ring A is selected from 5-membered heteroaryl containing 2 nitrogen atoms.

[0135] In some embodiments, X is selected from N; ring A is selected from the group consisting of 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl.

[0136] In some embodiments, X is selected from N; ring A is selected from the group consisting of 4-6-membered heterocycloalkenyl and 5-6-membered heteroaryl.

[0137] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N.

[0138] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 are selected from CH; X is selected from N; ring A is selected from the group consisting of 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl.

[0139] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4are selected from CH; X is selected from N; ring A is selected from the group consisting of 4-6-membered heterocycloalkenyl and 5-6-membered heteroaryl.

[0140] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N; ring A is selected from 5-6-membered heteroaryl.

[0141] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N; ring A is selected from 6-membered heteroaryl.

[0142] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N; ring A is selected from 6-membered heteroaryl containing 1 or 2 nitrogen atoms.

[0143] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4selected from CH; X is selected from N; ring A is selected from 6-membered heteroaryl containing 2 nitrogen atoms.

[0144] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N; ring A is selected from 5-membered heteroaryl.

[0145] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N; ring A is selected from 5-membered heteroaryl containing 1 or 2 nitrogen atoms.

[0146] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; X is selected from N; ring A is selected from 5-membered heteroaryl containing 2 nitrogen atoms.

[0147] In some embodiments, T 1 and T 5 selected from N, and T 2 , T 3 and T 4selected from CH; X is selected from N; ring A is selected from pyrazolyl

[0148] In some other embodiments, ring A is selected from the group consisting of oxetanyl, azetidinyl, morpholinyl, dihydropyridinyl, pyridinyl, pyrimidinyl, tetrahydropyrrolyl, triazolyl, pyrazolyl, furanyl, dihydropyrimidinyl, isoxazolyl, and imidazolyl.

[0149] In some other embodiments, ring A is selected from the group consisting of oxetanyl, morpholinyl, dihydropyridinyl, pyridinyl, pyrimidinyl, tetrahydropyrrolyl, triazolyl, pyrazolyl, furanyl, dihydropyrimidinyl, isoxazolyl, and imidazolyl.

[0150] In some embodiments, ring A is selected from the group consisting of , , , , , , , , , , , , , , , , , And .

[0151] In some embodiments, ring A is selected from the group consisting of , , , , , , , , , , , , , And .

[0152] In some embodiments, ring A is selected from the group consisting of , , , , , , And .

[0153] In some embodiments, ring A is selected from the group consisting of , , , , , And .

[0154] In some embodiments, ring A is selected from the group consisting of , , , And .

[0155] In some embodiments, ring A is selected from .

[0156] In some other embodiments, ring A is selected from the group consisting of 4-6-membered heterocycloalkyl containing 1 or 2 atoms selected from the group consisting of N and O, 4-6-membered heterocycloalkenyl containing 1 or 2 atoms selected from N, and 6-membered heteroaryl containing 1 or 2 atoms selected from N.

[0157] In some other embodiments, ring A is selected from the group consisting of 4-6 membered heterocyclyl containing 1 or 2 atoms selected from the group consisting of N and O, and 6 membered heteroaryl containing 1 or 2 atoms selected from N.

[0158] In some other embodiments, ring A is selected from the group consisting of oxetanyl, morpholinyl, 1,2-dihydropyridinyl, pyridinyl, and pyrimidinyl.

[0159] In some other embodiments, ring A is selected from the group consisting of , , , And .

[0160] In some embodiments, m is selected from the group consisting of 0, 1, 2, 3, and 4. In some embodiments, m is selected from the group consisting of 0, 1, 2, and 3. In some embodiments, m is selected from the group consisting of 0, 1, and 2.

[0161] In some embodiments, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C 6-10 aryl and C 1-6 alkoxy, where C 1-6 alkyl, C 3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C 6-10 aryl or C 1-6 alkoxy optionally substituted by one or more R a .

[0162] In some embodiments, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-4 alkyl, C 3-6cycloalkyl, 3-6 membered heterocycloalkyl and C 1-4 alkoxy, where C 1-4 alkyl, C 3-6 cycloalkyl, 3-6-membered heterocycloalkyl or C 1-4 alkoxy optionally substituted by one or more R a .

[0163] In some embodiments, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-3 alkyl, C 3-4 cycloalkyl and C 1-3 alkoxy, where C 1-3 alkyl, C 3-4 cycloalkyl or C 1-3 alkoxy optionally substituted by one or more R a .

[0164] In some embodiments, each R 3 independently selected from the group consisting of =O, fluoro, chlorine, hydroxy, amino, cyano, cyclopropyl and C 1-3 alkyl optionally substituted by one or more fluorine atoms.

[0165] In some embodiments, each R 3independently selected from the group consisting of =O, fluoro, hydroxy, amino, cyano, methyl, trifluoromethyl, and cyclopropyl.

[0166] In some embodiments, each R 3 independently selected from the group consisting of =O, fluorine, chlorine, amino, cyano, cyclopropyl and C 1-3 alkyl optionally substituted by one or more fluorine atoms.

[0167] In some embodiments, each R 3 independently selected from the group consisting of =O, fluoro, amino, cyano, methyl, trifluoromethyl, and cyclopropyl.

[0168] In some embodiments, each R 3 independently selected from the group consisting of cyano, cyclopropyl and C 1-3 alkyl optionally substituted by one or more fluorine atoms.

[0169] In some embodiments, each R 3 independently selected from the group consisting of cyano, methyl, trifluoromethyl and cyclopropyl.

[0170] In some other embodiments, each R 3independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-8 alkyl and C 1-8 alkoxy, where C 1-8 alkyl or C 1-8 alkoxy optionally substituted by one or more R a .

[0171] In some other embodiments, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-6 alkyl and C 1-6 alkoxy, where C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more R a .

[0172] In some other embodiments, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-3 alkyl and C 1-3 alkoxy, where C 1-3 alkyl or C 1-3 alkoxy optionally substituted by one or more R a .

[0173] In some embodiments, each R 3independently selected from the group consisting of =O, fluorine, chlorine, amino, cyano, and C 1-3 alkyl optionally substituted by one or more fluorine atoms.

[0174] In some embodiments, each R 3 independently selected from the group consisting of =O, fluoro, amino, cyano, methyl, and trifluoromethyl.

[0175] In some other embodiments, each R 3 independently selected from the group consisting of =O, fluorine, chlorine, bromine, and C 1-3 alkyl, where C 1-3 alkyl optionally substituted with one or more R a .

[0176] In some other embodiments, each R 3 independently selected from the group consisting of =O, fluorine, and methyl, wherein methyl is optionally substituted with one or more fluorine atoms.

[0177] In some embodiments, each R a is independently selected from the group consisting of halogen and cyano. In some embodiments, each R ais independently selected from the group consisting of fluorine, chlorine, and bromine. In some embodiments, each R a independently represents fluorine.

[0178] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , And .

[0179] In some embodiments, the structural unit selected from the group consisting of , , , , , , , And .

[0180] In some embodiments, the structural unit selected from the group consisting of , , And .

[0181] In some embodiments, the structural unit selected from the group consisting of , , , And .

[0182] In some embodiments, the structural unit selected from the group consisting of , And .

[0183] In some embodiments, the structural unit selected from .

[0184] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , And .

[0185] In some other embodiments, the structural unit selected from the group consisting of , , , And .

[0186] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , And .

[0187] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , And .

[0188] In some embodiments, the structural unit selected from the group consisting of , , , , , , And .

[0189] In some embodiments, the structural unit selected from the group consisting of , , , , , And .

[0190] In some embodiments, the structural unit selected from the group consisting of , , , And .

[0191] In some embodiments, the structural unit selected from .

[0192] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , And .

[0193] In some other embodiments, the structural unit selected from the group consisting of , , , And .

[0194] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0195] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0196] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , And .

[0197] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , And .

[0198] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , And .

[0199] In some embodiments, the structural unit selected from the group consisting of , And .

[0200] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0201] In some other embodiments, the structural unit selected from the group consisting of , , , , , , And .

[0202] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0203] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0204] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , And .

[0205] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , And .

[0206] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , And .

[0207] In some embodiments, the structural unit selected from the group consisting of , And .

[0208] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0209] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , And .

[0210] In some embodiments, the structural unit does not represent , , , , , , , , , , , or .

[0211] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , And .

[0212] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , And .

[0213] In some embodiments, the structural unit selected from the group consisting of , , , , , , And .

[0214] In some embodiments, the structural unit selected from the group consisting of , , , , , And .

[0215] In some embodiments, the structural unit selected from the group consisting of , , , And .

[0216] In some embodiments, the structural unit selected from .

[0217] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , And .

[0218] In some other embodiments, the structural unit selected from the group consisting of , , , And .

[0219] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , And .

[0220] In some embodiments, the structural unit selected from .

[0221] In some other embodiments, the structural unit selected from the group consisting of , , , , , , And .

[0222] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , And .

[0223] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , And .

[0224] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , And .

[0225] In some embodiments, the structural unit selected from the group consisting of , , , , , , And .

[0226] In some embodiments, the structural unit selected from the group consisting of , , , , , , , And .

[0227] In some embodiments, the structural unit selected from the group consisting of , , , , , And .

[0228] In some embodiments, the structural unit selected from .

[0229] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , And .

[0230] In some other embodiments, the structural unit selected from the group consisting of , , , And .

[0231] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , And .

[0232] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , And .

[0233] In some embodiments, the structural unit selected from the group consisting of , , , , , , , And .

[0234] In some embodiments, the structural unit selected from the group consisting of , , , , , And .

[0235] In some embodiments, the structural unit selected from the group consisting of , , , And .

[0236] In some embodiments, the structural unit selected from .

[0237] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , And .

[0238] In some other embodiments, the structural unit selected from the group consisting of , , , And .

[0239] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0240] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0241] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , And .

[0242] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , And .

[0243] In some embodiments, the structural unit selected from the group consisting of , , , , , , , And .

[0244] In some embodiments, the structural unit selected from the group consisting of , And .

[0245] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0246] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , And .

[0247] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0248] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0249] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , And .

[0250] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , And .

[0251] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , And .

[0252] In some embodiments, the structural unit selected from the group consisting of , , , , , , , , , , And .

[0253] In some embodiments, the structural unit selected from the group consisting of , And .

[0254] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0255] In some other embodiments, the structural unit selected from the group consisting of , , , , , , , , , , And .

[0256] In a further aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0257] ,

[0258] where

[0259] X is selected from the group consisting of N and CH;

[0260] each R 1 independently selected from halogen;

[0261] q is selected from the group consisting of 0, 1, and 2;

[0262] each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0263] n is selected from the group consisting of 0, 1 and 2;

[0264] each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH, and both T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from N;

[0265] ring A is selected from the group consisting of C 6-10aryl, 3-8-membered heterocycloalkenyl and 5-8-membered heteroaryl, wherein the 5-8-membered heteroaryl is selected from 5-8-membered heteroaryl containing 1 or 2 atoms selected from the group consisting of N and O;

[0266] each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-8 alkyl and C 1-8 alkoxy, where C 1-8 alkyl or C 1-8 alkoxy optionally substituted by one or more R a ;

[0267] m is selected from the group consisting of 0, 1, 2, 3, and 4;

[0268] every R a independently selected from the group consisting of halogen, hydroxy, amino, and cyano.

[0269] In a further aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0270] ,

[0271] where

[0272] X is selected from the group consisting of N and CH;

[0273] every R 1 independently selected from halogen;

[0274] q selected from 0;

[0275] each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0276] n selected from 0;

[0277] each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, where T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH;

[0278] Ring A is selected from the group consisting of C 6-10 aryl, 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl, wherein the 5-6-membered heterocycloalkenyl is selected from 5-6-membered heterocycloalkenyl containing 1 or 2 nitrogen atoms, and the 5-6-membered heteroaryl is selected from 5-6-membered heteroaryl containing 1 or 2 nitrogen atoms;

[0279] every R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, nitro, C 1-3 alkyl and C 1-3 alkoxy, where C 1-3 alkyl or C1-3 alkoxy optionally substituted by one or more R a ;

[0280] m is selected from the group consisting of 0, 1 and 2;

[0281] each R a independently selected from the group consisting of halogen and hydroxy.

[0282] In a further aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0283] ,

[0284] where

[0285] X is selected from the group consisting of N and CH;

[0286] each R 1 independently selected from halogen;

[0287] q selected from 0;

[0288] every R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0289] n selected from 0;

[0290] each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, where T 1 and T 5 selected from N, and T 2 , T 3 and T4 selected from CH;

[0291] ring A is selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from 5-membered heteroaryl containing 1 or 2 nitrogen atoms;

[0292] each R 3 independently selected from the group consisting of =O, halogen, hydroxy, and C 1-3 alkyl, while C 1-3 alkyl optionally substituted with one or more R a ; preferably each R 3 independently selected from the group consisting of =O, fluorine, chlorine, bromine, and C 1-3 alkyl, while C 1-3 alkyl optionally substituted with one or more R a ; more preferably each R 3 independently selected from the group consisting of =O, fluorine, and methyl, wherein methyl is optionally substituted with one or more fluorine atoms;

[0293] m is selected from the group consisting of 0, 1 and 2;

[0294] each R a independently selected from halogen.

[0295] In a further aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0296] ,

[0297] where

[0298] X is selected from the group consisting of N and CH;

[0299] each R 1 independently selected from halogen;

[0300] q selected from 0;

[0301] each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro;

[0302] n selected from 0;

[0303] each of T 1 , T 2 , T 3 , T 4 , and T 5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH, and both from T 1 and T 4 are not selected from N, and both T 2 and T 5 not selected from CH; preferably T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH, or T 1 or T 5are selected from N, and the remaining four are selected from CH;

[0304] ring A is selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl is selected from 5-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; preferably the 5-membered heteroaryl is selected from 5-membered heteroaryl containing 3 nitrogen atoms;

[0305] each R 3 independently selected from C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl optionally substituted with one or more R a ; preferably each R 3 independently selected from cyclopropyl optionally substituted with one or more R a ;

[0306] m is selected from the group consisting of 1 and 2;

[0307] every R a independently selected from halogen.

[0308] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula I-1, a compound of formula I-2, a compound of formula I-3, a compound of formula I-4, a compound of formula I-5, a compound of formula I-6, a compound of formula I-7, and pharmaceutically acceptable salts thereof:

[0309] , , , , , And ,

[0310] where T 6 selected from the group consisting of C and N; T 1 , T 2 , T 3 , T 4 , T 5 , X, R 3 , m and ring A are defined above;

[0311] each of T 7 , T 8 , T 9 , T 10 , T 11 and T 12 independently selected from the group consisting of CH, C, NH, N, O, and a bond;

[0312] represents a single bond or a double bond.

[0313] In some embodiments, each of T7 , T 8 , T 9 , T 10 , T 11 and T 12 , described above, is independently selected from the group consisting of CH, C, NH, N, O and a bond, wherein one or two of them are selected from the group consisting of NH and N. In some embodiments, each of T 7 , T 8 , T 9 , T 10 , T 11 and T 12 , described above, is independently selected from the group consisting of CH, C, NH, N, O and a bond, wherein one or two of them are selected from the group consisting of NH and N, and one of them is selected from a bond.

[0314] In some embodiments, each of T 7 , T 8 , T 9 , T 10 and T 11 , described above, is independently selected from the group consisting of CH, C, NH, N and O, wherein one or two of them are selected from the group consisting of NH and N.

[0315] In some embodiments, each of T 7 , T 8 , T 9 and T 10, described above, is independently selected from the group consisting of CH, C, NH, N and O, wherein one or two of them are selected from the group consisting of NH and N.

[0316] In some embodiments, each of T 7 , T 8 , T 9 and T 10 , described above, is independently selected from the group consisting of CH, C, NH and N, wherein one or two of them are selected from the group consisting of NH and N.

[0317] In some embodiments or , described above, represent a heteroaromatic ring system.

[0318] In some embodiments, the structural unit selected from the group consisting of And .

[0319] In some embodiments, the structural unit selected from .

[0320] In some embodiments, the structural unit selected from the group consisting of And .

[0321] In some embodiments, the structural unit selected from .

[0322] In some embodiments, the structural unit defined above.

[0323] In some embodiments, the structural unit selected from .

[0324] In some embodiments, the structural unit selected from the group consisting of , , And ; in some embodiments, the structural unit selected from the group consisting of And .

[0325] In some embodiments, the structural unit selected from ; in some embodiments, the structural unit selected from the group consisting of , And ; in some embodiments, the structural unit selected from the group consisting of , , , And In some embodiments, the structural unit or selected from the group consisting of , , , And In some embodiments, the structural unit or selected from .

[0326] In some embodiments, the present invention encompasses the variables defined above and their embodiments, as well as any combination thereof.

[0327] The heteroatom in the heterocyclyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl described above is selected from the group consisting of nitrogen, oxygen and sulfur, and the remaining ring atoms are selected from carbon. In some embodiments, the number of heteroatoms is selected from the group consisting of 1, 2, 3 and 4. In some embodiments, the number of heteroatoms is selected from the group consisting of 1, 2 and 3. In some embodiments, the number of heteroatoms is selected from the group consisting of 1 and 2.

[0328] As used herein, "one or more" refers to an integer ranging from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or "one or more" refers to one, two, three, four, five, or six; or "one or more" refers to one, two, or three.

[0329] In some embodiments, the compound disclosed herein is not a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0330] , , , , , , , , , And .

[0331] In some embodiments, the compound disclosed herein is not a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0332] , , , , , , , , , , , , , And .

[0333] In another aspect, the present invention provides a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0334] , , ,

[0335] , , ,

[0336] , , ,

[0337] , , ,

[0338] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

[0339] In another aspect, the present invention provides a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0340] , , , , , , , , , , , , , , And .

[0341] In another aspect, the present invention provides a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0342] , or .

[0343] In another aspect, the present invention provides a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0344] , , , , , , , , , , , , , , , , , , , , , , or .

[0345] In another aspect, the present invention provides a compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

[0346] or .

[0347] In another aspect, the present invention further provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof described herein above. In some embodiments, the pharmaceutical composition disclosed herein further comprises a pharmaceutically acceptable excipient.

[0348] In another aspect, the present invention further provides a method for treating or preventing various diseases associated with TYK2, comprising administering to a mammal, preferably a human, in need of treatment, a therapeutically or prophylactically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition based on it, described herein above.

[0349] In another aspect, the present invention further provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein above, in the preparation of a medicament for use in the treatment or prevention of various diseases associated with TYK2.

[0350] In another aspect, the present invention further provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein above, in the treatment or prevention of various diseases associated with TYK2.

[0351] In another aspect, the present invention further provides a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein above, for use in the treatment or prevention of various diseases associated with TYK2.

[0352] In some embodiments, the various TYK2-associated diseases are selected from inflammatory diseases and autoimmune diseases. In some embodiments, the various TYK2-associated diseases are selected from colitis.

[0353] The compound disclosed herein is characterized by adequate enzymatic or cellular activity in vitro, metabolic stability such as metabolic stability in liver microsomes, as well as pharmacokinetic properties and pharmacodynamic activity (e.g., in colitis models).

[0354] Definitions

[0355] Unless otherwise specified, the following terms used in the present invention shall have the following meanings. A defined term, unless specifically defined otherwise, is not to be considered vague or unclear, but is to be understood in accordance with its generally accepted meaning in the art. Reference to a trade name is intended to refer to the corresponding commercial product or its active ingredient.

[0356] If certain structural units or groups in the present invention have a covalent bond that is not attached to a specific atom, this means that the covalent bond may be attached to any atom within the given structural unit or group, provided that it complies with the rules of valence bonding.

[0357] The term "substituted" means that any one or more hydrogen atoms at a given atom are replaced by substituents, provided that the valence of the given atom is normal and the resulting compound is stable. If the substituent is an oxo group (i.e., =O), this means that two hydrogen atoms are replaced, and the oxo group is not present in the aromatic group.

[0358] The terms "optional" or "optionally" mean that the event or circumstance described below may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). Those skilled in the art will understand that for any groups containing one or more substituents, no substitutions or substitution patterns that are sterically inappropriate and / or synthetically impossible will be introduced.

[0359] Used in this document C m-n means that the fragment contains an integer number of carbon atoms in the specified range. For example, "C 1-6" means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, "C 1-3 " means that the group may contain 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0360] If any variable (e.g., R) occurs more than once in the composition or structure of a compound, the definition of the variable in each instance is independent. Therefore, for example, if a group is substituted with 2 R, the definition of each R is independent.

[0361] If the joining group is characterized by the number 0, such as -(CH2)0-, it means that the joining group is a covalent bond.

[0362] If the substituent is characterized by the number 0, for example, -(R 1 )0, this means that unsubstituted, for example, represents .

[0363] If one of the variables is chosen from a covalent bond, it means that the two groups attached to it are directly bonded. For example, in A-L'-Z, in which L' represents a covalent bond, this means that the structure is actually A-Z.

[0364] If the bond in a substituent is a cross-linking of two atoms in the ring, then this substituent can be bonded to any atoms in the ring. For example, the structural unit or represents that substitution can occur at any position of cyclohexyl or cyclohexadienyl.

[0365] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0366] The term "alkyl" refers to a non-cyclic hydrocarbon residue with the general formula C n H 2n+1 Alkyl can be linear or branched. For example, the term "C 1-6"alkyl" refers to alkyl containing 1-6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Alkyl moieties (i.e., alkyl) in alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio are defined similarly as above. As another example, the term "C 1-3 "alkyl" refers to an alkyl containing 1-3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0367] The term "alkoxy" refers to -O-alkyl.

[0368] The term "cycloalkoxy" refers to -O-cycloalkyl.

[0369] The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a monocyclic, bridged cyclic, or spirocyclic structure. Unless otherwise specified, the carbon ring is generally a 3- to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, dicyclo[1.1.1]pentan-1-yl, and the like. For example, C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.

[0370] The term "heterocyclyl" refers to a fully saturated or partially unsaturated (but not a fully unsaturated heteroaromatic group) non-aromatic ring, which may exist in the form of a monocyclic structure, a bridged cyclic structure, or a spirocyclic structure, including, for example, heterocycloalkyl and heterocycloalkenyl. Unless otherwise specified, heterocyclyl is typically a 3- to 10-membered or 3- to 7-membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyl include, without limitation, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, sulfomorpholinyl, tetrahydrothienyl, and the like.

[0371] The term "heterocycloalkyl" refers to a fully saturated cyclic group that may exist in the form of a monocyclic structure, a bridged cyclic structure (including a fused ring), or a spirocyclic structure. Unless otherwise specified, heterocycloalkyl is typically a 3- to 10-membered, 3- to 7-membered, 3- to 6-membered, 4- to 6-membered, or 5- to 6-membered ring containing 1-3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, and aziranyl. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, oxetanyl, and azetidinyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl.Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiapyranyl, morpholinyl, piperazinyl, 1,4-oxathianyl, 1,4-dioxanyl, sulfomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azacycloheptanyl, oxacycloheptanyl, and thiocycloheptanyl. Preferably, heterocycloalkyl is a monocyclic heterocycloalkyl containing 5 or 6 ring atoms.

[0372] The term “heterocycloalkenyl” refers to a non-aromatic cyclic group that is not fully saturated (but is not a fully unsaturated heteroaromatic group), and it may exist in the form of a monocyclic structure, a bridged cyclic structure, or a spirocyclic structure. Unless otherwise specified, heterocyclyl generally contains 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen, and / or nitrogen. Unless otherwise specified, heterocycloalkenyl generally is a 3 to 10-membered ring or a 4 to 8-membered ring. A specific example of heterocycloalkenyl is .

[0373] The term "aryl" refers to an aromatic monocyclic or fused polycyclic group of carbon atoms with a conjugated pi-electron system. For example, aryl may contain 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene, and the like.

[0374] The term "heteroaryl" refers to a monocyclic or fused polycyclic system that contains at least one ring atom selected from the group consisting of N, O and S, wherein the remaining ring atoms are C, and that contains at least one aromatic ring. Preferably, heteroaryl contains one 5-8-membered or 5-6-membered ring or is a plurality of fused rings containing 6-14 ring atoms, in particular 6-10 ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0375] The compounds disclosed herein may exist in the form of a particular geometric isomer or stereoisomer. All such compounds are contemplated herein, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are encompassed within the scope of the present invention. Substituents, such as alkyl, may have an additional asymmetric carbon atom. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0376] Unless otherwise stated, the absolute configuration of a stereogenic center is represented by a wedge-shaped continuous bond ( ) and a wedge-shaped dotted connection ( ), and the relative configuration of the stereogenic center is represented by a direct continuous bond ( ) and a direct dotted connection ( ). Wavy line ( ) represents a continuous wedge-shaped connection ( ) or a solid dotted connection ( ), or a wavy line ( ) represents a direct continuous connection ( ) and a direct dotted connection ( ).

[0377] Unless otherwise specified, when a double bond structure such as carbon-carbon double bond, carbon-nitrogen double bond and nitrogen-nitrogen double bond is present in a compound, and each atom in the double bond is bonded to two different substituents (in a double bond involving a nitrogen atom, the lone pair of electrons on the nitrogen atom is regarded as the substituent to which the nitrogen atom is bonded), if the atom in the double bond in the compound and its substituents are connected by a wavy line ( ), this means that the compound exists in the form of a (Z)-type isomer, an (E)-type isomer, or a mixture of the two isomers.

[0378] The term "treat," "treating," or "treatment" refers to the administration of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a formulation described herein, to alleviate or eliminate a disease or one or more symptoms associated with a disease, and includes:

[0379] (i) suppression of a disease or morbid condition, i.e., arresting its progress, and

[0380] (ii) reducing the intensity of a disease or morbid condition, i.e. ensuring its remission.

[0381] The term "prevent," "preventing," or "prevention" refers to the administration of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a formulation described herein, in a manner to prevent a disease or one or more symptoms associated with a disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is predisposed to the disease state but has not yet been diagnosed with it.

[0382] The term "therapeutically or prophylactically effective amount" refers to the amount of a compound disclosed herein for (i) treating or preventing a particular disease, condition, or disorder; (ii) reducing the intensity, alleviating, or eliminating one or more symptoms of a particular disease, condition, or disorder; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound disclosed herein constituting a "therapeutically effective amount" varies depending on the compound, the condition and its severity, the administration regimen, and the age of the mammal being treated, but can generally be determined by those skilled in the art based on their own knowledge and the present invention.

[0383] The term "pharmaceutically acceptable" is used in this document to refer to those compounds, materials, compositions and / or dosage forms that, under careful medical evaluation, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic reaction or other problems or complications and are commensurate with an acceptable benefit / risk ratio.

[0384] The pharmaceutically acceptable salt may, for example, be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, and the like.

[0385] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds or pharmaceutically acceptable salts thereof disclosed herein and a pharmaceutically acceptable excipient. The pharmaceutical composition is intended to facilitate the administration of the compound disclosed herein into the body.

[0386] The term "pharmaceutically acceptable excipient" refers to substances that do not significantly irritate the body and do not interfere with the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oil, solvent, or water.

[0387] The word "comprise" and its variations such as "contains" or "containing" shall be understood in an open, non-exclusive sense, i.e., "including without limitation."

[0388] The compounds and intermediates disclosed herein may also exist in various tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energy levels that can interconvert upon crossing a low-energy barrier. For example, for a proton tautomer (also known as a prototropic tautomer), interconversion via proton transfer is envisaged, such as keto-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can be transferred between two nitrogen atoms in the ring. A valence tautomer involves interconversion via recombination of some bond-forming electrons.

[0389] The present invention also provides isotopically labeled compounds that are identical to the compounds mentioned herein, but have one or more atoms replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number that are commonly found in nature. Examples of isotopes that may be included in the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 Oh, 17 Oh, 18 Oh, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl.

[0390] Certain isotopically labeled compounds disclosed herein (e.g., compounds labeled with 3 H and 14C) can be used in tissue distribution analysis of compounds and / or substrates. Tritium isotopes (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly preferred due to their ease of production and detectability. Positron-emitting isotopes such as 15 Oh, 13 N, 11 C and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds disclosed herein can generally be prepared using the following procedures, similar to those disclosed in the schemes and / or in the examples below, along with the substitution of an isotopically labeled reagent for a non-isotopically labeled reagent.

[0391] Also, substitution with heavier isotopes such as deuterium (i.e. 2H), may provide certain therapeutic advantages (e.g., increased half-life in vivo or reduced dosage) as a result of greater metabolic stability, and may therefore be preferred in certain circumstances, in which the deuterium substitution may be partial or complete, where partial deuterium substitution refers to the replacement of at least one hydrogen with at least one deuterium, and all such forms of the compounds are included within the scope of this invention.

[0392] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers, for example, enantiomers and diastereoisomers, are included in this application. The compounds with asymmetric carbon atoms disclosed herein may be isolated in optically pure form or racemic form. The optically pure form may be isolated from a racemic mixture or may be synthesized using a chiral starting material or a chiral reagent.

[0393] The pharmaceutical composition disclosed herein can be obtained by combining the compound or a pharmaceutically acceptable salt thereof disclosed herein with a suitable pharmaceutically acceptable excipient, and it can be formulated, for example, as a solid, semi-solid, liquid or gas composition, such as a tablet, pill, capsule, powder, granule, ointment, emulsion, suspension, suppository, injection, inhalant, gel, microsphere and aerosol.

[0394] Typical routes of administration of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof disclosed herein include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous routes of administration.

[0395] The pharmaceutical composition disclosed herein can be manufactured by using methods widely known in the art such as conventional mixing, dissolution, granulation, coating, trituration, emulsification and lyophilization.

[0396] In some embodiments, the pharmaceutical composition is in a form for oral administration. For oral administration, the pharmaceutical composition can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. Such excipients can allow the compound or a pharmaceutically acceptable salt thereof disclosed herein to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to patients.

[0397] A solid oral composition can be produced by conventional mixing, filling, or tabletting. For example, it can be produced by the following method: mixing the active compounds with solid excipients, optionally milling the resulting mixture, adding additional suitable excipients if required, and then forming the mixture into granules to form tablet cores or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents, etc.

[0398] The pharmaceutical composition may also be suitable for parenteral administration, for example, as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.

[0399] Therapeutic dosages of the compound disclosed herein can be determined, for example, in accordance with the specific use of the therapeutic agent, the route of administration of the compound, the health and condition of the patient, and the decision of the attending physician. The proportion or concentration of the compound disclosed herein in the pharmaceutical composition may not be constant and depends on various factors, including dosages, chemical properties (e.g., hydrophobicity), and routes of administration. For example, the compound disclosed herein can be provided for parenteral administration as a physiologically buffered aqueous solution containing about 0.1-10% w / v of the compound. Certain typical dosages are in the range of about 1 μg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dosage is in the range of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day.Dosage likely depends on variables such as the type and degree of progression of the disease or disorder, the overall health of the individual patient, the relative biological activity of the selected compound, the excipient formulation, and the route of administration. Effective doses can be extrapolated from dose-response curves obtained from in vitro test systems or animal models.

[0400] The compounds disclosed herein can be prepared using various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments obtained by combining them with other chemical synthetic methods, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0401] The chemical reactions according to the embodiments disclosed herein are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention, and with the necessary reagents and materials. In order to obtain the compounds disclosed herein, those skilled in the art may sometimes need to modify or select a synthetic procedure or reaction method based on the presented embodiments.

[0402] An important factor in planning a synthetic route in this field is the selection of suitable protecting groups for reactive functional groups (e.g., the amino group in the present invention). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc.

[0403] In some embodiments, the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis according to the following routes:

[0404]

[0405]

[0406]

[0407] where X, R 1 , q, R 2 , n, T 1 , T 2 , T 3 , T 4 , T 5 , ring A, m or R 3 defined above.

[0408] The following abbreviations are used in the present invention:

[0409] DMF represents N,N-dimethylformamide; DIPEA represents diisopropylethylamine; LiHMDS represents lithium bis(trimethylsilyl)amide; Pd(dba)2 represents bis(dibenzylideneacetone)palladium(0); Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; DMSO represents dimethyl sulfoxide.

[0410] For clarity of the present invention, the following examples are further described, which, however, are not intended to limit the scope of the present invention. All reagents used in the present invention are commercially available and can be used without further purification.

[0411] All patents, patent applications, and other publications cited herein are expressly incorporated by reference for purposes of description and disclosure. Any reference to such publications in this document shall not be construed as an admission that the publications are part of the general knowledge in the art.

[0412] DETAILED DESCRIPTION

[0413] Example 1. Connection 1-j

[0414]

[0415] 1) Method for obtaining connection 1-a.

[0416] Lithium 4,6-dichloropyridazine-3-carboxylate (50 g) was dissolved in dichloromethane (500 ml), and then a catalytic amount of DMF was added at 0 °C, and oxalyl chloride (96 g) was slowly added dropwise into the solution. After the dropwise addition was completed, the mixture was stirred and allowed to react at room temperature for another 2 h until the reaction was completed. The reaction solution was concentrated. Methyl d3-amine hydrochloride (18.6 g) and DIPEA (162 g) were dissolved in dichloromethane (200 ml) and stirred until completely dissolved at -25 °C. The concentrate was dissolved in 300 ml of dichloromethane and slowly added dropwise to the above solution. After complete dropwise addition, the mixture was stirred for another 2 h. The reaction mixture was quenched by adding water (750 mL) and extracted twice with dichloromethane (2 × 500 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, and filtered.The filtrate was concentrated to give compound 1-a (52 g). ESI-MS: m / z = 209.2 [M+H]. + .

[0417] 2) Method for obtaining connection 1-c.

[0418] Compound 1-a (2 g) and compound 1-b (2.3 g) were dissolved in tetrahydrofuran (40 mL), and 1 M LiHMDS-tetrahydrofuran solution (48 mL) was added dropwise at -10°C. After the dropwise addition was completed, the mixture was stirred overnight at room temperature. Purified water and ethyl acetate were added. The resulting mixture was stirred, and the phases were separated. The organic phases were washed with brine, dried, filtered, and rotary evaporated to give compound 1-c (3.5 g). ESI-MS: m / z = 373.90 [M+H] + .

[0419] 3) Method of obtaining connection 1-e.

[0420] Compound 1-c (1.8 g), compound 1-d (0.41 g), Pd2(dba)3 (0.88 g), Xantphos (0.56 g), and cesium carbonate (3.13 g) were dissolved sequentially in 50 mL of dioxane, and the mixture was heated to 105 °C and reacted for 24 h under a nitrogen atmosphere. The reaction solution was concentrated and purified by column chromatography to give compound 1-e (1.6 g). ESI-MS: m / z = 422.97 [M+H] + .

[0421] 4) Method for obtaining connection 1-f.

[0422] Compound 1-e (1.6 g), bis(pinacolato)diboron (4.8 g), Pd(dppf)Cl2 (1.38 g), and potassium acetate (1.12 g) were dissolved sequentially in dioxane (50 mL), and the mixture was heated to 100°C and reacted for 5 h under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to an oil. Methanol in-heptane was added. The resulting mixture was stirred, and the phases were separated. The methanol phase was rotary evaporated to give compound 1-f (1.3 g). ESI-MS: m / z = 471.09 [M+H] + .

[0423] 5) Method for obtaining connection 1-h.

[0424] Compound 1-f (1 g), compound 1-g (0.67 g), Pd(dppf)Cl2 (0.31 g), and potassium carbonate (0.59 g) were dissolved sequentially in dioxane (50 mL) and water (10 mL), and the mixture was heated to 80°C and reacted for 8 h under a nitrogen atmosphere. The reaction solution was concentrated and purified by column chromatography to obtain compound 1-h (0.3 g). ESI-MS: m / z = 501.08 [M+H] + .

[0425] 6) Method for obtaining connection 1-j.

[0426] Compound 1-h (70 mg), compound 1-i (17 mg), Pd(dppf)Cl2 (10 mg), and potassium carbonate (38 mg) were dissolved sequentially in dioxane (6 mL) and 1 mL of water, and the mixture was heated to 110°C and reacted for 8 h under a nitrogen atmosphere. The reaction solution was concentrated and purified and separated to give compound 1-j (0.3 g). ESI-MS: m / z = 500.14 [M+H] + .

[0427] Example 2. Connection 2-h

[0428]

[0429] Compound 2-h was obtained according to the method for preparing compound 1-h in Step 5) of Example 1, wherein compound 1-g was replaced with compound 2-g. ESI-MS: m / z = 479.10 [M+H] + .

[0430] Example 3. Connection 3-j

[0431]

[0432] Compound 3-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 3-i. ESI-MS: m / z = 518.10 [M+H] + .

[0433] Example 4. Connection 4-j

[0434]

[0435] Compound 4-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 4-i. ESI-MS: m / z = 518.09 [M+H] + .

[0436] Example 5. Connection 5-j

[0437]

[0438] Compound 5-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 5-i. ESI-MS: m / z = 518.10 [M+H] + .

[0439] Example 6. Connection 6-j

[0440]

[0441] Compound 6-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 6-i. ESI-MS: m / z = 568.09 [M+H] + .

[0442] Example 7. Connection 7-j

[0443]

[0444] Compound 7-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 7-i. ESI-MS: m / z = 568.11 [M+H] + .

[0445] Example 8. Connection 8-j

[0446]

[0447] Compound 8-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 8-i. ESI-MS: m / z = 568.10 [M+H] + .

[0448] Example 9. Connection 9-j

[0449]

[0450] Compound 9-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 9-i. ESI-MS: m / z = 516.06 [M+H] + .

[0451] Example 10. Connection 10-j

[0452]

[0453] Compound 10-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 10-i. ESI-MS: m / z = 501.13 [M+H] + .

[0454] Example 11. Connection 11-h

[0455]

[0456] Compound 11-h was obtained according to the method for preparing compound 1-h in Step 5) of Example 1, wherein compound 1-g was replaced with compound 11-g. ESI-MS: m / z = 507.08 [M+H] + .

[0457] Example 12. Connection 12-j

[0458]

[0459] Compound 12-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-i was replaced with compound 12-i. ESI-MS: m / z = 536.04 [M+H] + .

[0460] Examples 13-41. The target compounds were obtained according to the method for producing compound 2-h of Example 2, wherein compound 2-g was replaced with the compounds from the starting materials shown in the table below.

[0461]

[0462] 2-pyrrolidone (1.0 g), 5-iodo-2-bromopyrimidine (1.7 g), Pd2(dba)3 (1.88 g), Xantphos (1.1 g), and cesium carbonate (11 g) were dissolved sequentially in 50 mL of dioxane, and the mixture was heated to 105 °C and reacted for 0.5 h under a nitrogen atmosphere. The reaction solution was concentrated and subjected to separation and purification to obtain the compound (60 mg). ESI-MS: m / z = 242.08 [M+H] + .

[0463]

[0464] 1-Methyl-1H-pyrazole-5-boronic acid pinacol ester (2.0 g), 5-iodo-2-bromopyrimidine (2.8 g), Pd(dppf)Cl2 (1.4 g), and potassium carbonate (4.1 g) were dissolved sequentially in dioxane (30 mL), and the mixture was heated to 100 °C and reacted for 3 h under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to an oil. The oil was subjected to column chromatography to give the product (0.6 g). ESI-MS: m / z = 239.11 [M+H] + .

[0465]

[0466] Stage 1

[0467] 3-bromo-1-cyclopropyl-1H-1,2,4-triazole (5.0 g), bis(pinacolato)diboron (10.2 g), Pd(dppf)Cl2 (1.9 g), and potassium acetate (7.8 g) were dissolved sequentially in dioxane (50 ml), and the mixture was heated to 80°C and reacted for 3 h under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to an oil. The oil was subjected to column chromatography to give int. compound 1 (1.2 g).

[0468] Stage 2

[0469] Ind. compound 1 (1.2 g), 5-iodo-2-bromopyrimidine (0.7 g), Pd(dppf)Cl2 (0.7 g), and potassium carbonate (2.1 g) were dissolved sequentially in dioxane (20 mL), and the mixture was heated to 100 °C and reacted for 3 h under nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to an oil. The oil was subjected to column chromatography to give ind. compound 2 (0.2 g). ESI-MS: m / z = 266.23 [M+H] + .

[0470]

[0471]

[0472]

[0473]

[0474] Examples 42-55 The target compounds were obtained according to the method for preparing compound 1-j of Example 1, wherein compound 1-i was replaced with the compounds from the starting materials shown in the table below.

[0475]

[0476]

[0477] Example 57. Connection 57-j

[0478]

[0479] 1) Method for obtaining connection 57-a.

[0480] Compound 57-a was obtained according to the method for producing compound 1-a in Step 1) of Example 1, wherein lithium 4,6-dichloropyridazine-3-carboxylate was replaced with lithium 4,6-dichloropyridine-3-carboxylate.

[0481] 2) Method for obtaining connection 57-c.

[0482] Compound 57-c was obtained according to the method for producing compound 1-c in Step 2) of Example 1, wherein compound 1-a was replaced with compound 57-a.

[0483] 3) Method for obtaining connection 57-e.

[0484] Compound 57-e was obtained according to the method for obtaining compound 1-e in Step 3) of Example 1, wherein compound 1-c was replaced with compound 57-c.

[0485] 4) Method for obtaining connection 57-f.

[0486] Compound 57-f was obtained according to the method for obtaining compound 1-f in Step 4) of Example 1, wherein compound 1-e was replaced with compound 57-e.

[0487] 5) Method for obtaining connection 57-h.

[0488] Compound 57-h was obtained according to the method for obtaining compound 1-h in Step 5) of Example 1, wherein compound 1-e was replaced with compound 57-f.

[0489] 6) Method for obtaining connection 57-j.

[0490] Compound 57-j was obtained according to the method for preparing compound 1-j in Step 6) of Example 1, wherein compound 1-h was replaced with compound 57-h and compound 1-i was replaced with compound 57-i. ESI-MS: m / z = 517.46 [M+H] + .

[0491] Examples 58-60 The following compounds were prepared according to the preparation method in Example 57, wherein compound 57-i was replaced with compounds from the starting materials.

[0492]

[0493] Example 61. Connection 61-h

[0494]

[0495] Compound 61-h was obtained according to the method for preparing compound 1-h in Step 5) of Example 1, wherein compound 1-g was replaced with compound 63-g and compound 1-f was replaced with compound 57-f. ESI-MS: m / z = 488.21 [M+H] + .

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502] Experimental Example 1. Thermal Stability Analysis of JH2TYK2

[0503] JH2 TYK2 protein stock solution (Beijing Sino Biological) with a concentration of 0.52 mg / mL was diluted to 50 ng / μL with phosphate-buffered saline (PBS), and 5000× protein dye (Orange dye) was diluted to 20× with DMSO. 16 μL of JH2 TYK2 protein diluent was added to each well, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette, achieving final compound concentrations of 10 μM and 1 μM (two concentrations in total). Blank control wells (without enzyme) and negative control wells (with enzyme plus DMSO vehicle medium) were prepared, and the samples were tested in duplicate. Finally, 4 µl of Orange dye protein was added to each well and the mixture was thoroughly mixed by centrifugation. Detection was performed using a Roche LightCycler480 fluorescence quantitative PCR instrument with an assay system at 20°C for 15 s; 30-90°C at 0.02°C / s; and 20°C for 15 s.Melting point (Tm) values ​​were determined by analysis using LightCycler temperature shift analysis software.

[0504] The compound disclosed in this document, provided that the final concentration is 10 μM, is characterized by a melting point (Tm) of more than 40°C, preferably more than 45°C, and more preferably more than 55°C, and provided that the final concentration is 1 μM, the compound is characterized by a melting point (Tm) of more than 40°C, preferably more than 45°C, and more preferably more than 50°C.

[0505] Experimental Example 2. Detection of STAT3 phosphorylation using Jurkat cells

[0506] Twenty microliters of Jurkat cells growing in logarithmic phase were collected and counted, and the required number of cells (mL) were taken and centrifuged at 1300 rpm for 3 min. 1640 basic medium without phenol red (Hyclone) was added to adjust the cell density to approximately 1.7 * 10E7 cells / mL. The cells were seeded according to the above cell density in a 384-well plate (small volume white plate) at 8 μL per well. The compound was added using a nanoliter pipette, and the plate was incubated for 1.5 h. IFN-α (Beijing Sino Biological) was diluted to 75 ng / mL (with a final concentration of 25 ng / mL) with 1640 basic medium without phenol red. Then, 4 µl of IFN-α (3×) were added to each well according to the distribution on the plate. The blank group was seeded with cells without the compound and IFN-α. The control group was seeded with cells without the compound but with IFN-α. The plate was incubated at 37°C for 30 min.Four microliters of lysis buffer (4×) containing blocking buffer were immediately added, and the cells were lysed by shaking at room temperature for 40 min. Four microliters of premixed antibody (volume / volume) in assay buffer were added, and the plate was covered. The mixture was thoroughly mixed by centrifugation and incubated overnight at room temperature. Signal values ​​at 665 nm / 620 nm were determined using a PE Envision multifunctional microplate reader and IC. 50 calculated using four-parameter approximation.

[0507] The results are shown in Table 1.

[0508]

[0509] Experimental Example 3. In vitro stability in liver microsomes

[0510] 300 μL of the final incubation system contained 30 μL of liver microsomes (protein concentration: 5 mg / mL), 30 μL of NADPH + MgCl2, 3 μL of the test compound (in acetonitrile), and 237 μL of PBS buffer (pH 7.4), where the proportion of the organic solvent (acetonitrile) was 1% (volume ratio). Samples were prepared in duplicate from 0.30 mL for each type. The tubes, each containing 270 μL of the mixed solution of substrate, enzyme, and NADPH, were pre-incubated at 37°C for 5 min. 30 μL of NADPH + MgCl2 were added and the mixture was mixed. 50 µl of the mixture were taken at 0 min, 10 min, 30 min and 60 min and 300 µl of ice-cold acetonitrile containing the internal standard was added to stop the reaction.

[0511] 300 μL of ice-cold acetonitrile containing an internal standard (20 ng / mL) was added to 50 μL of the incubated sample for precipitation. The mixture was shaken for 10 min and centrifuged (13,000 rpm, 20°C) for 10 min. 70 μL of the supernatant was removed and diluted with 70 μL of ultrapure water. After thorough mixing, 0.5 μL of the resulting sample was analyzed by LC / MS / MS. The results are shown in Table 2.

[0512]

[0513] Experimental example 4. Pharmacokinetics in vivo in mice

[0514] ICR (Shanghai Institute of Family Planning Research) mice aged 6-8 weeks, weighing 20-24 g were randomly divided into groups of 9 individuals after 3-5 days of acclimatization and intragastrically administered the compounds at a dose of 15 mg / kg or 30 mg / kg.

[0515] The animals to be tested (ICR mice) were fasted for 12 h before administration and provided food 4 h after administration, and drinking water was provided freely before and after the experiment and during the experiment.

[0516] After intragastric administration, approximately 0.1 ml of blood was collected from the orbit at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 10 h. Each mouse was subjected to blood collection at 3-4 time points, using three mice at each time point. Blood samples were mixed with EDTA-K2 anticoagulant, transferred to a centrifuge for 30 min, and then centrifuged at 4000 rpm for 10 min at 4°C to separate the blood plasma. All plasma samples were collected and immediately stored at -20°C for testing.

[0517] 400 μL of acetonitrile solution containing an internal standard (20 ng / mL) was added to 20 μL of the collected plasma sample to be tested. The mixture was shaken and mixed thoroughly for 10 min and centrifuged at 13,000 rpm for 10 min. 50 μL of the supernatant was removed and diluted with 100 μL of ultrapure water. After thorough mixing, 0.5 μL of the resulting sample was subjected to LC / MS / MS, and the chromatogram was recorded.

[0518] The oral exposure of the compounds disclosed in this document was assessed using in vivo pharmacokinetic experiments in mice. The results are shown in Table 3 below.

[0519]

[0520] Experimental Example 5. Pharmacodynamics in a mouse model of colitis induced by mAbkCD40 antibody

[0521] Male CB17-SCID mice (6-8 weeks old) matching SPF were divided into groups on the first day of the experiment. On the first day of the experiment, mice in the blank group were injected intraperitoneally with PBS, while mice in the model group were injected intraperitoneally with mouse anti-CD40 antibody (100 μg, diluted with PBS as a model solution), establishing a mouse colitis model. The injection volume for all groups of mice was 0.1 ml.

[0522]

[0523] The day of group formation was defined as day 1, and intragastric administration began on the day of group formation at a volume of 2 ml / kg, administered twice a day for 6 consecutive days. The vehicle medium for intragastric administration was DMSO:PEG400 = 5:95 (volume ratio).

[0524] Body weights of animals were monitored daily throughout the experiment. On day 7, the endpoint of the experiment, all mice were euthanized and tissue samples were collected. Mice were euthanized by cervical dislocation, the abdomen was opened, and the spleens were collected, weighed, and photographed. The colon and rectum were separated from the small intestine from the end of the cecum to the anus. The entire colon and rectum were removed, photographed, and then longitudinally dissected along its longitudinal axis. The intestinal contents were cleaned with pre-chilled saline. The washed colon and rectum were laid out on a large flat dish with the mucosal surface facing up. Residual saline was removed from the colon and rectum with filter paper, and the colon tissues were collected for weighing.

[0525] The inhibition rate (%) was calculated according to the following formula: inhibition rate (%) = (MT) / (MC) * 100% (T: treatment group; C: blank control group; M: model control group).

[0526] The results are shown in Table 5.

[0527]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, , Where X is selected from the group consisting of N and CH; each R 1 independently selected from halogen; q is 0; each R 2 independently selected from the group consisting of halogen, hydroxy, amino, cyano, and nitro; n is 0; each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein at least one of them is selected from CH; ring A is selected from 4-6-membered heterocyclyl and 5-6-membered heteroaryl; each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, C 1-8 alkyl and C3cycloalkyl, where C 1-8 alkyl optionally substituted with one or more R a ; m is selected from the group consisting of 0, 1, 2 and 3; each Ra is a halogen; wherein heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from N and O.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is N; alternatively X is CH.

3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein each R 1 independently selected from the group consisting of fluorine and chlorine; alternatively, each R 1 independently represents fluorine.

4. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R 2 independently selected from the group consisting of fluorine, chlorine, and bromine; alternatively, each R 2 independently selected from the group consisting of fluorine and chlorine; alternatively, each R 2 independently represents fluorine.

5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein three of them are selected from N and two of them are selected from CH; alternatively, each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein two of them are selected from N and three of them are selected from CH; alternatively, each of T 1 , T 2 , T 3 , T 4 and T 5 independently selected from the group consisting of CH and N, wherein one of them is selected from N and four of them are selected from CH; optional T 1 , T 3 and T 5 selected from N, and T 2 and T 4 selected from CH; as an alternative to T 1 and T 3 selected from N, and T 2 , T 4and T 5 selected from CH; as an alternative to T 1 and T 5 selected from N, and T 2 , T 3 and T 4 selected from CH; as an alternative to T 2 and T 4 selected from N, and T 1 , T 3 and T 5 selected from CH; as an alternative to T 1 and T 2 selected from N, and T 3 , T 4 and T 5 selected from CH; as an alternative to T 2 and T 3 selected from N, and T 1 , T 4 and T 5 selected from CH; as an alternative to T 1 and T 4 selected from N, and T 2 , T 3 and T 5 selected from CH; as an alternative to T 2 and T 3 selected from N, and T 1 , T 4 and T 5 selected from CH; as an alternative to T 1 selected from N, and T 2 , T 3 , T 4and T 5 selected from CH; as an alternative to T 2 selected from N, and T 1 , T 3 , T 4 and T 5 selected from CH; as an alternative to T 3 selected from N, and T 1 , T 2 , T 4 and T 5 selected from CH.

6. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring A is selected from the group consisting of 4-6-membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O, 4-6-membered heterocycloalkenyl containing 1-2 heteroatoms selected from N and O, and 5-6-membered heteroaryl containing 1-3 heteroatoms selected from N and O; alternatively, ring A is selected from the group consisting of oxetanyl, azetidinyl, morpholinyl, dioxanyl, dihydropyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, tetrahydropyrrolyl, triazolyl, pyrazolyl, furanyl, dihydropyrimidinyl, oxazolyl, isoxazolyl and imidazolyl; alternatively, ring A is selected from the group consisting of dihydropyridinyl, pyridinyl, pyrimidinyl, triazolyl, pyrazolyl, dihydropyrimidinyl, isoxazolyl and imidazolyl; alternatively, ring A is selected from the group consisting of pyrazolyl and imidazolyl; alternatively, ring A is selected from the group consisting of , , , , , , , , , , , , , , , , , , And ; alternatively, ring A is selected from the group consisting of , , , , , , And ; optionally ring A is selected from 6-membered heteroaryl containing 1 or 2 atoms selected from N; alternatively, ring A is selected from a 5-membered heteroaryl containing 1 or 2 atoms selected from N; alternatively, ring A is selected from the group consisting of pyridinyl and pyrimidinyl.

7. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein m is selected from the group consisting of 0, 1 and 2.

8. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, C 1-6 alkyl and C3cycloalkyl, where C 1-6 alkyl optionally substituted with one or more R a ; alternatively, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, C 1-4 alkyl and C3cycloalkyl, where C 1-4 alkyl optionally substituted with one or more R a ; alternatively, each R 3independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, C 1-3 alkyl and C3cycloalkyl, where C 1-3 alkyl optionally substituted with one or more R a ; alternatively, each R 3 independently selected from the group consisting of =O, fluoro, chlorine, hydroxy, amino, cyano, cyclopropyl and C 1-3 alkyl optionally substituted by one or more fluorine atoms; alternatively, each R 3 independently selected from the group consisting of =O, fluoro, hydroxy, amino, cyano, methyl, trifluoromethyl, and cyclopropyl; alternatively, each R 3 independently selected from the group consisting of cyano, methyl and cyclopropyl; not necessarily every R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, and C 1-8 alkyl, where C 1-8 alkyl optionally substituted with one or more R a ; alternatively, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, and C 1-6 alkyl, where C 1-6 alkyl optionally substituted with one or more R a ; alternatively, each R 3 independently selected from the group consisting of =O, halogen, hydroxy, amino, cyano, and C 1-3 alkyl; alternatively, each R 3 independently selected from the group consisting of =O, fluorine, chlorine, bromine, and C 1-3 alkyl, where C 1-3 alkyl optionally substituted with one or more R a ; alternatively, each R 3 independently selected from the group consisting of =O, fluorine, and methyl, wherein methyl is optionally substituted with one or more fluorine atoms.

9. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein each R a independently selected from the group consisting of fluorine, chlorine, and bromine; alternatively, each R a independently represents fluorine.

10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the structural unit selected from the group consisting of , , , , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

11. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , And ; alternatively, a structural unit selected from a group consisting of a group consisting of , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And ; alternatively, a structural unit selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, selected from the group consisting of a compound of formula I-1, a compound of formula I-2, a compound of formula I-3, a compound of formula I-4, a compound of formula I-5, a compound of formula I-6, a compound of formula I-7, and pharmaceutically acceptable salts thereof: , , , , , And , where T 6 selected from the group consisting of CH and N; each of T 7 , T 8 , T 9 , T 10 , T 11 and T 12 independently selected from the group consisting of CH, C, NH, N, O and a bond, and represents a single bond or a double bond; alternatively, each of T 7 , T 8 , T 9 , T 10 , T 11 and T 12 independently selected from the group consisting of CH, C, NH, N, O and a bond, wherein one or two of them are selected from the group consisting of NH and N; alternatively, each of T 7 , T 8 , T 9 , T 10 , T 11 and T 12 independently selected from the group consisting of CH, C, NH, N, O and a bond, wherein one or two of them are selected from the group consisting of NH and N, and one of them is selected from a bond; not necessarily a structural unit selected from the group consisting of And ; not necessarily a structural unit selected from not necessarily a structural unit selected from the group consisting of And ; not necessarily a structural unit selected from not necessarily a structural unit selected from not necessarily a structural unit selected from the group consisting of , , And ; not necessarily a structural unit selected from the group consisting of And ; not necessarily a structural unit selected from not necessarily a structural unit selected from the group consisting of , And ; not necessarily a structural unit selected from the group consisting of , , , And .

13. A compound of a formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

14. A pharmaceutical composition for inhibiting TYK2, comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 and a pharmaceutically acceptable excipient.

15. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 in the preparation of a medicinal product intended for use in the treatment of a disease associated with TYK2.

16. The use according to claim 15, wherein the disease associated with TYK2 is selected from autoimmune diseases.

17. A method for treating a disease associated with TYK2, comprising administering to a mammal in need of treatment a therapeutically or prophylactically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 or a pharmaceutical composition according to claim 14.

18. The method according to claim 17, wherein the disease associated with TYK2 is selected from inflammatory diseases and autoimmune diseases.

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