TYK2 inhibitor compounds containing an amide group

Abstract

This application belongs to the field of medicinal chemistry and provides an amide-containing TYK2 inhibitor compound. Specifically, it relates to the compound of formula I, its preparation method, and its use in the preparation of drugs for treating or preventing TYK2-related diseases.

Description

[0001] Citation of Related Applications

[0002] This application claims the benefit of Chinese Patent Application No. 202010756321.X, filed with the State Intellectual Property Office of the People's Republic of China on July 31, 2020, Chinese Patent Application No. 202010757310.3, filed with the State Intellectual Property Office of the People's Republic of China on July 31, 2020, Chinese Patent Application No. 202010889706.3, filed with the State Intellectual Property Office of the People's Republic of China on August 31, 2020, and Chinese Patent Application No. 202011546160.8, filed with the State Intellectual Property Office of the People's Republic of China on December 23, 2020, the entire contents of which are hereby incorporated herein by reference in their entirety. Technical Field

[0003] This application belongs to the field of medicinal chemistry and provides an amide-containing TYK2 inhibitor compound and its preparation method, and relates to its use in the preparation of a drug for treating or preventing TYK2-related diseases. Background of the Invention

[0004] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown in both mice and humans to be essential in the regulatory signal transduction cascades downstream of the IL-12, IL-23, and type I interferon receptors. TYK2 mediates the phosphorylation of members of the STAT transcription factor family induced by receptors, which is an essential signal leading to the dimerization of STAT proteins and the transcription of STAT-dependent pro-inflammatory genes. TYK2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, thus demonstrating the importance of TYK2-mediated signal transduction in autoimmunity and related disorders. In humans, individuals expressing an inactive variant of TYK2 are protected from multiple sclerosis and possibly other autoimmune disorders.

[0005] In view of the disorders that can benefit from treatments involving the modulation of cytokines and / or interferons, TYK2 inhibitor compounds capable of modulating cytokines and / or interferons such as IL-12, IL-23, and / or IFNα, and methods of using these compounds can provide substantial therapeutic benefits to numerous patients in need thereof. Summary of the Invention

[0007] On the one hand, this application provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Wherein,

[0010] Cy is selected from C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

[0011] L 1 Selected from -C(O)-, -SO 2 -、-C(O)NR f -、-S(O) 2 NR h -、-NR g C(O)- or -NR j S(O) 2 -;

[0012] R f , R g , R h or R j are independently selected from hydrogen or C 1-6 alkyl;

[0013] R is selected from hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl or 3-10 membered heterocycloalkyl, the C 1-8 Alkyl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl or 3-10 membered heterocycloalkyl is optionally substituted with one or more R a replace;

[0014] Or, R and R g or R and R j are connected to each other to form a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group is optionally substituted by one or more halogen, amino, C 1-6 Alkyl or cyano substitution;

[0015] Alternatively, R and Cy are connected to each other so that R, Cy and L 1 Together they form an 8-10 membered heterocyclic group, the 8-10 membered heterocyclic group being optionally substituted by one or more halogen, amino, C 1-6 Alkyl or cyano substitution;

[0016] Every R a are independently selected from halogen, deuterium, cyano, =O, C 3-8 Cycloalkyl, C 1-6 Alkyl, hydroxyl, amino or C 1-6 Alkoxy, the C 3-8 Cycloalkyl, C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more halogens;

[0017] Each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 1-8 alkylNH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkylNH-, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 1-8 alkylC(O)-, C 1-8 alkylC(O)NH-, NH 2 C(O)-, C 1-8 alkylNHC(O)-, (C 1-8 alkyl) 2 NC(O)-, C 1-8 alkylOC(O)- or C 1-8 alkylC(O)O-, wherein the C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, C 1-8 alkylNH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkylNH-, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 1-8 alkylC(O)-, C 1-8 alkylC(O)NH-, NH 2 C(O)-, C 1-8 alkylNHC(O)-, (C 1-8 alkyl) 2 NC(O)-, C 1-8 alkylOC(O)- or C 1-8 alkylC(O)O- is optionally substituted with one or more halogen, hydroxy, cyano, amino;

[0018] n is selected from 0, 1, 2, 3 or 4;

[0019] L is selected from -C(O)- or a bond;

[0020] R 4 is selected from 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, C 6-10 aryl or 3- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, C 6-10 aryl or 3- to 10-membered heterocycloalkyl is optionally substituted with one or more Rb Substituted;

[0021] R b selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyloxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, C 1-8 alkylNH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkylNH-, -C(O)NHC 1-8 alkyl, -C(O)N(C 1-8 alkyl) 2 , -C(O)OC 1-8 alkyl, -OC(O)C 1-8 alkyl, C 1-8 alkylC(O)NH-, C 3-10 cycloalkylC(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C 1-8 alkyl substituted with one or more halogens;

[0022] R c , R d or R e are each independently selected from hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or R d is connected to R e to form a 3-7 membered heterocycloalkyl, and the 3-7 membered heterocycloalkyl is optionally substituted with one or more groups selected from: halogen, hydroxy, cyano, amino, C 1-8 alkyl, C 1-8 alkoxy or C 1-8 alkyl substituted with one or more halogens.

[0023] On the other hand, the present application also provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.

[0024] On the other hand, the present application also provides a method for treating or preventing various diseases related to TYK2, which includes administering to a mammal in need of such treatment, preferably a human, a therapeutically or prophylactically effective amount of the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0025] On the other hand, the present application also provides the use of the above-mentioned compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing various TYK2-related diseases.

[0026] On the other hand, the present application also provides the use of the above-mentioned compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in treating or preventing various TYK2-related diseases.

[0027] On the other hand, the present application also provides the above-mentioned compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating or preventing various TYK2-related diseases. SUMMARY OF THE INVENTION

[0028] On the one hand, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0029]

[0030] Wherein,

[0031] Cy is selected from C 6-10 aryl, 5-10-membered heteroaryl or 5-10-membered heterocyclic group;

[0032] L 1 is selected from -C(O)-, -SO 2 -, -C(O)NR f -, -S(O) 2 NR h -, -NR g C(O)- or -NR j S(O) 2 -;

[0033] R f 、R g 、R h or R j are each independently selected from hydrogen or C 1-6 alkyl;

[0034] R is selected from hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, 5-10-membered heteroaryl, C 6-10 aryl or 3-10-membered heterocycloalkyl, and the C 1-8 alkyl, C 3-10 cycloalkyl, 5-10-membered heteroaryl, C 6-10 aryl or 3-10-membered heterocycloalkyl is optionally substituted with one or more R a ;

[0035] Alternatively, R and R gOr R and R j are connected to each other to form a 5- to 10-membered heterocyclic group, and the 5- to 10-membered heterocyclic group is optionally substituted by one or more halogens, amino groups, C 1-6 alkyl groups or cyano groups;

[0036] Alternatively, R and Cy are connected to each other such that R, Cy and L 1 together form an 8- to 10-membered heterocyclic group, and the 8- to 10-membered heterocyclic group is optionally substituted by one or more halogens, amino groups, C 1-6 alkyl groups or cyano groups;

[0037] Each R a is independently selected from halogens, deuterium, cyano groups, =O, C 3-8 cycloalkyl groups, C 1-6 alkyl groups, hydroxyl groups, amino groups or C 1-6 alkoxy groups, and the C 3-8 cycloalkyl groups, C 1-6 alkyl groups or C 1-6 alkoxy groups are optionally substituted by one or more halogens;

[0038] Each R 1 is independently selected from amino groups, halogens, cyano groups, hydroxyl groups, C 1-8 alkyl groups, C 1-8 alkoxy groups, C 3-10 cycloalkyl groups, C 3-10 cycloalkoxy groups, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkyl NH-, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 1-8 alkyl C(O)-, C 1-8 alkyl C(O)NH-, NH 2 C(O)-, C 1-8 alkyl NHC(O)-, (C 1-8 alkyl) 2 NC(O)-, C 1-8 alkyl OC(O)- or C 1-8 alkyl C(O)O-, and the C 1-8 alkyl groups, C 1-8 alkoxy groups, C 3-10 cycloalkyl groups, C 3-10 cycloalkoxy groups, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkyl NH-, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 1-8 alkyl C(O)-, C 1-8alkyl C(O)NH-, NH 2 C(O)-, C 1-8 alkyl NHC(O)-, (C 1-8 alkyl) 2 NC(O)-, C 1-8 alkyl OC(O)- or C 1-8 alkyl C(O)O- is optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups;

[0039] n is selected from 0, 1, 2, 3 or 4;

[0040] L is selected from -C(O)- or a bond;

[0041] R 4 is selected from 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, C 6-10 aryl or 3- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl, C 3-10 cycloalkyl, C 6-10 aryl or 3- to 10-membered heterocycloalkyl is optionally substituted by one or more R b substituents;

[0042] R b is selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyloxy, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, amino, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkyl NH-, -C(O)NHC 1-8 alkyl, -C(O)N(C 1-8 alkyl) 2 、-C(O)OC 1-8 alkyl, -OC(O)C 1-8 alkyl, C 1-8 alkyl C(O)NH-, C 3-10 cycloalkyl C(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C 1-8 alkyl substituted by one or more halogens;

[0043] R c 、R d or R e are each independently selected from hydrogen, C 1-8 alkyl, C3-10 Cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or R d is connected to R e to form a 3- to 7-membered heterocycloalkyl, which is optionally substituted by one or more groups selected from the following: halogen, hydroxy, cyano, amino, C 1-8 alkyl, C 1-8 alkoxy or C alkyl substituted by one or more halogens 1-8 alkyl.

[0044] In some embodiments, Cy is selected from C 6-10 aryl, 5- to 10-membered heteroaryl or benzo 4- to 6-membered heterocyclic group.

[0045] In some embodiments, Cy is selected from C 6-10 aryl, 5- to 6-membered heteroaryl or benzo 5- to 6-membered heterocyclic group.

[0046] In some embodiments, Cy is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl or benzo 6-membered heterocyclic group.

[0047] In some embodiments, Cy is selected from phenyl, naphthyl, pyridyl, thienyl or 2,3-dihydrobenzo[b][1,4]dioxinyl.

[0048] In some embodiments, Cy is selected from phenyl or pyridyl.

[0049] In some embodiments, the L 1 is selected from -C(O)- or -SO 2 -.

[0050] In some embodiments, the L 1 is selected from -C(O)-, -SO 2 -, -S(O) 2 NR h - or -NR g C(O)-.

[0051] In some embodiments, the L 1 is selected from -C(O)NR f -, -S(O) 2 NR h -, -NR g C(O)- or -NR j S(O) 2 -.

[0052] In some embodiments, the L 1 is selected from -C(O)NR f - or -S(O) 2NR h -.

[0053] In some embodiments, the L 1 is selected from -NR g C(O)- or -NR j S(O) 2 -.

[0054] In some embodiments, R f , R g , R h or R j is independently selected from hydrogen or C 1-3 alkyl.

[0055] In some embodiments, R f , R g , R h or R j is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0056] In some embodiments, the R is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl or 3- to 6-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-8 cycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl or 3- to 6-membered heterocycloalkyl is optionally substituted with one or more R a ;

[0057] Alternatively, R is connected to R g or R is connected to R j to form a 5- to 8-membered heterocyclic group, and the 5- to 8-membered heterocyclic group is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0058] Alternatively, R is connected to Cy such that R, Cy and L 1 together form an 8- to 10-membered heterocyclic group, and the 8- to 10-membered heterocyclic group is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0059] In some embodiments, the R is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, phenyl or 5- to 6-membered heterocycloalkyl, and the C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more R a ;

[0060] Alternatively, R and R g alternatively R and R j are connected to each other to form a 5- to 7-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups;

[0061] Alternatively, R and Cy are connected to each other such that R, Cy and L 1 together form an 8- to 10-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups.

[0062] In some embodiments, R is selected from hydrogen, C 1-3 alkyl groups, C 3-6 cycloalkyl groups, phenyl groups or 5- to 6-membered heterocycloalkyl groups, and the C 1-3 alkyl groups, C 3-6 cycloalkyl groups, phenyl groups or 5- to 6-membered heterocycloalkyl groups are optionally substituted by one or more R a substituents;

[0063] Alternatively, R and R g alternatively R and R j are connected to each other to form a 5- to 6-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups;

[0064] Alternatively, R and Cy are connected to each other such that R, Cy and L 1 together form a 9-membered heterocyclic group.

[0065] In some embodiments, R is selected from hydrogen, C 1-3 alkyl groups, C 3-6 cycloalkyl groups, phenyl groups or 5- to 6-membered heterocycloalkyl groups, and the C 1-3 alkyl groups, C 3-6 cycloalkyl groups, phenyl groups or 5- to 6-membered heterocycloalkyl groups are optionally substituted by one or more R a substituents;

[0066] Alternatively, R and R g alternatively R and R j are connected to each other to form a 5- to 6-membered heterocyclic group;

[0067] Alternatively, R and Cy are connected to each other such that R, Cy and L 1 together form a 9-membered heterocyclic group.

[0068] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl is optionally substituted with one or more R a substituents;

[0069] Alternatively, R and R g or R and R j are connected to each other to form the which is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0070] Alternatively, R and R g or R and R j are connected to each other to form

[0071] Alternatively, R and R g or R and R j are connected to each other to form

[0072] Alternatively, R and Cy are connected to each other such that R, Cy and L 1 together form

[0073] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, is optionally substituted with one or more R a substituents;

[0074] Alternatively, R and R g or R and R j are connected to each other to form the which is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0075] Alternatively, R and R g or R and R j are connected to each other to form

[0076] Alternatively, R and R g or R and R j are connected to each other to form

[0077] Alternatively, R is connected to Cy such that R, Cy and L 1 together form

[0078] In some embodiments, R is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5- or 6-membered heteroaryl, C 6-10 aryl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 5- or 6-membered heteroaryl, C 6-10 aryl or 3- to 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents;

[0079] Alternatively, R is connected to R g or R is connected to R j to form a 5- to 8-membered heterocyclic group, which is optionally substituted with halogen, amino, C 1-3 alkyl or cyano.

[0080] In some embodiments, R is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- or 6-membered heterocycloalkyl, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- or 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents;

[0081] Alternatively, R is connected to R g or R is connected to R j to form a 5- to 7-membered heterocyclic group, which is optionally substituted with one or more halogen, amino, C 1-3 alkyl or cyano.

[0082] In some embodiments, R is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- or 6-membered heterocycloalkyl, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- or 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents;

[0083] Alternatively, R is connected to R g or R is connected to R j to form a 5- to 6-membered heterocyclic group, which is optionally substituted with one or more halogen, amino, C 1-3 alkyl or cyano.

[0084] In some embodiments, R is selected from hydrogen, C 1-3 alkyl, C3-6 A cycloalkyl group, a phenyl group or a 5- to 6-membered hetero cycloalkyl group, said C 1-3 alkyl group, C 3-6 The cycloalkyl group, phenyl group or 5- to 6-membered hetero cycloalkyl group is optionally substituted by one or more R a substituents;

[0085] Alternatively, R and R g Or R and R j are connected to each other to form a 5- to 6-membered hetero cyclic group.

[0086] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl is optionally substituted by one or more R a substituents;

[0087] Alternatively, R and R g Or R and R j are connected to each other to form the which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups;

[0088] Alternatively, R and R g Or R and R j are connected to each other to form Alternatively, where R and R g Or R and R j are connected to each other to form

[0089] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, is optionally substituted by one or more R a substituents;

[0090] Alternatively, R and R g Or R and R j are connected to each other to form the which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups;

[0091] Alternatively, R and R g Or R and R j are connected to each other to form

[0092] Or, where R and R g Or R and R j are connected to each other to form

[0093] In some embodiments, R is selected from C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl, and the C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents;

[0094] Or, R and R g Or R and R j are connected to each other to form a 6-membered heterocyclic group, and the 6-membered heterocyclic group is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0095] In some embodiments, R is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, the cyclopropyl, cyclopentyl, cyclohexyl, phenyl, is optionally substituted with one or more R a substituents;

[0096] Or, R and R g Or R and R j are connected to each other to form the is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0097] Or, R and R g Or R and R j are connected to each other to form the is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0098] Or, R and R g Or R and R j are connected to each other to form the is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0099] In some embodiments, R is selected from cyclohexyl or 5- to 6-membered heterocycloalkyl, and the cyclohexyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents;

[0100] Or, R and R g Or R and Rj are interconnected to form a 6-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0101] In some embodiments, R is selected from cyclohexyl, pyrrolidinyl or piperidinyl, and the cyclohexyl, pyrrolidinyl or piperidinyl is optionally substituted by one or more R a substituents;

[0102] Alternatively, R and R g or R and R j are interconnected to form the which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0103] Alternatively, R and R g or R and R j are interconnected to form the which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl or cyano groups;

[0104] Alternatively, R and R g or R and R j are interconnected to form the which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0105] In some embodiments, the R is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl or 3- to 6-membered heterocycloalkyl, and the C 1-6 alkyl, C 3-8 cycloalkyl, 5- to 6-membered heteroaryl, C 6-10 aryl or 3- to 6-membered heterocycloalkyl is optionally substituted by one or more R a substituents.

[0106] In some embodiments, the R is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, phenyl or 5- to 6-membered heterocycloalkyl, and the C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted by one or more R a substituents.

[0107] In some embodiments, the R is selected from hydrogen, C 1-3alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more R a .

[0108] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl is optionally substituted with one or more R a .

[0109] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, is optionally substituted with one or more R a .

[0110] In some embodiments, R and R g or R and R j are connected to each other to form a 5- to 8-membered heterocyclic group, and the 5- to 8-membered heterocyclic group is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0111] In some embodiments, R and R g or R and R j are connected to each other to form a 5- to 7-membered heterocyclic group, and the 5- to 7-membered heterocyclic group is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0112] In some embodiments, R and R g or R and R j are connected to each other to form a 5- to 6-membered heterocyclic group, and the 5- to 6-membered heterocyclic group is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl or cyano groups.

[0113] In some embodiments, R and R g or R and R j are connected to each other to form a 5- to 6-membered heterocyclic group.

[0114] In some embodiments, R and R g or R and R j are connected to each other to form

[0115] In some embodiments, R and R g or R and R j are connected to each other to form

[0116] In some embodiments, R and R g or R and R j are connected to each other to form

[0117] In some embodiments, R is connected to Cy such that R, Cy, and L 1 together form a 9- to 10-membered heterocyclic group, which is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl groups, or cyano groups. In some embodiments, R is connected to Cy such that R, Cy, and L 1 together form a 9-membered heterocyclic group, which is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl groups, or cyano groups.

[0118] In some embodiments, R is connected to Cy such that R, Cy, and L 1 together form a 9-membered heterocyclic group containing a nitrogen ring atom and a sulfur ring atom, which is optionally substituted with one or more halogens, amino groups, C 1-3 alkyl groups, or cyano groups.

[0119] In some embodiments, Cy is selected from phenyl, and R is connected to Cy such that R, Cy, and L 1 together form a 9-membered heterocyclic group containing a nitrogen ring atom and a sulfur ring atom.

[0120] In some embodiments, R is connected to Cy such that R, Cy, and L 1 together form

[0121] In some embodiments, R is connected to Cy such that R, Cy, and L 1 together form

[0122] In some embodiments, each R a is independently selected from halogen, deuterium, cyano, ═O, C 3-6 cycloalkyl, C 1-3 alkyl, hydroxyl, amino, or C 1-3 alkoxy, wherein the C 3-6 cycloalkyl or C 1-3 alkyl is optionally substituted with one or more halogens.

[0123] In some embodiments, each R a is independently selected from halogen, deuterium, cyano, ═O, C 3-6 cycloalkyl or C 1-3 alkyl optionally substituted with one or more halogens.

[0124] In some embodiments, each R a is independently selected from fluorine, chlorine, bromine, deuterium, cyano, ═O, C 5-6 cycloalkyl or methyl optionally substituted with one or more fluorines.

[0125] In some embodiments, each R a is independently selected from fluorine, cyclopentyl, cyclohexyl, cyano, ═O, methyl, trifluoromethyl or deuterium.

[0126] In some embodiments, each R a is independently selected from fluorine or methyl.

[0127] In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, or R is connected to R g or R is connected to R j to form Alternatively, R is connected to Cy such that R, Cy and L 1 together form or R is connected to R g or R is connected to R j to form or R is connected to R g or R is connected to R j to form Alternatively, R is connected to Cy such that R, Cy and L 1 together form

[0128] In some embodiments, R is selected from

[0129] In some embodiments, each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkylNH-, (C1-6 alkyl 2 N-, C 3-6 cycloalkylNH-, 3- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl, C 1-6 alkylC(O)-, C 1-6 alkylC(O)NH-, NH 2 C(O)-, C 1-6 alkylNHC(O)-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylOC(O)- or C 1-6 alkylC(O)O-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkylNH-, 3- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl, C 1-6 alkylC(O)-, C 1-6 alkylC(O)NH-, NH 2 C(O)-, C 1-6 alkylNHC(O)-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylOC(O)- or C 1-6 alkylC(O)O- is optionally substituted with one or more halogens, hydroxyl groups, cyano groups or amino groups.

[0130] In some embodiments, each R 1 is independently selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkoxy, C 1-3 alkylC(O)-, NH 2 C(O)-, C 1-6 alkylNHC(O)- or (C 1-6 alkyl) 2 NC(O)-, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkoxy, C 1-3 alkylC(O)-, C 1-6 alkylNHC(O)- or (C 1-6 alkyl) 2 NC(O)- is optionally substituted with one or more halogens.

[0131] In some embodiments, each R 1 is independently selected from fluorine, chlorine, bromine, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkoxy, CH 3 C(O)- or NH 2 C(O)-, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with one or more fluorines.

[0132] In some embodiments, each R 1 is independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, CH 3 CH 2 O-, CH 3 CH(CH 3 )O-, cyclopropyl-O-, CF 3 O-, CH 3 C(O)- or NH 2 C(O)-.

[0133] In some embodiments, n is selected from 0, 1, 2 or 3.

[0134] In some embodiments, n is selected from 0, 1 or 2.

[0135] In some embodiments, n is selected from 0 or 1.

[0136] In some embodiments, n is selected from 1 or 2.

[0137] In some embodiments, n is selected from 0. In some embodiments, L is selected from -CO-.

[0138] In some embodiments, L is selected from a bond.

[0139] In some embodiments, R 4 is selected from 6- to 10-membered heteroaryl, C 3-6 cycloalkyl, phenyl or 3- to 6-membered heterocycloalkyl, wherein the 6- to 10-membered heteroaryl, C 3-6 cycloalkyl, phenyl or 3- to 6-membered heterocycloalkyl is optionally substituted with one or more R b groups.

[0140] In some embodiments, R 4 is selected from 6-membered or 10-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the 6-membered or 10-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted with one or more R b groups.

[0141] In some embodiments, R 4 is selected from pyridyl, pyrimidinyl, pyrazinyl, isoquinolyl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the pyridyl, pyrimidinyl, pyrazinyl, isoquinolyl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted with one or more R b .

[0142] In some embodiments, R 4 is selected from pyridyl or cyclopropyl, the pyridyl or cyclopropyl is optionally substituted with one or more R b .

[0143] In some embodiments, R 4 is selected from cyclopropyl optionally substituted with one or more R b .

[0144] In some embodiments, R 4 is selected from cyclopropyl.

[0145] In some embodiments, R b is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(O)OC 1-6 alkyl, -OC(O)C 1-6 alkyl, C 1-6 alkylC(O)NH-, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH-, R d R e NSO 2 -, or C 1-6 alkyl substituted with one or more halogens.

[0146] In some embodiments, R b is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C1-3 alkyl, C 1-3 alkyl C(O)NH-, C 3-6 cycloalkyl C(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C substituted by one or more fluorines 1-3 alkyl.

[0147] In some embodiments, R b is selected from fluorine, chlorine, bromine, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl C(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C substituted by 1, 2 or 3 fluorines 1-3 alkyl.

[0148] In some embodiments, R c , R d or R e are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, or R d is connected to R e to form a 3- to 6-membered heterocycloalkyl, which is optionally substituted by one or more groups selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C substituted by one or more halogens 1-6 alkyl.

[0149] In some embodiments, R c , R d or R e are each independently selected from C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl.

[0150] In some embodiments, R c , R d or R e are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl or 5- to 6-membered heteroaryl.

[0151] In some embodiments, R c , R d or R e is independently selected from C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl. In some embodiments, R c , R d or R e is independently selected from cyclopropyl or phenyl.

[0152] In some embodiments, R b is selected from fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl-CONH-, cyclopropyl-SO 2 NH-, phenyl-SO 2 NH- or trifluoromethyl.

[0153] In some embodiments, the structural unit is selected from

[0154] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; in some embodiments, m is selected from 0, 1, 2, 3 or 4.

[0155] In some embodiments, the structural unit is selected from In some embodiments, the structural unit is selected from In some embodiments, the structural unit is selected from In some embodiments, the structural unit is selected from

[0156] In some embodiments, the structural unit is selected from

[0157] Furthermore, the structural unit is selected from

[0158]

[0159] In some embodiments, the above structural unit is selected from Among them, the definition of m is the same as above.

[0160] In some embodiments, the structural unit is selected from In some embodiments, the structural unit is selected from

[0161] In some embodiments, the structural unit is selected from In some embodiments, the structural unit is selected from

[0162] In some embodiments, the structural unit is selected from Or R is connected to Cy such that R, Cy, and L 1 together form

[0163] In some embodiments, the structural unit is selected from Or R is connected to Cy such that R, Cy, and L 1 together form

[0164] In some embodiments, the structural unit is selected from

[0165] In some embodiments, the structural unit is selected from

[0166] In some embodiments, the structural unit is selected from

[0167] In some embodiments, the above structural unit is selected from

[0168]

[0169]

[0170] In some embodiments, the above structural unit is selected from

[0171]

[0172]

[0173] In some embodiments, the above structural unit is selected from

[0174] In some embodiments, the above structural unit is selected from

[0175] In some embodiments, the above structural unit is selected from

[0176] In some embodiments, the above compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula I', a compound of formula I", or a pharmaceutically acceptable salt thereof:

[0177]

[0178] wherein,

[0179] Cy is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclic group;

[0180] each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylC(O)-, C 1-8 alkylNH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkylNH-, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 1-8 alkylC(O)NH-, C1-8 alkyl NHC(O)-, (C 1-8 alkyl) 2 NC(O)-, C 1-8 alkyl OC(O)-, C 1-8 alkyl C(O)O-, C 3-10 cycloalkyl or C 3-10 cycloalkoxy, wherein the C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkyl C(O)-, C 1-8 alkyl NH-, (C 1-8 alkyl) 2 N-, C 3-10 cycloalkyl NH-, 3- to 10-membered heteroalkyl, 3- to 10-membered heteroaryl, C 1-8 alkyl C(O)NH-, C 1-8 alkyl NHC(O)-, (C 1-8 alkyl) 2 NC(O)-, C 1-8 alkyl OC(O)-, C 1-8 alkyl C(O)O-, C 3-10 cycloalkyl or C 3-10 cycloalkoxy is optionally substituted with one or more halogens;

[0181] n is selected from 0, 1, 2, 3 or 4;

[0182] R 2 、R 3 are each independently selected from hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, phenyl or halogen-substituted C 1-8 alkyl;

[0183] Alternatively, R 2 、R 3 are joined to form a 3- to 7-membered heteroalkyl, which is optionally substituted with one or more R a substituents;

[0184] R a is selected from deuterium, oxo, halogen, hydroxy, cyano, amino, C 1-8 alkyl or C 1-8 alkoxy, wherein the C 1-8 alkyl or C 1-8 alkoxy is optionally substituted with one or more groups selected from halogen, hydroxy, cyano or amino;

[0185] L is selected from -C(O)- or a bond;

[0186] R 4 is selected from 5- to 10-membered heteroaryl, C3-10 Cycloalkyl, C 6-10 Aryl or 3-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl, C 3-10 Cycloalkyl, C 6-10 Aryl or 3-10 membered heterocycloalkyl is optionally substituted by one or more R b Substituted;

[0187] R b Is selected from halogen, cyano, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, C 1-8 Alkyl-NH-, (C 1-8 Alkyl) 2 N-, C 3-10 Cycloalkyl-NH-, -C(O)NH-C 1-8 Alkyl, -C(O)N(C 1-8 Alkyl) 2 、-C(O)O-C 1-8 Alkyl, -OC(O)-C 1-8 Alkyl, C 1-8 Alkyl-C(O)NH-, C 3-10 Cycloalkyl-C(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C 1-8 Alkyl substituted by one or more halogens;

[0188] R c 、R d Or R e Are each independently selected from hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, or R d Is connected to R e To form a 3-7 membered heterocycloalkyl, and the 3-7 membered heterocycloalkyl is optionally substituted by one or more groups selected from the following: halogen, hydroxy, cyano, amino, C 1-8 Alkyl or C 1-8 Alkoxy or C 1-8 Alkyl substituted by one or more halogens.

[0189] In some embodiments, Cy is selected from C 6-10 Aryl, 5-10 membered heteroaryl or benzo 4-6 membered heterocyclic group.

[0190] In some embodiments, Cy is selected from C 6-10 aryl, 5- or 6-membered heteroaryl, or benzo-5- or 6-membered heterocyclic group.

[0191] In some embodiments, Cy is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, or benzo-6-membered heterocyclic group.

[0192] In some embodiments, Cy is selected from phenyl, naphthyl, pyridyl, thienyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl.

[0193] In some embodiments, n is selected from 0, 1, 2, or 3.

[0194] In some embodiments, n is selected from 0, 1, or 2.

[0195] In some embodiments, n is selected from 0 or 1.

[0196] In some embodiments, n is selected from 1 or 2.

[0197] In some specific embodiments, each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylC(O)-, C 3-10 cycloalkyl, or C 3-10 cycloalkoxy, wherein the C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylC(O)-, C 3-10 cycloalkyl, or C 3-10 cycloalkoxy is optionally substituted with one or more halogens.

[0198] In some specific embodiments, each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylC(O)-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkylNH-, 3- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C 1-6 alkylC(O)NH-, C 1-6 alkylNHC(O)-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C3-6 Cycloalkyl or C 3-6 cycloalkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C(O)-, C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl NH-, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 alkyl C(O)NH-, C 1-6 alkyl NHC(O)-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkyl OC(O)-, C 1-6 alkyl C(O)O-, C 3-6 cycloalkyl or C 3-6 cycloalkoxy is optionally substituted with one or more halogens.

[0199] In some embodiments, each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C(O)-, C 3-6 cycloalkyl or C 3-6 cycloalkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C(O)-, C 3-6 cycloalkyl or C 3-6 cycloalkoxy is optionally substituted with one or more halogens.

[0200] In some specific embodiments, each R 1 is independently selected from amino, fluoro, chloro, bromo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl C(O)-, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 3-6 cycloalkyl NH-, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-3 alkyl C(O)NH-, C 1-3 alkyl NHC(O)-, (C 1-3 alkyl) 2 NC(O)-, C 1-3 alkyl OC(O)-, C 1-3 alkyl C(O)O- or C3-6 Cyclanoxy, C substituted by one or more fluorines 1-3 alkyl or C substituted by one or more fluorines 1-3 alkoxy.

[0201] In some specific embodiments, each R 1 is independently selected from amino, fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl C(O)-, C 1-3 alkyl NH-, (C 1-3 alkyl) 2 N-, C 3-6 cycloalkyl NH-, 3-6 membered heteroalkyl, 5-6 membered heteroaryl, C 1-3 alkyl C(O)NH-, C 1-3 alkyl NHC(O)-, (C 1-3 alkyl) 2 NC(O)-, C 1-3 alkyl OC(O)-, C 1-3 alkyl C(O)O-, C 3-6 cyclanoxy, C substituted by 1, 2 or 3 fluorines 1-3 alkyl or C substituted by 1, 2 or 3 fluorines 1-3 alkoxy. In some specific embodiments, each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkyl C(O)-, C 3-10 cycloalkyl or C 3-10 cyclanoxy, the C 1-8 alkyl, C 1-8 alkoxy, C 1-6 alkyl C(O)-, C 3-10 cycloalkyl or C 3-10 cyclanoxy is optionally substituted by one or more halogens.

[0202] In some specific embodiments, each R 1 is independently selected from amino, halogen, cyano, hydroxy, fluorine, chlorine, bromine, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C(O)-, C 3-6 cycloalkyl or C 3-6 cyclanoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C(O)-, C 3-6A cycloalkyl group or C 3-6 The cycloalkyloxy group is optionally substituted with one or more halogens.

[0203] In some specific embodiments, each R 1 is independently selected from amino, fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkyloxy, C 1-3 alkyl C(O)-, C 3-6 cycloalkyloxy, C alkyl substituted with one or more fluorines 1-3 or C alkyloxy substituted with one or more fluorines. 1-3

[0204] In some specific embodiments, each R 1 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkyloxy, C 1-3 alkyl C(O)-, C 3-6 cycloalkyloxy, C alkyl substituted with one or more fluorines 1-3 or C alkyloxy substituted with one or more fluorines. 1-3

[0205] In some specific embodiments, each R 1 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkyloxy, C 1-3 alkyl-CO-, C 3-6 cycloalkyloxy, C alkyl substituted with 1, 2 or 3 fluorines 1-3 or C alkyloxy substituted with 1, 2 or 3 fluorines. In some specific embodiments, each R 1-3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, CH 1 C(O)-, CF 3 O-, CH 3 CH 3 CH 2 O-, CH 3 CH(CH 3 )O- or cyclopropyl-O-. In some embodiments, R 2 , R 3 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or halogen-substituted C 1-6 alkyl, or R 2 , R 3 are connected to each other to form a 5-6 membered heteroalkyl ring, and the 5-6 membered heteroalkyl ring is optionally substituted with one or more R a ​​Substituted.

[0206] In some embodiments, R 2 , R 3 are each independently selected from hydrogen, C 1-3 alkyl, C 3-4 cycloalkyl, or halogen-substituted C 1-3 alkyl, or R 2 , R 3 are joined to form a 5- to 6-membered heteroalkyl, which 5- to 6-membered heteroalkyl is optionally substituted with one or more R a Substituted.

[0207] In some embodiments, R 2 , R 3 are each independently selected from hydrogen, methyl, ethyl, n-propyl, or cyclopropyl, or R 2 , R 3 are joined to form pyrrolidinyl, piperidinyl, or morpholinyl, which pyrrolidinyl, piperidinyl, or morpholinyl is optionally substituted with one or more R a Substituted.

[0208] In some embodiments, R 2 , R 3 are joined to form a 3- to 7-membered heteroalkyl, which 3- to 7-membered heteroalkyl is optionally substituted with one or more R a Substituted.

[0209] In some embodiments, R 2 , R 3 are joined to form a 3- to 6-membered heteroalkyl, which 3- to 6-membered heteroalkyl is optionally substituted with one or more R a Substituted.

[0210] In some embodiments, R 2 , R 3 are joined to form a 4-, 5-, or 6-membered heteroalkyl, which 4-, 5-, or 6-membered heteroalkyl is optionally substituted with one or more R a Substituted.

[0211] In some embodiments, R 2 , R 3 are joined to form a 4-, 5-, or 6-membered heteroalkyl, which 4-, 5-, or 6-membered heteroalkyl is optionally substituted with one or more R a Substituted, wherein the 4-, 5-, or 6-membered heteroalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0212] In some embodiments, R 2 , R 3Combine to form a pyrrolidinyl, piperidinyl or morpholinyl group, which pyrrolidinyl, piperidinyl or morpholinyl group is optionally substituted by one or more R a substituents.

[0213] In some embodiments, R 2 is selected from hydrogen, and R 3 is selected from hydrogen, methyl, ethyl, n-propyl, cyclopropyl, or R 2 , R 3 combine to form a pyrrolidinyl, piperidinyl or morpholinyl group, which pyrrolidinyl, piperidinyl or morpholinyl group is optionally substituted by one or more R a substituents.

[0214] In some embodiments, R a is selected from deuterium, oxo, halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more groups selected from halogen, hydroxy, cyano or amino.

[0215] In some embodiments, R a is selected from deuterium, oxo, halogen, hydroxy, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by one or more groups selected from halogen, hydroxy, cyano or amino.

[0216] In some embodiments, R a is selected from deuterium, oxo, fluorine, chlorine, bromine, hydroxy, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxy, cyano or amino.

[0217] In some embodiments, R a is selected from deuterium, oxo, fluorine, chlorine, cyano, amino or C 1-3 alkyl optionally substituted by one or more fluorines.

[0218] In some embodiments, R a is selected from deuterium, oxo, fluorine, -CF 3 3, cyano or methyl.

[0219] In still other embodiments, R a is selected from halogen, hydroxy, cyano, amino, C 1-8alkyl or C 1-8 alkoxy group.

[0220] In some other embodiments, R a is selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy group.

[0221] In some other embodiments, R a is selected from halogen, hydroxyl, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy group. In some embodiments, R 2 is selected from hydrogen, and R 3 is selected from hydrogen, methyl, ethyl, n-propyl, cyclopropyl, or R 2 , R 3 are connected to each other to form pyrrolidinyl, piperidinyl or morpholinyl.

[0222] In some embodiments, R 2 , R 3 are each independently selected from hydrogen.

[0223] In some embodiments, R 2 , R 3 are connected to each other to form a 3- to 7-membered heterocycloalkyl group.

[0224] In some embodiments, R 2 , R 3 are connected to each other to form a 3- to 6-membered heterocycloalkyl group.

[0225] In some embodiments, R 2 , R 3 are connected to each other to form a 4-, 5- or 6-membered heterocycloalkyl group.

[0226] In some embodiments, L is selected from -CO-.

[0227] In some embodiments, L is selected from a bond.

[0228] In some embodiments, R 4 is selected from a 5- to 10-membered heteroaryl group, C 3-10 cycloalkyl group or C 6-10 aryl group, wherein the 5- to 10-membered heteroaryl group, C 3-10 cycloalkyl group or C 6-10 aryl group is optionally substituted with one or more R b groups.

[0229] In some embodiments, R 4 is selected from a 6- to 10-membered heteroaryl group, C 3-6 cycloalkyl group or phenyl, wherein the 6- to 10-membered heteroaryl group, C3-6 The cycloalkyl or phenyl is optionally substituted by one or more R b .

[0230] In some embodiments, R 4 is selected from 6- or 10-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the 6- or 10-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted by one or more R b .

[0231] In some embodiments, R 4 is selected from pyridyl, pyrimidinyl, pyrazinyl, isoquinolinyl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the pyridyl, pyrimidinyl, pyrazinyl, isoquinolinyl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted by one or more R b .

[0232] In some specific embodiments, R b is selected from halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylC(O)NH-, R c SO 2 NH- or C 1-8 alkyl substituted by one or more halogen

[0233] In some embodiments, R b is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH- or C 1-6 alkyl substituted by one or more halogen

[0234] In some embodiments, R b is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, 5-6-membered heteroaryl, 3-6-membered heterocycloalkyl, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(O)OC 1-6 alkyl, -OC(O)-C 1-6 alkyl, C 1-6 alkyl-C(O)NH-, C 3-6Cycloalkyl-C(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C alkyl substituted by one or more halogens 1-6 alkyl

[0235] In some embodiments, R b is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH- or C alkyl substituted by one or more fluorines 1-3 alkyl

[0236] In some embodiments, R b is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, -C(O)NH-C 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 -, -C(O)OC 1-3 alkyl, -OC(O)-C 1-3 alkyl, C 1-3 alkyl-C(O)NH-, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH-, R d R e NSO 2 - or C alkyl substituted by one or more fluorines 1-3 alkyl

[0237] In some embodiments, R b is selected from fluorine, chlorine, bromine, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkylCONH-, R c SO 2 NH-, or C alkyl substituted by 1, 2 or 3 fluorines 1-3 alkyl

[0238] In some embodiments, R b is selected from fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl-CONH-, cyclopropyl-SO 2NH-, phenyl-SO 2 NH- or trifluoromethyl.

[0239] In some embodiments, R c , R d or R e are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, or R d is joined to R e to form a 3- to 6-membered heterocycloalkyl, which 3- to 6-membered heterocycloalkyl is optionally substituted with one or more groups selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy or one or more halogen-substituted C 1-6 alkyl.

[0240] In some embodiments, R c , R d or R e are each independently selected from C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl.

[0241] In some embodiments, R c , R d or R e are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl or 5- to 6-membered heteroaryl.

[0242] In some embodiments, R c , R d or R e are each independently selected from C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl.

[0243] In some embodiments, R c , R d or R e are each independently selected from cyclopropyl or phenyl.

[0244] In some embodiments, R c is selected from hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl.

[0245] In some embodiments, Rc Selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl or 5- or 6-membered heteroaryl.

[0246] In some embodiments, R c is selected from C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- or 6-membered heteroaryl.

[0247] In some embodiments, R c is selected from cyclopropyl or phenyl.

[0248] In some embodiments, the heteroatom in the heterocyclic group, heteroaryl or heterocycloalkyl is selected from N, O or S.

[0249] In some embodiments, the heteroatom in the heterocyclic group, heteroaryl or heterocycloalkyl is selected from N or O.

[0250] In some embodiments, the heteroatom in the heterocyclic group, heteroaryl or heterocycloalkyl is selected from N or S.

[0251] In some embodiments, the heteroatom in the heterocyclic group, heteroaryl or heterocycloalkyl is selected from N.

[0252] In some embodiments, the compound of formula I, I' or I'' or a pharmaceutically acceptable salt thereof is selected from the compounds of formula I-1, I-2, II-1, II-2 or II-3 or a pharmaceutically acceptable salt thereof

[0253] wherein R 1 , R 2 , R 3 , R 4 , n, L are as defined above.

[0254] In some specific embodiments, the above structural unit is selected from

[0255] In some specific embodiments, the above structural unit is selected from

[0256] In some specific embodiments, the above structural unit is selected from

[0257] In some specific embodiments, the above structural unit selected from further optionally selected from even further optionally selected from

[0258] In some specific embodiments, the above structural unit selected from where m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, m is selected from 0, 1, 2, 3 or 4.

[0259] In some specific embodiments, the above structural unit selected from further selected from where m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some specific embodiments, m is selected from 0, 1, 2, 3 or 4. In some specific embodiments, the above structural unit selected from further selected from where m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some specific embodiments, m is selected from 0, 1, 2, 3 or 4.

[0260] In some specific embodiments, the above structural unit selected from where m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some specific embodiments, m is selected from 0, 1, 2, 3 or 4.

[0261] In some specific embodiments, the above structural unit selected from

[0262]

[0263]

[0264] In some specific embodiments, the above structural unit selected from

[0265] In some other specific embodiments, the above structural unit selected from

[0266]

[0267] In some embodiments, the above structural units are selected from

[0268] In some embodiments, the above structural units are selected from In some embodiments, the above structural units are selected from In some embodiments, the above structural units are selected from

[0269] In some specific embodiments, the structural units are selected from

[0270] In some specific embodiments, the structural units are selected from

[0271] In some other specific embodiments, the above structural units are selected from

[0272] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the compounds of IV-1, IV-2, V-1, V-2, VI-1 or VI-2 or a pharmaceutically acceptable salt thereof:

[0273]

[0274] wherein, R, R 1 , R a , n, L 1 , m, and Cy are as defined above.

[0275] In some embodiments, the present application includes the variables defined above and their embodiments, as well as any combination thereof.

[0276] On the other hand, the present application provides the following compounds or pharmaceutically acceptable salts thereof:

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] On the other hand, the present application provides the following compounds or their pharmaceutically acceptable salts:

[0289]

[0290]

[0291]

[0292] On the other hand, the present application also provides a pharmaceutical composition comprising the above-mentioned compound of the present application or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0293] On the other hand, the present application also provides a method for treating or preventing various diseases related to TYK2, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically or prophylactically effective amount of the above-mentioned compound of the present application, its pharmaceutically acceptable salt, or its pharmaceutical composition.

[0294] On the other hand, the present application also provides the use of the above-mentioned compound of the present application, its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating or preventing various diseases related to TYK2.

[0295] On the other hand, the present application also provides the use of the above-mentioned compound of the present application, its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment or prevention of various diseases related to TYK2.

[0296] On the other hand, the present application also provides the above-mentioned compound of the present application, its pharmaceutically acceptable salt, or its pharmaceutical composition for treating or preventing various diseases related to TYK2.

[0297] In some embodiments, the various TYK2-related diseases are selected from inflammatory or autoimmune diseases.

[0298] The compounds of the present application have good in vitro enzyme or cell activity, metabolic stability such as liver microsome metabolic stability, good in vivo pharmacodynamic and pharmacokinetic properties.

[0299] Definitions

[0300] Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0301] When a covalent bond in certain structural units or groups in the present application is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group, as long as the valence bond connection rule is not violated.

[0302] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0303] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, ethyl "optionally" substituted by a halogen means that ethyl can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 , etc.) or fully substituted (CF 2 CF 3 ). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0304] C m-n herein means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0305] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by two Rs, each R has independent options.

[0306] When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.

[0307] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly linked. For example, in A-L’-Z, when L’ represents a covalent bond, it means that the structure is actually A-Z.

[0308] When a substituent's bond cross-links to two atoms on a ring, such a substituent can bond to any atom on this ring. For example, the structural unit means that it can be substituted at any position on cyclohexyl or cyclohexadiene.

[0309] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0310] The term "alkyl" refers to a hydrocarbon group with the general formula C n H 2n+1 . This alkyl can be straight-chain or branched-chain. For example, the term "C 1-6 alkyl" refers to an alkyl containing 1 to 6 carbon atoms (such as 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.). Similarly, the alkyl moieties of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio (i.e., alkyl) have the same definition as above. Also, for example, the term "C 1-3 alkyl" refers to an alkyl containing 1 to 3 carbon atoms (such as methyl, ethyl, propyl, and isopropyl).

[0311] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), etc.

[0312] The term "alkoxy" refers to -O-alkyl.

[0313] The term "cyclalkyloxy" means -O-cycloalkyl.

[0314] The term "cycloalkyl" means a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically 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, bicyclo[1.1.1]pent-1-yl, etc. For example, C 3-4 Cycloalkyl includes cyclopropyl and cyclobutyl.

[0315] The term "heterocycloalkyl" refers to a fully saturated cyclic group that can exist as a monocyclic, bridged (including fused) or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, aziridinyl; non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl; examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl; examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred is a monocyclic heterocycloalkyl having 5 or 6 ring atoms.

[0316] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3- to 10-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Non-limiting examples of heterocyclic group include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 1,4-benzodioxanyl, etc. One or more ═O groups may also be present on the carbon or sulfur atoms of the heterocyclic group. For example, non-limiting examples of 5-membered heterocyclic group include, but are not limited to Non-limiting examples of 6-membered heterocyclic group include, but are not limited to Non-limiting examples of 9-membered heterocyclic group include, but are not limited to

[0317] The term "aryl" refers to an aromatic ring group of a fully carbon monocyclic or fused polycyclic system having a conjugated π electron system. For example, an aryl may have 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, anthracenyl, 1,2,3,4-tetrahydronaphthalene, etc.

[0318] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5 - 8 membered ring, or multiple fused rings containing 6 - 14, especially 6 - 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.

[0319] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present application.

[0320] Unless otherwise specified, a solid wedge bond and a dashed wedge bond represent the absolute configuration of a stereocenter, a straight solid bond and a straight dashed bond represent the relative configuration of a stereocenter, a wavy line represents a solid wedge bond or a dashed wedge bond or a wavy line represents a straight solid bond and a straight dashed bond

[0321] Unless otherwise specified, when there is a double bond structure in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a pair of lone pairs on the nitrogen atom is regarded as one of the substituents it is connected to), if the atoms on the double bond in the compound are connected to their substituents by a wavy line it represents the (Z)-isomer, (E)-isomer or a mixture of the two isomers of the compound.

[0322] The term "treatment" means administering the compounds or formulations described in the present application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0323] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0324] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to subside.

[0325] The term "prevention" means administering the compounds or formulations described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0326] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0327] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0328] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, etc. can be mentioned.

[0329] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0330] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair 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, oils, solvents, water, etc.

[0331] The term "comprise" or "comprises" or its English variants such as "comprises" or "comprising" shall be construed in an open, non-exclusive sense, i.e., "including but not limited to".

[0332] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Specific examples of proton tautomers are imidazole moieties where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0333] The present application also includes isotopically labeled compounds of the present application that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present application 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 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and so on.

[0334] Certain isotopically labeled compounds of the present application (e.g., those labeled with 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O, 13 N, 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an unlabeled reagent with an isotopically labeled reagent by procedures similar to those in the protocols and / or examples disclosed below.

[0335] In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and may thus be preferred in certain cases, where deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of the compound are included within the scope of the present application.

[0336] Compounds of the present application can be asymmetric, e.g., having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present application containing an asymmetric carbon atom can be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0337] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0338] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0339] The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, sugarcoating pill-making, grinding, emulsifying, freeze-drying methods, etc.

[0340] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to a patient.

[0341] Solid oral compositions can be prepared by conventional mixing, filling, or tabletting methods. For example, they can be obtained by the following method: mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or dragee. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents, etc.

[0342] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in suitable unit dosage forms.

[0343] The therapeutic dose of the compounds of the present application can depend on, for example: the specific use of the treatment, the manner of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed and depends on various factors, including the dose, chemical properties (such as hydrophobicity), and the route of administration. For example, the compounds of the present application can be provided by a physiologically buffered aqueous solution containing about 0.1 - 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight per day. In certain embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dose is likely to depend on such variables as the type and progression of the disease or disorder, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and its route of administration. The effective dose can be extrapolated from the dose - response curve derived from in vitro or animal model test systems.

[0344] The compounds of the present application can be prepared by a variety of synthetic methods well - known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of these with other chemical synthesis methods, and equivalent replacement methods well - known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0345] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0346] An important consideration in synthetic route planning in this field is to select a suitable protecting group for reactive functional groups (such as the amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0347] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:

[0348] Route 1:

[0349]

[0350] Route 2:

[0351]

[0352] Route 3:

[0353]

[0354] Among them, the definitions of Cy, R, R 1 , R 2 , R 3 , R 4 , n, L, L 1 are as described above.

[0355] The following abbreviations are used in this application:

[0356] DIPEA represents diisopropylethylamine; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd(dba) 2 represents bis(dibenzylideneacetone)palladium; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT represents 1-hydroxybenzotriazole.

[0357] For clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All reagents used in this application are commercially available and can be used without further purification. Detailed Description of the Invention

[0358] Example 1: Compound 1-e

[0359]

[0360] 1) Preparation method of Compound 1-a:

[0361] Dissolve lithium 4,6-dichloropyridazine-3-carboxylate (50 g) in 500 mL of dichloromethane. At 0 °C, after adding a catalytic amount of DMF, slowly add oxalyl chloride (96 g) to the above solution. After the addition is complete, continue stirring the reaction at room temperature for 2 h until the reaction is complete. Concentrate the reaction solution. Dissolve deuterated methylamine (18.6 g) and DIPEA (162 g) in 200 mL of dichloromethane. At -25 °C, stir until clear, dissolve the above concentrate in 300 mL of dichloromethane, and slowly add it to the above solution. After the addition is complete, continue stirring for 2 h. Add 750 mL of water to quench the reaction, extract twice with dichloromethane (2 × 500 mL), combine the organic phases, wash with saturated aqueous sodium chloride solution, and anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate to obtain compound 1-a (52 g). ESI-MS: m / z = 209.2 [M+H] + 。

[0362] 2) Preparation method of compound 1-b:

[0363] Dissolve compound 1-a (12 g), 2-methoxy-3-aminobenzoic acid hydrochloride (11.7 g), and zinc acetate (31.6 g) in 200 mL of isopropanol. Stir at 50 °C for 8 h. Concentrate the reaction solution, add purified water, stir at room temperature overnight, filter, and dry in vacuo at 50 °C to obtain compound 1-b (10.7 g).

[0364] 1 H-NMR (DMSO-d 6 ) δ: 13.10 (1H, brs), 11.33 (1H, s), 10.96 (1H, s), 9.14 (1H, s), 8.11 (1H, s), 7.63 (1H, dd, J = 1.0, 7.5), 7.51 (1H, dd, J = 1.5, 8.5), 7.27 (1H, t, J = 8.0), 3.76 (3H, s), 2.09 (1H, m), 0.83 (4H, m).

[0365] 13 C-NMR (DMSO-d 6 ) δ: 174.2, 167.3, 167.0, 162.8, 156.3, 152.2, 145.1, 135.5, 132.9, 127.7, 127.0, 125.9, 124.6, 97.2, 62.2, 40.0, 14.9, 8.6.

[0366] ESI-MS: m / z = 340.09 [M+H] + 。

[0367] 3) Preparation of Compound 1-c:

[0368] Dissolve Compound 1-b (2.0 g), cyclopropylcarboxamide (0.5 g), palladium acetate (0.2 g), Xantphos (0.6 g) and cesium carbonate (3.8 g) in 3 mL of dioxane in sequence. Under nitrogen protection, heat to 130 °C and react for 5 h. Concentrate the reaction solution and purify it by column chromatography to obtain Compound 1-c (1.3 g). ESI-MS: m / z = 389.16 [M+H] + .

[0369] 4) Preparation of Compound 1-e:

[0370] Dissolve Compound 1-c (0.15 g), 2-aminobenzoyl (Compound 1-d, 0.06 g), EDCI (0.16 g), HOBT (0.1 g) and triethylamine (0.17 g) in DMF and react at room temperature for 5 h. Concentrate and purify the concentrate by preparative liquid phase to obtain Compound 1-e (32 mg).

[0371] 1 1H-NMR (DMSO-d 6 ) δ: 12.17 (1H, brs), 11.36 (1H, s), 11.02 (1H, s), 9.17 (1H, s), 8.63 - 8.65 (1H, s), 8.20 - 8.26 (2H), 7.66 - 7.90 (4H, m), 7.63 (1H, m), 7.55 (1H, m), 7.20 (1H, m), 3.79 (3H, s), 2.10 (1H, m), 0.83 (4H, m).

[0372] 13 13C-NMR (DMSO-d 6 ) δ: 174.2, 170.9, 167.0, 163.8, 156.4, 150.9, 145.0, 139.2, 135.5, 132.5, 132.3, 130.1, 128.9, 126.4, 125.6, 125.1, 123.5, 122.3, 121.6, 97.2, 62.5, 40.0, 14.9, 8.6.

[0373] ESI-MS: m / z = 507.1 [M+H] + .

[0374] Example 2-e: Compound 2-e

[0375]

[0376] Preparation method of Compound 2-e

[0377] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 2-d to obtain compound 2-e. ESI-MS: m / z = 575.14 [M+H] + 。

[0378] Example 3: Compound 3-e

[0379]

[0380] Preparation method of compound 3-e

[0381] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 3-d to obtain compound 3-e. ESI-MS: m / z = 521.14 [M+H] + 。

[0382] 1 H-NMR(DMSO-d 6 ) δ: 12.32(1H, s), 11.42(1H, s), 11.02(1H, s), 9.18(1H, s), 8.52(1H, s), 8.20(2H, s), 7.71(1H, d, J = 8.0), 7.66(2H, m), 7.59(1H, d, J = 8.0), 7.35(1H, t, J = 8.0), 7.01(1H, d, J = 8.0), 3.77(3H, s), 2.38(3H, s), 2.12(1H, m), 0.84(4H, m).

[0383] Example 4: Compound 4-e

[0384]

[0385] Preparation method of compound 4-e

[0386] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 4-d to obtain compound 4-e. ESI-MS: m / z = 541.04 [M+H] + 。

[0387] Example 5: Compound 5-e

[0388]

[0389] Preparation method of compound 5-e

[0390] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), replace Compound 1-d with Compound 5-d to obtain Compound 5-e. ESI-MS: m / z = 525.11 [M+H] + 。

[0391] 1 H-NMR (DMSO-d 6 ) δ: 12.38 (1H, s), 11.37 (1H, s), 11.02 (1H, s), 9.18 (1H, s), 8.78 (1H, m), 8.34 (1H, s), 8.19 (1H, s), 7.84 (2H, m), 7.69 (2H, dd, J = 8.0, 8.0), 7.37 (1H, t, J = 8.0), 7.30 (1H, m), 3.78 (3H, s), 2.12 (1H, m), 0.84 (4H, m).

[0392] Example 6: Compound 6-e

[0393]

[0394] Preparation method of Compound 6-e

[0395] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), replace Compound 1-d with Compound 6-d to obtain Compound 6-e. ESI-MS: m / z = 537.12 [M+H] + 。

[0396] Example 7: Compound 7-e

[0397]

[0398] Preparation method of Compound 7-e

[0399] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), replace Compound 1-d with Compound 7-d to obtain Compound 7-e. ESI-MS: m / z = 521.15 [M+H] + 。

[0400] Example 8: Compound 8-e

[0401]

[0402] Preparation method of Compound 8-e

[0403] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), replace Compound 1-d with Compound 8-d to obtain Compound 8-e. ESI-MS: m / z = 575.09 [M+H]+ .

[0404] Example 9: Compound 9-e

[0405]

[0406] Preparation method of Compound 9-e

[0407] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), replace Compound 1-d with Compound 9-d to obtain Compound 9-e. ESI-MS: m / z = 508.11 [M+H] + .

[0408] Example 10: Compound 10-e

[0409]

[0410] Preparation method of Compound 10-e

[0411] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), replace Compound 1-d with Compound 10-d to obtain Compound 10-e. ESI-MS: m / z = 508.08 [M+H] + .

[0412] Example 11: Compound 11-e

[0413]

[0414] Preparation method of Compound 11-e

[0415] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), replace Compound 1-d with Compound 11-d to obtain Compound 11-e. ESI-MS: m / z = 525.13 [M+H] + .

[0416] Example 12: Compound 12-e

[0417]

[0418] Preparation method of Compound 12-e

[0419] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), replace Compound 1-d with Compound 12-d to obtain Compound 12-e. ESI-MS: m / z = 508.08 [M+H] + .

[0420] Example 13: Compound 13-e

[0421]

[0422] Preparation method of Compound 13-e

[0423] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), Compound 1-d was replaced with Compound 13-d to obtain Compound 13-e. ESI-MS: m / z = 521.13 [M+H] + 。

[0424] 1 H-NMR (DMSO-d 6 ) δ: 12.04 (1H, s), 11.36 (1H, s), 11.01 (1H, s), 9.18 (1H, s), 8.53 (1H, d, J = 8.0), 8.19 (2H, s), 7.68 (4H, m), 7.36 (2H, m), 3.77 (3H, s), 2.33 (3H, s), 2.10 (1H, m), 0.84 (4H, m).

[0425] Example 14: Compound 14-e

[0426]

[0427] Preparation method of Compound 14-e

[0428] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), Compound 1-d was replaced with Compound 14-d to obtain Compound 14-e. ESI-MS: m / z = 557.13 [M+H] + 。

[0429] 1 H-NMR (DMSO-d 6 ) δ: 12.02 (1H, s), 11.37 (1H, s), 11.03 (1H, s), 9.19 (1H, s), 9.12 (1H, s), 8.47 (1H, s), 8.38 (1H, s), 8.21 (1H, s), 7.95 (3H, m), 7.70 (2H, m), 7.63 (1H, t, J = 8.0, 7.0), 7.54 (1H, t, J = 8.0, 7.0), 7.39 (1H, t, J = 7.5, 8.0), 3.82 (3H, s), 2.11 (1H, m), 0.85 (4H, m).

[0430] Example 15: Compound 15-e

[0431]

[0432] Preparation method of Compound 15-e

[0433] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 15-d to obtain Compound 15-e. ESI-MS: m / z = 513.07 [M+H] + 。

[0434] Example 16: Compound 16-e

[0435]

[0436] Preparation method of Compound 16-e

[0437] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 16-d to obtain Compound 16-e. ESI-MS: m / z = 507.12 [M+H] + 。

[0438] Example 17: Compound 17-e

[0439]

[0440] Preparation method of Compound 17-e

[0441] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 17-d to obtain Compound 17-e. ESI-MS: m / z = 507.11 [M+H] + 。

[0442] Example 18: Compound 18-e

[0443]

[0444] Preparation method of Compound 18-e

[0445] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 18-d to obtain Compound 18-e. ESI-MS: m / z = 575.11 [M+H] + 。

[0446] 1 H-NMR(DMSO-d 6)δ: 12.20 (1H, s), 11.37 (1H, s), 11.02 (1H, s), 9.19 (1H, s), 9.05 (1H, s), 8.46 (1H, s), 8.19 (1H, s), 8.01 (1H, s), 7.97 (1H, d, J = 8), 7.72 (2H, m), 7.59 (1H, d, J = 8), 7.39 (1H, t, J = 8), 3.81 (3H, s), 2.12 (1H, m), 0.84 (4H, m).

[0447] Example 19: Compound 19-e

[0448]

[0449] Preparation method of Compound 19-e

[0450] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), Compound 1-d was replaced with Compound 19-d to obtain Compound 19-e. ESI-MS: m / z = 508.11 [M+H] + .

[0451] 1 H-NMR (DMSO-d 6 )δ: 12.93 (1H, s), 11.35 (1H, s), 11.06 (1H, s), 9.19 (2H, d, J = 7.5), 8.50 (1H, s), 8.38 (1H, d, J = 3), 8.20 (1H, s), 7.96 (1H, s), 7.70 (3H, m), 7.38 (1H, t, J = 7.5), 3.79 (3H, s), 2.10 (1H, m), 0.84 (4H, m).

[0452] Example 20: Compound 20-e

[0453]

[0454] Preparation method of Compound 20-e

[0455] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), Compound 1-d was replaced with Compound 20-d to obtain Compound 20-e. ESI-MS: m / z = 521.17 [M+H] + .

[0456] 1 H-NMR (DMSO-d 6)δ: 11.37 (1H, s), 10.95 (1H, s), 10.21 (1H, s), 9.20 (1H, d, J = 7.5), 8.14 (1H, s), 8.06 (2H, t, J = 5), 7.93 (1H, s), 7.80 (1H, d, J = 8), 7.70 (1H, d, J = 9), 7.39 (1H, t, J = 9), 7.33 (1H, t, J = 9), 7.07 (1H, d, J = 7.5), 3.84 (3H, s), 2.50 (3H, m), 2.34 (1H, s), 0.83 (4H, m).

[0457] Example 21: Compound 21-e

[0458]

[0459] Preparation method of Compound 21-e

[0460] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), Compound 1-d was replaced with Compound 21-d to obtain Compound 21-e. ESI-MS: m / z = 567.13 [M+H] + 。

[0461] Example 22: Compound 22-h

[0462]

[0463] 1) Preparation method of Compound f:

[0464] Dissolve Compound 1-b (30 g), Compound 1-d (12 g), EDCI (34 g), HOBT (22 g) and triethylamine (35 g) in 150 mL of DMF, and react at room temperature for 12 h. Concentrate. Add 1000 ml of purified water, stir for 2 h, filter, and dry to obtain Compound f (30 g). ESI-MS: m / z = 458.07 [M+H] + 。

[0465] 2) Preparation method of Compound 22-h:

[0466] Dissolve Compound f (120 mg), Compound 22-g (44 mg), Pd 2 (dba) 3 (48 mg), Xantphos (30 mg) and cesium carbonate (254 mg) in 3 mL of dioxane in sequence, protect with nitrogen, heat to 130 °C and react for 5 h. Concentrate the reaction solution, and purify by column chromatography to obtain Compound 22-h (39 mg).

[0467] 1 H-NMR (DMSO-d6 ) δ: 12.22 (1H, s), 11.00 (1H, s), 10.19 (1H, s), 9.13 (1H, s), 8.67 (1H, d, J = 8.0), 8.30 (1H, brs), 8.22 (1H, dd, J = 1.5, 5.0), 8.14 (1H, brs), 7.80 (3H, m), 7.72 (1H, td, J = 1.5, 8.5), 7.55 - 7.65 (3H, m), 7.39 (1H, t, J = 8.0), 7.22 (1H, t, J = 7.0), 6.93 (1H, dd, J = 5.5, 6.5), 3.80 (3H, s).

[0468] 13 C-NMR (DMSO-d 6 ) δ: 171.0, 167.4, 164.0, 158.1, 154.4, 150.4, 147.8, 144.1, 139.4, 138.4, 134.1, 132.9, 132.4, 130.2, 129.0, 125.7, 125.05, 124.96, 123.5, 121.9, 121.5, 117.3, 113.3, 95.2, 62.4, 40.0.

[0469] ESI-MS: m / z = 516.14 [M + H] + 。

[0470] Example 23: Compound 23-h

[0471]

[0472] Preparation method of Compound 23-h:

[0473] Referring to the preparation method of Compound 22-h in Reference Example 22, in step 2), replace Compound 22-g with Compound 23-g to obtain Compound 23-h. ESI-MS: m / z = 521.15 [M + H] + 。

[0474] Example 24: Compound 24-h

[0475]

[0476] Preparation method of Compound 24-h:

[0477] Referring to the preparation method of Compound 22-h in Reference Example 22, in step 2), replace Compound 22-g with Compound 24-g to obtain Compound 24-h. ESI-MS: m / z = 549.15 [M + H] + 。

[0478] Example 25: Compound 25-h

[0479]

[0480] Preparation method of Compound 25-h:

[0481] Referring to the preparation method of Compound 22-h in Reference Example 22, in step 2), replace Compound 22-g with Compound 25-g to obtain Compound 25-h. ESI-MS: m / z = 534.3 [M+H] + 。

[0482] Example 26: Compound 26-h

[0483]

[0484] Preparation method of Compound 26-h:

[0485] Referring to the preparation method of Compound 22-h in Reference Example 22, in step 2), replace Compound 22-g with Compound 26-g to obtain Compound 26-h. ESI-MS: m / z = 530.3 [M+H] + 。

[0486] Example 27: Compound 27-h

[0487]

[0488] Preparation method of Compound 27-h:

[0489] Referring to the preparation method of Compound 22-h in Reference Example 22, in step 2), replace Compound 22-g with Compound 27-g to obtain Compound 27-h. ESI-MS: m / z = 530.15 [M+H] + 。

[0490] Example 28: Compound 28-h

[0491]

[0492] Preparation method of Compound 28-h:

[0493] Referring to the preparation method of Compound 22-h in Reference Example 22, in step 2), replace Compound 22-g with Compound 28-g to obtain Compound 28-h. ESI-MS: m / z = 548.10 [M+H] + 。

[0494] Example 29: Compound 29-h

[0495]

[0496] Preparation method of Compound 29-h:

[0497] Referring to the preparation method of Compound 22-h in Reference Example 22, in Step 2), replace Compound 22-g with Compound 29-g to obtain Compound 29-h. ESI-MS: m / z = 566.3 [M+H] + 。

[0498] Example 30: Compound 30-e

[0499]

[0500] Preparation method of Compound 30-e

[0501] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), replace Compound 1-d with Compound 30-d to obtain Compound 30-e. ESI-MS: m / z = 557.14 [M+H] + 。

[0502] Example 31: Compound 31-h

[0503]

[0504] Preparation method of Compound 31-h:

[0505] Referring to the preparation method of Compound 22-h in Reference Example 22, in Step 2), replace Compound 22-g with Compound 31-g to obtain Compound 31-h. ESI-MS: m / z = 531.12 [M+H] + 。

[0506] 1H-NMR (DMSO-d6) δ: 12.22 (1H, s), 11.09 (2H, m), 9.27 (1H, s), 8.81 (1H, s), 8.67 (1H, s), 8.30 (1H, s), 7.80 (5H, m), 7.64 (1H, d, J = 9), 7.57 (1H, d, J = 9), 7.42 (1H, d, J = 9), 7.20 (1H, m), 3.80 (3H, s), 2.50 (3H, m).

[0507] Example 32: Compound 32-h

[0508]

[0509] Preparation method of Compound 32-h:

[0510] Refer to the preparation method of Compound 22-h in Reference Example 22. In Step 2), replace Compound 22-g with Compound 32-g to obtain Compound 32-h. ESI-MS: m / z = 517.08 [M+H] + 。

[0511] Example 33: Compound 33-h

[0512]

[0513] Preparation method of Compound 33-h:

[0514] Refer to the preparation method of Compound 22-h in Reference Example 22. In Step 2), replace Compound 22-g with Compound 33-g to obtain Compound 33-h. ESI-MS: m / z = 531.3 [M+H] + 。

[0515] Example 34: Compound 34-h

[0516]

[0517] Preparation method of Compound 34-h:

[0518] Refer to the preparation method of Compound 22-h in Reference Example 22. In Step 2), replace Compound 22-g with Compound 34-g to obtain Compound 34-h. ESI-MS: m / z = 534.07 [M+H] + 。

[0519] Example 35: Compound 35-h

[0520]

[0521] Preparation method of Compound 35-h:

[0522] Refer to the preparation method of Compound 22-h in Reference Example 22. In Step 2), replace Compound 22-g with Compound 35-g to obtain Compound 35-h. ESI-MS: m / z = 530.07 [M+H] + 。

[0523] Example 36: Compound 36-h

[0524]

[0525] Preparation method of Compound 36-h:

[0526] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 36-g to obtain compound 36-h. ESI-MS: m / z = 584.10 [M+H] + 。

[0527] Example 37: Compound 37-h

[0528]

[0529] Preparation method of compound 37-h:

[0530] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 37-g to obtain compound 37-h. ESI-MS: m / z = 546.09 [M+H] + 。

[0531] Example 38: Compound 38-h

[0532]

[0533] Preparation method of compound 38-h:

[0534] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 38-g to obtain compound 38-h. ESI-MS: m / z = 546.14 [M+H] + 。

[0535] 1 H-NMR(DMSO-d 6 ) δ: 12.23(1H, s), 11.08(1H, s), 9.10(1H, s), 8.66(1H, d, J = 9), 8.31(1H, s), 8.24(1H, d, J = 6.5), 7.81(2H, m), 7.74(1H, d, J = 7), 7.69(1H, d, J = 9), 7.56(1H, m), 7.39(2H, m), 7.20(1H, d, J = 8), 7.00(1H, s), 6.86(1H, d, J = 6), 3.92(3H, s), 3.82(3H, s), 2.55(1H, s).

[0536] Example 39: Compound 39-h

[0537]

[0538] Preparation method of compound 39-h:

[0539] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 39-g to obtain compound 39-h. ESI-MS: m / z = 550.01 [M+H] + 。

[0540] Example 40: Compound 40-h

[0541]

[0542] Preparation method of compound 40-h:

[0543] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 40-g to obtain compound 40-h. ESI-MS: m / z = 550.03 [M+H] + 。

[0544] Example 41: Compound 41-h

[0545]

[0546] Preparation method of compound 41-h:

[0547] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 41-g to obtain compound 41-h. ESI-MS: m / z = 541.09 [M+H] + 。

[0548] 1 H-NMR(DMSO-d 6 ) δ 12.21(1H, s), 11.06(1H, s), 10.77(1H, s), 9.2(1H, s), 8.66(2H, d, J = 9.5), 8.30(1H, s), 8.11(2H, m), 7.76(4H, m), 7.57(2H, d, J = 7.5), 7.50(1H, d, J = 7.5), 7.2(1H, t, J = 7.5), 3.80(3H, s)

[0549] Example 42: Compound 42-h

[0550]

[0551] Preparation method of compound 42-h:

[0552] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 42-g to obtain compound 42-h. ESI-MS: m / z = 541.07 [M+H] + 。

[0553] Example 43: Compound 43-h

[0554]

[0555] Preparation method of compound 43-h:

[0556] Referring to the preparation method of compound 22-h in Reference Example 22, in step 2), replace compound 22-g with compound 43-g to obtain compound 43-h. ESI-MS: m / z = 544.12 [M+H] + 。

[0557] Example 44: Compound 44-e

[0558]

[0559] Preparation method of compound 44-e

[0560] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 44-d to obtain compound 44-e. ESI-MS: m / z = 549.11 [M+H] + 。

[0561] Example 45: Compound 45-e

[0562]

[0563] Preparation method of compound 45-e

[0564] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 45-d to obtain compound 45-e. ESI-MS: m / z = 537.06 [M+H] + 。

[0565] Example 46: Compound 46-e

[0566]

[0567] Preparation method of compound 46-e

[0568] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 46-d to obtain Compound 46-e. ESI-MS: m / z = 549.14 [M+H] + 。

[0569] 1 H-NMR(DMSO-d 6 ) δ 12.08(1H, s), 11.36(1H, s), 11.02(1H, s), 9.18(1H, s), 8.54(1H, d, J = 8.5), 8.22(1H, m), 7.65(4H, m), 7.42(1H, m), 7.35(1H, m), 3.78(3H, s), 3.34(1H, s), 3.31(1H, s), 2.12(1H, s), 1.25(6H, m), 0.84(4H, d, J = 6)

[0570] Example 47: Compound 47-e

[0571]

[0572] Preparation method of Compound 47-e

[0573] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 47-d to obtain Compound 47-e. ESI-MS: m / z = 591.08 [M+H] + 。

[0574] 1 H-NMR(DMSO-d 6 ) δ 12.16(1H, s), 11.36(1H, s), 11.02(1H, s), 9.18(1H, s), 8.73(1H, d, J = 9.5), 8.39(1H, s), 8.19(1H, d, J = 5), 7.92(1H, s), 7.77(1H, d, J = 2.5), 7.67(2H, t, J = 8.5), 7.60(1H, d, J = 8.5), 7.35(1H, t, J = 8), 3.79(3H, s), 2.09(1H, m), 0.83(4H, d, J = 6)

[0575] Example 48: Compound 48-e

[0576]

[0577] Preparation method of Compound 48-e

[0578] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 48-d to obtain compound 48-e. ESI-MS: m / z = 575.07 [M+H] + 。

[0579] 1 H-NMR(DMSO-d 6 ) δ 11.37(1H, s), 11.03(1H, s), 10.84(1H, s), 9.17(1H, s), 8.45(1H, s), 8.35(1H, s), 8.24(1H, s), 8.19(1H, s), 7.96(1H, s), 7.62(2H, m), 7.41(2H, d, J = 1.5), 3.78(3H, s), 2.09(2H, s), 0.83(4H, m)

[0580] Example 49: Compound 49-e

[0581]

[0582] Preparation method of compound 49-e

[0583] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 49-d to obtain compound 49-e. ESI-MS: m / z = 537.08 [M+H] + 。

[0584] Example 50: Compound 50-e

[0585]

[0586] Preparation method of compound 50-e

[0587] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 50-d to obtain compound 50-e. ESI-MS: m / z = 575.14 [M+H] + 。

[0588] 1 H-NMR(DMSO-d 6)δ 11.36 (1H, s), 11.00 (1H, s), 10.55 (1H, s), 9.16 (1H, s), 8.18 (1H, s), 7.8 (2H, d, J = 8.5), 7.597 (1H, m), 7.36 (3H, m), 7.31 (1H, m), 3.76 (4H, m), 3.33 (2H, m), 2.50 (1H, m), 1.60 (7H, m), 0.83 (4H, m)

[0589] Example 51: Compound 51-e

[0590]

[0591] Preparation method of compound 51-e

[0592] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 51-d to obtain compound 51-e. ESI-MS: m / z = 561.22 [M + H] + 。

[0593] 1 H-NMR (DMSO-d 6 ) δ: 11.36 (1H, br), 11.00 (1H, br), 10.56 (1H, br), 9.16 (1H, br), 8.19 (1H, s), 7.81 - 7.79 (2H, m), 7.62 - 7.60 (1H, m), 7.55 - 7.53 (2H, m), 7.38 - 7.36 (1H, m), 7.33 - 7.30 (1H, m), 3.77 (3H, s), 3.48 - 3.43 (4H, m), 2.13 - 2.09 (1H, m), 1.88 - 1.81 (4H, m), 0.85 - 0.83 (4H, m).

[0594] Example 52: Compound 52-e

[0595]

[0596] Preparation method of compound 52-e

[0597] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 52-d to obtain compound 52-e. ESI-MS: m / z = 579.17 [M + H] + 。

[0598] Example 53: Compound 53-e

[0599]

[0600] Preparation method of compound 53-e

[0601] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 53-d to obtain compound 53-e. ESI-MS: m / z = 562.18 [M+H] + 。

[0602] Example 54: Compound 54-h

[0603]

[0604] 1) Preparation method of compound 54i:

[0605] Referring to the preparation method of compound 1-c in Reference Example 1, replace cyclopropylcarboxamide with 2-aminopyridine to obtain compound 54i. ESI-MS: m / z = 398.15 [M+H] + 。

[0606] 2) Preparation method of compound 54-h:

[0607] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 51-d and replace compound 1-c with compound 54i to obtain compound 54-h. ESI-MS: m / z = 570.17 [M+H] + 。

[0608] Example 55: Compound 55-e

[0609]

[0610] Preparation method of compound 55-e

[0611] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 55-d to obtain compound 55-e. ESI-MS: m / z = 579.20 [M+H] + 。

[0612] 1 H-NMR(DMSO-d 6)δ: 11.36 (1H, br), 11.01 (1H, br), 10.41 (1H, br), 9.18 (1H, br), 8.16 - 8.13 (2H, m), 7.66 (1H, d, J = 8.0), 7.58 (1H, d, J = 7.5), 7.50 (1H, d, J = 11.0), 7.42 (1H, d, J = 8.5), 7.35 (1H, t, J = 7.5), 3.82 (3H, s), 3.48 - 3.45 (4H, m), 2.11 - 2.08 (1H m), 1.89 - 1.82 (4H, m), 0.84 - 0.82 (4H, m)

[0613] Example 56: Compound 56 - e

[0614]

[0615] Preparation method of compound 56 - e

[0616] Referring to the preparation method of compound 1 - e in Reference Example 1, in step 4), replace compound 1 - d with compound 56 - d to obtain compound 56 - e. ESI - MS: m / z = 593.22 [M + H] + .

[0617] Example 57: Compound 57 - h

[0618]

[0619] 2) Preparation method of compound 57j:

[0620] Referring to the preparation method of compound 1 - c in Reference Example 1, replace cyclopropylcarboxamide with 5 - fluoro - 2 - aminopyridine to obtain compound 57j. ESI - MS: m / z = 416.19 [M + H] + .

[0621] 2) Preparation method of compound 57 - h:

[0622] Referring to the preparation method of compound 1 - e in Reference Example 1, in step 4), replace compound 1 - d with compound 53 - d, and replace compound 1 - c with compound 57j to obtain compound 57 - h. ESI - MS: m / z = 589.4 [M + H] + .

[0623] 1 H - NMR (DMSO - d 6)δ: 11.14 (1H, br), 10.81 (1H, br), 10.53 (1H, br), 9.14 (1H, br), 8.92 (1H, d, J = 2.5), 8.33 - 8.31 (1H, m), 8.27 (1H, d, J = 3.0), 7.91 (1H, s), 7.81 (1H, d, J = 8.5), 7.78 - 7.74 (2H, m), 7.62 - 7.59 (1H, m), 7.44 - 7.42 (2H, m), 3.80 (3H, s), 3.70 - 3.67 (2H, m), 3.52 - 3.49 (2H, m), 1.87 - 1.83 (4H, m).

[0624] Example 58: Compound 58-h

[0625]

[0626] Preparation method of compound 58-h

[0627] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 51-d and replace compound 1-c with compound 57j to obtain compound 58-h. ESI-MS: m / z = 588.23 [M + H] + .

[0628] Example 59: Compound 59-h

[0629]

[0630] Preparation method of compound 59-h

[0631] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 53-d and replace compound 1-c with compound 54i to obtain compound 59-h. ESI-MS: m / z = 571.20 [M + H] + .

[0632] Example 60: Compound 60-e

[0633]

[0634] Preparation method of compound 60-e

[0635] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 60-d to obtain compound 60-e. ESI-MS: m / z = 611.4 [M + H] + .

[0636] Example 61: Compound 61-e

[0637]

[0638] Preparation method of compound 61-e

[0639] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 61-d to obtain compound 61-e. ESI-MS: m / z = 611.4 [M+H] + 。

[0640] 1 H-NMR(DMSO-d 6 ) δ: 11.39(1H,br), 11.03(1H,br), 10.60(1H,br), 9.17(1H,br), 8.17(1H,s), 7.83(2H,d,J = 8.5), 7.62 - 7.60(1H,m), 7.42 - 7.38(3H,m), 7.32 - 7.30(1H,m), 3.91(2H,s), 3.87(3H,s), 3.84 - 3.51(2H,m), 2.15 - 2.07(3H,m), 1.71(2H,s), 0.85 - 0.83(4H,m).

[0641] Example 62: Compound 62-e

[0642]

[0643] Preparation method of compound 62-e

[0644] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 62-d to obtain compound 62-e. ESI-MS: m / z = 593.22 [M+H] + 。

[0645] Example 63: Compound 63-e

[0646]

[0647] Preparation method of compound 63-e

[0648] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 63-d to obtain compound 63-e.

[0649] Example 64: Compound 64-e

[0650]

[0651] Preparation method of compound 64-e

[0652] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 64-d to obtain compound 64-e. ESI-MS: m / z = 597.26 [M+H] + 。

[0653] 1 H-NMR(DMSO-d 6 ) δ11.37(1H,br), 11.00(1H,br), 10.61(1H,br), 9.16(1H,br), 8.18(1H,s), 7.84 - 7.82(2H,m), 7.62 - 7.58(3H,m), 7.38 - 7.30(2H,m), 3.93 - 3.90(2H,m), 3.76 - 3.72(5H,m), 2.48 - 2.41(2H,m), 2.12 - 2.07(1H,m), 0.86 - 0.83(4H,m).

[0654] Example 65: Compound 65-e

[0655]

[0656] Preparation method of compound 65-e

[0657] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 65-d to obtain compound 65-e. ESI-MS: m / z = 579.21 [M+H] + 。

[0658] Example 66: Compound 66-e

[0659]

[0660] Preparation method of compound 66-e

[0661] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 66-d to obtain compound 66-e. ESI-MS: m / z = 579.23 [M+H] + 。

[0662] Example 67: Compound 67-e

[0663]

[0664] Preparation method of compound 67-e

[0665] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 67-d to obtain compound 67-e. ESI-MS: m / z = 629.30 [M+H] + 。

[0666] Example 68: Compound 68-e

[0667]

[0668] Preparation method of compound 68-e

[0669] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 68-d to obtain compound 68-e.

[0670] Example 69: Compound 69-e

[0671]

[0672] Preparation method of compound 69-e

[0673] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 69-d to obtain compound 69-e. ESI-MS: m / z = 586.22 [M+H] + 。

[0674] Example 70: Compound 70-e

[0675]

[0676] Preparation method of compound 70-e

[0677] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 70-d to obtain compound 70-e.

[0678] Example 71: Compound 71-e

[0679]

[0680] Preparation method of compound 71-e

[0681] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 71-d to obtain compound 71-e. ESI-MS: m / z = 575.19 [M+H] + 。

[0682] 1 H-NMR(DMSO-d6 )δ: 11.38 (1H, s), 11.01 (1H, s), 10.55 (1H, s), 9.16 (1H, s), 8.17 (1H, s), 7.79 (2H, d, J = 8.5), 7.62 (1H, m), 7.50 (2H, m), 7.39 (1H, m), 7.33 (1H, m), 4.13 (1H, s), 3.77 (3H, s), 3.52 (1H, m), 3.36 (1H, s), 2.08 (2H, m), 1.87 (1H, s), 1.70 (1H, s), 1.55 (1H, s), 1.25 (2H, s), 0.85 (5H, m,).

[0683] Example 72: Compound 72-e

[0684]

[0685] Preparation method of compound 72-e

[0686] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 72-d to obtain compound 72-e. ESI-MS: m / z = 575.25 [M + H] + .

[0687] Example 73: Compound 73-e

[0688]

[0689] Preparation method of compound 73-e

[0690] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 73-d to obtain compound 73-e.

[0691] Example 74: Compound 74-e

[0692]

[0693] Preparation method of compound 74-e

[0694] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), replace compound 1-d with compound 74-d to obtain compound 74-e.

[0695] Example 75: Compound 75-e

[0696]

[0697] Preparation method of compound 75-e

[0698] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 75-d to obtain Compound 75-e. ESI-MS: m / z = 543.10 [M+H] + .

[0699] 1 H-NMR (DMSO-d 6 ) δ: 11.39 (1H, s), 11.04 (1H, s), 10.70 (1H, s), 9.17 (1H, s), 8.41 (1H, s), 8.18 (1H, s), 7.83 (1H, m), 7.62 (1H, m), 7.56 (2H, m), 7.40 (3H, m), 7.30 (1H, m), 3.77 (3H, s), 2.10 (1H, m), 0.85 (4H, m).

[0700] Example 76: Compound 76-e

[0701]

[0702] Preparation method of Compound 76-e

[0703] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 76-d to obtain Compound 76-e. ESI-MS: m / z = 543.10 [M+H] + .

[0704] 1 H-NMR (DMSO-d 6 ) δ: 11.38 (1H, s), 11.03 (1H, s), 10.72 (1H, s), 9.17 (1H, s), 8.18 (1H, s), 7.90 (2H, d J = 8.5), 7.81 (2H, d, J = 8.5), 7.62 (1H, d, J = 8.0), 7.38 (1H, d, J = 7.0), 7.31 (2H, m), 3.76 (3H, s), 2.09 (1H, m), 1.23 (1H, s), 0.84 (4H, m).

[0705] Example 77: Compound 77-e

[0706]

[0707] Preparation method of Compound 77-e

[0708] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 77-d to obtain Compound 77-e. ESI-MS: m / z = 542.30 [M+H] + 。

[0709] Example 78: Compound 78-h

[0710]

[0711] Preparation method of Compound 78-h

[0712] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 78-d, and Compound 1-c was replaced with Compound 54i to obtain Compound 78-h. ESI-MS: m / z = 552.3 [M+H] + 。

[0713] Example 79: Compound 79-h

[0714]

[0715] Preparation method of Compound 79-h

[0716] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 79-d, and Compound 1-c was replaced with Compound 54i to obtain Compound 79-h. ESI-MS: m / z = 551.11 [M+H] + 。

[0717] 1 H-NMR(DMSO-d 6 ) δ: 11.17(1H, s), 10.86(2H, s), 9.14(1H, s), 8.31(1H, m), 8.01(2H, m), 8.95(3H, m), 7.83(1H, m), 7.75(1H, m), 7.46(1H, m), 7.42(2H, m), 7.07(1H, t, J = 12.5), 3.80(3H, s), 3.19(3H, s).

[0718] Example 80: Compound 80-e

[0719]

[0720] Preparation method of Compound 80-e

[0721] Referring to the preparation method of Compound 1-e in Reference Example 1, in Step 4), Compound 1-d was replaced with Compound 80-d to obtain Compound 80-e. ESI-MS: m / z = 629.28 [M+H] + 。

[0722] Example 81: Compound 81-e

[0723]

[0724] Preparation method of Compound 81-e

[0725] 1) Preparation method of Compound k:

[0726] 2 g of Compound 1-c, 0.54 g of ammonium chloride, 1.48 g of EDCI, 1.04 g of HOBt, 1.56 g of triethylamine and 30 ml of DMF were added to a reaction flask and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated, 50 ml of water was added for pulping for 2 hours, filtered, and dried to obtain Compound k (1.8 g). ESI-MS: m / z = 388.15 [M+H] + 。

[0727] 2) Preparation method of Compound 81-e:

[0728] Compound k (70 mg), Compound 81-l (69 mg), Pd 2 (dba) 3 (16 mg), Xantphos (10 mg) and cesium carbonate (117 mg) were successively dissolved in 3 mL of dioxane, protected by nitrogen, and refluxed for 5 h. After preparation and purification, Compound 81-e (33 mg) was obtained.

[0729] 1 1H-NMR (DMSO-d 6 ) δ: 11.36 (1H, s), 11.01 (1H, s), 10.73 (1H, s), 9.16 (1H, s), 8.18 (1H, s), 7.91 (2H, d, J = 8.5), 7.79 (2H, d, J = 8.5), 7.62 (1H, dd, J = 1.5, 8.0), 7.54 (1H, d, J = 7.5), 7.38 (1H, dd, J = 1.5, 8.5), 7.32 (1H, t, J = 8.0), 3.76 (3H, s), 2.92 (1H, m), 2.09 (1H, m), 1.58 (4H, m), 1.44 (1H, m), 1.12 (5H, m), 1.04 (4H, m).

[0730] 13 13C-NMR (DMSO-d 6)δ: 174.2, 167.0, 165.6, 156.3, 150.2, 145.0, 142.6, 137.3, 135.5, 132.2, 132.1, 127.9, 125.3, 124.9, 124.8, 119.8, 97.2, 62.4, 52.5, 40.9, 33.7, 25.4, 24.8, 14.9, 8.6.

[0731] ESI-MS: m / z=625.24 [M+H] + 。

[0732] Example 82: Compound 82-e

[0733]

[0734] Preparation method of Compound 82-e

[0735] Referring to the preparation method of Compound 1-e in Reference Example 1, in step 4), replace Compound 1-d with Compound 82-d to obtain Compound 82-e. ESI-MS: m / z=543.09 [M+H] + 。

[0736] Example 83: Compound 83-e

[0737]

[0738] Preparation method of Compound 83-e

[0739] Referring to the preparation method of Compound 81-e in Reference Example 81, in step 2), replace Compound 81-l with Compound 83-l to obtain Compound 83-e. ESI-MS: m / z=542.08 [M+H] + 。

[0740] Example 84: Compound 84-e

[0741]

[0742] Preparation method of Compound 84-e

[0743] Referring to the preparation method of Compound 81-e in Reference Example 81, in step 2), replace Compound 81-l with Compound 84-l to obtain Compound 84-e. ESI-MS: m / z=597.21 [M+H] + 。

[0744] Example 85: Compound 85-e

[0745]

[0746] Preparation method of compound 85-e

[0747] Referring to the preparation method of compound 85-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 85-l to obtain compound 85-e. ESI-MS: m / z = 557.09 [M+H] + .

[0748] Example 86: Compound 86-e

[0749]

[0750] Preparation method of compound 86-e

[0751] Referring to the preparation method of compound 86-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 86-l to obtain compound 86-e. ESI-MS: m / z = 555.17 [M+H] + .

[0752] Example 87: Compound 87-e

[0753]

[0754] Preparation method of compound 87-e

[0755] Referring to the preparation method of compound 87-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 87-l to obtain compound 87-e. ESI-MS: m / z = 555.17 [M+H] + .

[0756] Example 88: Compound 88-e

[0757]

[0758] Preparation method of compound 88-e

[0759] Referring to the preparation method of compound 88-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 88-l to obtain compound 88-e. ESI-MS: m / z = 611.19 [M+H] + .

[0760] 1 H-NMR(DMSO-d 6)δ: 11.39 (1H, s), 11.02 (1H, s), 10.80 (1H, s), 9.17 (1H, s), 8.17 (1H, s), 7.97 (2H, d, J = 8.5), 7.82 (2H, d J = 8.5), 7.62 (1H, d, J = 7.5), 7.35 (2H, m), 3.76 (3H, s), 3.63 (1H, m), 3.33 (1H, m), 3.10 (1H, m), 2.09 (1H, m), 1.76 (1H, m), 1.62 (1H, m), 1.43 (2H, m), 1.23 (3H, m), 0.84 (4H, m)

[0761] Example 89: Compound 89-e

[0762]

[0763] Preparation method of compound 89-e

[0764] Referring to the preparation method of compound 89-e in Reference Example 81, in step 2), compound 81-l was replaced with compound 89-l to obtain compound 89-e. ESI-MS: m / z = 611.18 [M + H] + .

[0765] Example 90: Compound 90-e

[0766]

[0767] Preparation method of compound 90-e

[0768] Referring to the preparation method of compound 90-e in Reference Example 81, in step 2), compound 81-l was replaced with compound 90-l to obtain compound 90-e. ESI-MS: m / z = 615.19 [M + H] + .

[0769] Example 91: Compound 91-e

[0770]

[0771] Preparation method of compound 91-e

[0772] Referring to the preparation method of compound 91-e in Reference Example 81, in step 2), compound 81-l was replaced with compound 91-l to obtain compound 91-e. ESI-MS: m / z = 615.19 [M + H] + .

[0773] Example 92: Compound 92-e

[0774]

[0775] Preparation method of compound 92-e

[0776] Referring to the preparation method of compound 92-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 92-l to obtain compound 92-e. ESI-MS: m / z = 633.26 [M+H] + .

[0777] 1 1H-NMR (500 MHz, DMSO-d 6 ) δ: 11.37 (1H, s), 11.01 (1H, s), 10.87 (1H, s), 9.17 (1H, s), 8.18 (1H, s), 8.02 - 8.00 (2H, d), 7.89 - 7.84 (2H, m), 7.63 - 7.62 (1H, m), 7.39 (1H, m), 7.38 - 7.31 (1H, m), 3.76 (3H, s), 3.60 - 3.55 (2H, m), 3.37 - 3.34 (2H, m), 2.39 - 2.30 (2H, m), 2.11 - 2.08 (1H, m), 0.85 - 0.82 (4H, m).

[0778] Example 93: Compound 93-e

[0779]

[0780] Preparation method of compound 93-e

[0781] Referring to the preparation method of compound 93-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 93-l to obtain compound 93-e. ESI-MS: m / z = 647.24 [M+H] + .

[0782] Example 94: Compound 94-e

[0783]

[0784] Preparation method of compound 94-e

[0785] Referring to the preparation method of compound 94-e in Reference Example 81, in step (2), compound 81-l was replaced with compound 94-l to obtain compound 94-e. ESI-MS: m / z = 647.24 [M+H] + .

[0786] Example 95: Compound 95-e

[0787]

[0788] Preparation method of compound 95-e

[0789] Referring to the preparation method of compound 95-e in Reference Example 81, in step 2), compound 81-l was replaced with compound 95-l to obtain compound 95-e. ESI-MS: m / z = 665.24 [M+H] + 。

[0790] Example 96: Compound 96-e

[0791]

[0792] Preparation method of compound 96-e

[0793] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 96-d to obtain compound 96-e. ESI-MS: m / z = 596.21 [M+H] + 。

[0794] Referring to the preparation method of compound 81-e in step 2) of Reference Example 81, the compound 81-1 in Example 81 was respectively replaced with the compounds shown in the raw materials in Table 1 to obtain the target compound.

[0795] Table 1

[0796]

[0797]

[0798]

[0799]

[0800] Example 121: Compound 121-e

[0801]

[0802] Preparation method of compound 121-e

[0803] Referring to the preparation method of compound 1-e in Reference Example 1, in step 4), compound 1-d was replaced with compound 121-d to obtain compound 121-e. ESI-MS: m / z = 547.18 [M+H] + 。

[0804] 1 H-NMR(500MHz, DMSO-d 6)δ: 11.36 (1H, s), 11.00 (1H, s), 10.36 (1H, s), 9.16 (1H, s), 8.17 (1H, s), 7.74 - 7.72 (2H, d), 7.64 - 7.58 (3H, m), 7.37 - 7.28 (2H, m), 3.84 - 3.76 (5H, m), 2.47 (2H, m), 2.08 - 2.05 (3H, m), 0.83 (4H, s).

[0805] Example 122: Compound 122 - e

[0806]

[0807] Preparation method of Compound 122 - e

[0808] Referring to the preparation method of Compound 1 - e in Reference Example 1, in step 4), replace Compound 1 - d with Compound 122 - d to obtain Compound 122 - e. ESI - MS: m / z = 561.21 [M + H] + .

[0809] Examples 123 - 127 Referring to the preparation method of Compound 1 - e in Reference Example 1, in step 4), replace Compound 1 - d with the compounds shown in the raw materials in Table 2 below to obtain the target compounds.

[0810] Table 2

[0811]

[0812]

[0813]

[0814]

[0815] Experimental Example 1 Determination of TYK2 JH2 Thermal Stability

[0816] Dilute the mother liquor of TYK2 JH2 protein at 0.52 mg / mL with phosphate buffer (PBS) to 50 ng / μL. At the same time, dilute the protein dye (Orange dye) (manufacturer: Sigma; catalog number: S5692) at 5000x with DMSO to 20x. First, add 16 μL of the diluted TYK2 JH2 protein solution to each well, and then use a nanoliter pipettor to add the example compounds dissolved in DMSO to the wells so that the final concentrations of the compounds are 10 μM and 1 μM, with a total of 2 concentrations. At the same time, set blank control wells (without enzyme) and negative control wells (with enzyme, added with solvent DMSO), set 2 replicates, and finally add 4 μL of Orange dye protein dye to each well, and centrifuge and mix well. Detect with a Roche LightCycler 480 fluorescence quantitative PCR instrument, and the running system is: 20 °C for 15 s; 30 °C to 90 °C at 0.02 °C / s; 20 °C for 15 s. Use the LightCycler Thermal Shift Analysis software to analyze and obtain the melting temperature (Tm).

[0817] For the compounds of the present application, under the condition of a final concentration of 10 μM, the melting temperature (Tm) is greater than 40 °C; preferably greater than 45 °C; more preferably greater than 55 °C; under the condition of a final concentration of 1 μM, the melting temperature (Tm) is greater than 40 °C; preferably greater than 45 °C; more preferably greater than 50 °C.

[0818] Experimental Example 2 Method for Detecting STAT3 Phosphorylation in Jurkat

[0819] STAT3 Phosphorylation Detection Kit (Y705), manufactured by Cisbio, catalog number 62AT3PEG. Take Jurakt cells in the logarithmic growth phase, take 20 μL for counting, take the required number of cells (mL), centrifuge at 1300 rpm for 3 min, and add phenol red-free 1640 basal medium (manufactured by Gibco, catalog number 11835-030) to adjust the cell density to approximately 1.7×10E7 cells / mL. Seed the cells at the above cell density (384-well small-volume white plate), 8 μL / well; add samples with a nanoliter pipette, incubate the compounds for 1.5 h; dilute IFN-α (manufactured by Sino Biological, catalog number 13833-HNAY) to 75 ng / mL (final concentration 25 ng / mL) with phenol red-free 1640 complete medium; then add 4 μL of IFN-α (3X) to each well according to the plate layout. In the blank group, seed the cells, do not add compounds, and do not add IFN-α; in the control group, seed the cells, do not add compounds, and add IFN-α; incubate at 37 °C for 20 min. Immediately add 4 μL of lysis buffer (4X) supplemented with blocking solution, and shake and incubate at room temperature for 40 min. Add 4 μL of pre-mixed antibody prepared with detection buffer (vol / vol), cover the plate, centrifuge to mix evenly, and incubate overnight at room temperature. Use a PE Envision multimode reader to detect the signal values at 665 nm / 620 nm, and calculate the IC by four-parameter fitting 50 . The experimental results are shown in Table 3.

[0820] Table 3

[0821]

[0822]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: Wherein, Cy is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl or benzo-6-membered heterocyclic group; L 1 selected from -SO 2 -, -C(O)NR f -, -S(O) 2 NR h -, -NR g C(O)- or -NR j S(O) 2 -; R f 、R g 、R h or R j are each independently selected from hydrogen or C 1-6 alkyl; R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents; Alternatively, R and R g or R and R j are connected to each other to form a fully saturated or partially unsaturated 5- or 6-membered heterocyclic group, which is optionally substituted by one or more halogen atoms, amino groups, C 1-3 alkyl groups or cyano groups; Alternatively, R is connected to Cy such that R, Cy, and L 1 together form Each R a is independently selected from halogen, deuterium, cyano, =O, C 1-6 alkyl optionally substituted with one or more halogens, or C 3-8 cycloalkyl; Each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-4 cycloalkoxy, C 1-6 alkylNH-, C 1-6 alkylC(O)- or NH 2 C(O)-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-4 cycloalkoxy, C 1-6 alkylNH-, or C 1-6 alkylC(O)- is optionally substituted with one or more halogen, hydroxy, cyano, amino; n is selected from 0, 1, 2, 3 or 4; L is selected from -C(O)- or a bond; R 4 selected from 5- to 10-membered heteroaryl or C 3-6 cycloalkyl, wherein the 5- to 10-membered heteroaryl or C 3-6 cycloalkyl is optionally substituted with one or more R b substituents; R b Selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylNH-, C 1-6 alkylC(O)NH-, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH-, or C 1-6 alkyl substituted by one or more halogens; R c each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or phenyl.

2. A compound of formula I', a compound of formula I" or a pharmaceutically acceptable salt thereof, Wherein, Cy is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl or benzo-6-membered heterocyclic group; Each R 1 is independently selected from amino, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-4 cycloalkoxy, C 1-6 alkylNH-, C 1-6 alkylC(O)- or NH 2 C(O)-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-4 cycloalkoxy, C 1-6 alkylNH-, or C 1-6 alkylC(O)- is optionally substituted with one or more halogen, hydroxy, cyano, amino; n is selected from 0, 1, 2, 3 or 4; R 2 、R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; Alternatively, R 2 , R 3 are connected to each other to form a 3- to 6-membered heterocycloalkyl group, and the 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more R a substituents; R a selected from deuterium, oxo, halogen, cyano or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogens; L is selected from -C(O)- or a bond; R 4 selected from 5- to 10-membered heteroaryl or C 3-6 cycloalkyl, wherein the 5- to 10-membered heteroaryl or C 3-6 cycloalkyl is optionally substituted with one or more R b substituents; R b Selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-8 alkylNH-, C 1-6 alkylC(O)NH-, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH-, or C 1-6 alkyl substituted by one or more halogens; R c each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or phenyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Cy is selected from phenyl, naphthyl, pyridyl, thienyl or 2,3-dihydrobenzo[b][1,4]dioxinyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Cy is selected from phenyl, naphthyl, pyridyl or thienyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -SO 2 -.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, Wherein, The L 1 selected from -SO 2 -, -S(O) 2 NR h - or -NR g C(O)-.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, Wherein, R f 、R g 、R h or R j are each independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl, and the C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted by one or more R a ; or, R and R g or R and R j are connected to each other to form a fully saturated or partially unsaturated 5- to 6-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups; or, R is connected to Cy such that R, Cy, and L 1 form together 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl, and the C 1-3 alkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted with one or more R a substituents.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R and R g or R and R j are connected to each other to form a fully saturated or partially unsaturated 5- to 6-membered heterocyclic group, and the 5- to 6-membered heterocyclic group is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups.

11. The compound or its pharmaceutically acceptable salt according to claim 1, wherein R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl or thiazolidinyl is optionally substituted by one or more R a substituents; or, R and R g or R and R j are connected to form Or, R is connected to Cy so that R, Cy and L 1 together form 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, optionally substituted by one or more R a substituents; or, R and R g or R and R j are connected to form Or, R is connected to Cy such that R, Cy, and L 1 together form 13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from C 3-6 cycloalkyl, phenyl or 5- to 6-membered hetero cycloalkyl, and the C 3-6 cycloalkyl, phenyl or 5- to 6-membered hetero cycloalkyl is optionally substituted with one or more R a ; or, R and R g or R and R j are connected to each other to form a fully saturated or partially unsaturated 6-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, The cyclopropyl, cyclopentyl, cyclohexyl, phenyl, optionally substituted by one or more R a substituted; or, R and R g or R and R j are connected to each other to form the optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from cyclohexyl or 5- to 6-membered heteroalkyl, and the cyclohexyl or 5- to 6-membered heteroalkyl is optionally substituted with one or more R a substituents; or, R and R g or R and R j are connected to each other to form a fully saturated or partially unsaturated 6-membered heterocyclic group, which is optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from cyclohexyl, pyrrolidinyl or piperidinyl, and the cyclohexyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more R a substituents; or, R and R g or R and R j are connected to each other to form the optionally substituted by one or more halogens, amino groups, C 1-3 alkyl groups or cyano groups.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, or R and R g or R and R j are connected to form alternatively, R and Cy are interconnected so that R, Cy and L 1 form together 18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from 19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from halogen, deuterium, cyano, ═O, C 3-6 cycloalkyl, C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more halogens.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from fluorine, chlorine, bromine, deuterium, cyano, =O, C 5-6 ycloalkyl or methyl optionally substituted with one or more fluorines.

21. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R a is independently selected from fluorine, cyclopentyl, cyclohexyl, cyano, ═O, methyl, trifluoromethyl or deuterium.

22. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from fluorine, chlorine, bromine, deuterium, cyano, ═O or methyl optionally substituted with one or more fluorines.

23. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein each R a is independently selected from fluorine, cyano, =O, methyl, trifluoromethyl or deuterium.

24. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit is selected from where m is selected from 0, 1, 2, 3 or 4.

25. The compound or a pharmaceutically acceptable salt thereof according to claim 1, Among them, the structural unit Selected from 26. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit selected from 27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 28. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit is selected from 29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 30. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit is selected from 31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from Wherein m is selected from 0, 1, 2, 3 or 4.

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 35. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 36. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit is selected from Alternatively, R is connected to Cy such that R, Cy, and L 1 together form 37. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 38. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the structural unit is selected from 39. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the structural unit is selected from the structural units selected from 40. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the structural unit is selected from 41. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, each R 1 is independently selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkoxy, C 1-3 alkylC(O)-, or NH 2 C(O)-, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkoxy, or C 1-3 alkylC(O)- is optionally substituted with one or more halogens.

42. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, each R 1 is independently selected from fluorine, chlorine, bromine, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkoxy, CH 3 C(O)- or NH 2 C(O)-, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with one or more fluorines.

43. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is selected from 0, 1, 2 or 3.

44. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is selected from 0, 1 or 2.

45. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is selected from 0 or 1.

46. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is selected from 1 or 2.

47. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, each R 1 is independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, CH 3 CH 2 O-, CH 3 CH(CH 3 )O-, cyclopropyl-O-, CF 3 O-, CH 3 C(O)- or NH 2 C(O)-.

48. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from 6- to 10-membered heteroaryl, or C 3-6 cycloalkyl, wherein the 6- to 10-membered heteroaryl or C 3-6 cycloalkyl is optionally substituted with one or more R b .

49. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a 6- or 10-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the 6- or 10-membered heteroaryl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted with one or more R b substituents.

50. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from pyridyl, pyrimidinyl, pyrazinyl, isoquinolinyl, cyclopropyl, cyclobutyl or cyclohexyl, wherein the pyridyl, pyrimidinyl, pyrazinyl, isoquinolinyl, cyclopropyl, cyclobutyl or cyclohexyl is optionally substituted with one or more R b substituents.

51. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R b is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-C(O)NH-, C 3-6 cycloalkylC(O)NH-, R c SO 2 NH-, or C 1-3 alkyl substituted with one or more fluorines.

52. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R b is selected from fluorine, chlorine, bromine, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl-C(O)NH-, R c SO 2 NH-, or C 1-3 alkyl substituted with 1, 2 or 3 fluorines.

53. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R c is selected from C 1-3 alkyl, C 3-6 cycloalkyl or phenyl.

54. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R c is selected from cyclopropyl or phenyl.

55. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R b is selected from fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl-CONH-, cyclopropyl-SO 2 NH-, phenyl-SO 2 NH- or trifluoromethyl.

56. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the structural unit is selected from 57. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl C(O)-, C 3-6 cycloalkoxy, C 1-3 alkyl substituted with one or more fluorines or C 1-3 alkoxy substituted with one or more fluorines.

58. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-CO-, C 3-6 cycloalkoxy, C 1-3 alkyl substituted with 1, 2 or 3 fluorine atoms or C 1-3 alkoxy substituted with 1, 2 or 3 fluorine atoms.

59. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, CH 3 C(O)-, CF 3 O-, CH 3 CH 2 O-, CH 3 CH(CH 3 )O- or cyclopropyl-O-.

60. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from hydrogen, C 1-3 alkyl, C 3-4 cycloalkyl or halogen-substituted C 1-3 alkyl, or R 2 and R 3 are connected to each other to form a 5- or 6-membered heteroalkyl group, which 5- or 6-membered heteroalkyl group is optionally substituted with one or more R a .

61. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are each independently selected from hydrogen, methyl, ethyl, n-propyl or cyclopropyl, or R 2 , R 3 are joined to form pyrrolidinyl, piperidinyl or morpholinyl, and the pyrrolidinyl, piperidinyl or morpholinyl is optionally substituted by one or more R a .

62. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are connected to each other to form a 5- or 6-membered heteroalkyl group, and the 5- or 6-membered heteroalkyl group is optionally substituted with one or more R a .

63. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are connected to each other to form a 6-membered heteroalkyl group, and the 6-membered heteroalkyl group is optionally substituted with one or more R a .

64. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are connected to each other to form a 4-, 5- or 6-membered heteroalkyl ring, and the 4-, 5- or 6-membered heteroalkyl ring is optionally substituted with one or more R a , and the 4-, 5- or 6-membered heteroalkyl ring contains 1, 2 or 3 heteroatoms selected from N, O or S.

65. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are connected to each other to form a pyrrolidinyl, piperidinyl or morpholinyl group, and the pyrrolidinyl, piperidinyl or morpholinyl group is optionally substituted by one or more R a substituents.

66. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, and R 3 is selected from hydrogen, methyl, ethyl, n-propyl, cyclopropyl, or R 2 , R 3 are connected to each other to form pyrrolidinyl, piperidinyl or morpholinyl, and the pyrrolidinyl, piperidinyl or morpholinyl is optionally substituted by one or more R a substituents.

67. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, and R 3 is selected from hydrogen, methyl, ethyl, n-propyl, cyclopropyl, or R 2 , R 3 are connected to each other to form pyrrolidinyl, piperidinyl or morpholinyl.

68. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently selected from hydrogen.

69. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R 2 , R 3 are connected to each other to form a 3- to 7-membered heteroalkyl ring.

70. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are connected to each other to form a 3- to 6-membered heteroalkyl ring.

71. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are connected to each other to form a 4-, 5- or 6-membered heteroalkyl ring.

72. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R a is selected from deuterium, oxo, halogen, cyano, or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more substituents selected from halogen.

73. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R a is selected from deuterium, oxo, fluorine, chlorine, bromine, cyano, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more substituents selected from fluorine, chlorine or bromine.

74. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R a is selected from deuterium, oxo, fluorine, chlorine, cyano or C 1-3 alkyl optionally substituted by one or more fluorines.

75. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R a is selected from halogen, cyano, C 1-6 alkyl.

76. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R a is selected from halogen, cyano, C 1-3 alkyl.

77. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 78. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 79. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 80. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 81. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the structural unit is selected from 82. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 83. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from Wherein, Said m is selected from 0, 1, 2, 3 or 4.

84. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 85. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 86. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the structural unit is selected from 87. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from 88. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound of formula I' or a pharmaceutically acceptable salt thereof is selected from the compounds of formula I-1, I-2, II-1, II-2 or II-3 or a pharmaceutically acceptable salt thereof wherein R 1 , R 2 , R 3 , R 4 , n, and L are defined as described in claim 2.

89. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the compounds of formula IV-1, IV-2, V-1, V-2, VI-1 or VI-2 or a pharmaceutically acceptable salt thereof:

90. The following compound or a pharmaceutically acceptable salt thereof:

91. The following compound or a pharmaceutically acceptable salt thereof:

92. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-91.

93. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-91, or the pharmaceutical composition according to claim 92, in the manufacture of a medicament for treating or preventing various diseases related to TYK2. The use according to claim 93, wherein the disease is selected from inflammatory or autoimmune diseases.

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