TYK2 inhibitor compounds containing a linkage

Abstract

The present invention relates to a TYK2 inhibitor compound comprising a linkage and its use in the manufacture of a medicament for treating or preventing a TYK2-related disorder. [Formula 1] TIFF2024505912000359.tif68143

Description

[Technical Field]

[0001] This disclosure claims the benefit of and priority of Chinese Invention Patent Application No. 202110165856.4 filed with the State Intellectual Property Office of China on February 6, 2021, the benefit of and priority of Chinese Invention Patent Application No. 202110935764.X filed with the State Intellectual Property Office of China on August 16, 2021, the benefit of and priority of Chinese Invention Patent Application No. 202111063960.9 filed with the State Intellectual Property Office of China on September 10, 2021, and the benefit of and priority of Chinese Invention Patent Application No. 202210056272.8 filed with the State Intellectual Property Office of China on January 18, 2022, the contents of which are hereby incorporated by reference in their entireties.

[0002] The present disclosure is in the field of medicinal chemistry and provides TYK2 inhibitor compounds containing a linkage ring and methods for their preparation, and their use in the manufacture of a medicament for treating or preventing a TYK2-related disease. [Background technology]

[0003] Tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases, has been shown to be crucial in regulating signaling cascades downstream of the IL-12, IL-23, and type I interferon receptors in both mice and humans. TYK2 mediates the phosphorylation of members of the receptor-inducible STAT transcription factor family, a signal essential for STAT protein dimerization and STAT-dependent proinflammatory gene transcription. The importance of TYK2-mediated signaling in autoimmune and related pathologies has been demonstrated in experimental models of colitis, psoriasis, and resistance to multiple sclerosis in TYK2-deficient mice. In humans, individuals expressing an inactive TYK2 mutant are protected from the effects of multiple sclerosis and potentially other autoimmune conditions.

[0004] Because there are disease states that would benefit from treatment that modulates cytokines and / or interferons, TYK2 inhibitor compounds that can modulate cytokines and / or interferons (e.g., IL-12, IL-23 and / or IFNα) and methods of using those compounds could provide substantial therapeutic benefit to many patients in need thereof. Summary of the Invention

[0005] In one aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is selected from 0, 1 or 2; Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH; Ring A is C 3~10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group or C 1~8 alkoxy groups, 1~8 Alkyl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1, 2, 3 or 4; Each R a are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group.

[0006] In one aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is selected from 0, 1 or 2; Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH; Ring A is C 3~10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 6~10 Aryl group or C 1~8 alkoxy groups, 1~8 Alkyl group, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 6~10 Aryl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1, 2, 3 or 4; Each R a are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group.

[0007] In another aspect, the present disclosure further provides a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0008] In another aspect, the present disclosure further provides a method for treating or preventing a disease associated with TYK2, comprising administering to a mammal, preferably a human, in need of treatment a therapeutically or prophylactically effective amount of said compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0009] In another aspect, the present disclosure further provides the use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease associated with TYK2.

[0010] In another aspect, the present disclosure further provides the use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a disease associated with TYK2.

[0011] "Detailed Description of the Invention" In one aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is selected from 0, 1 or 2; Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH; Ring A is C 3~10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group or C 1~8 alkoxy groups, 1~8 Alkyl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1, 2, 3 or 4; Each R a are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group.

[0012] In one aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is selected from 0, 1 or 2; Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH; Ring A is C 3~10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 6~10 Aryl group or C 1~8 alkoxy groups, 1~8 Alkyl group, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 6~10 Aryl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1, 2, 3 or 4; Each R a are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group.

[0013] In some embodiments, ring A is C 5~10 Cycloalkyl groups, C 6~10 aryl group, 3- to 10-membered heterocycloalkenyl group, or 5- to 10-membered heteroaryl group, and the condition is [ka] but, [ka] It is not, Or, [ka] is selected from a pyrrolidinyl group, 3-hydroxypyrrolidin-1-yl-, 3-oxopyrrolidin-1-yl-, 3-methyl-2-oxopyrrolidin-1-yl-, 4,4-dimethyl-2-oxopyrrolidin-1-yl-, 3,3-dimethyl-2-oxopyrrolidin-1-yl-, oxetanyl group, azetidinyl group, 3-oxoazetidin-1-yl- or 3-hydroxyazetidin-1-yl-.

[0014] In some embodiments, ring A is C 5~6 Cycloalkyl groups, C 6~10 aryl group, 3- to 8-membered heterocycloalkenyl group, or 5- to 8-membered heteroaryl group, and the condition is [ka] but, [ka] It is not, Or, structural unit [ka] teeth, [ka] Selected from.

[0015] In some embodiments, ring A is C 5~6 Cycloalkyl groups, C 6~10 aryl group, a 5- to 6-membered heterocycloalkenyl group, or a 5- to 6-membered heteroaryl group, and the condition is [ka] but, [ka] It is not, Or, structural unit [ka] teeth, [ka] Selected from.

[0016] In some embodiments, ring A is selected from a 5- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group, with the proviso that the structural unit [ka] but, [ka] It is not, Or, structural unit [ka] teeth, [ka] Selected from.

[0017] In some embodiments, the structural unit [ka] teeth, [ka] isn't it.

[0018] In some embodiments, X is N. In some embodiments, X is CH.

[0019] In some embodiments, each R 1 are each independently selected from fluorine or chlorine. 1 are each independently fluorine.

[0020] In some embodiments, q is selected from 0 or 1. In some embodiments, q is 0.

[0021] In some embodiments, q is 1 and R 1 is fluorine.

[0022] In some embodiments, each R 2 are each independently selected from fluorine, chlorine, or bromine. 2 are each independently selected from fluorine or chlorine. 2 are each independently fluorine.

[0023] In some embodiments, n is selected from 0 or 1. In some embodiments, n is 0.

[0024] In some embodiments, the T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, three of which are selected from N and two of which are selected from CH.

[0025] In some embodiments, the T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, two of which are selected from N and three of which are selected from CH.

[0026] In some embodiments, T 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N.

[0027] In some embodiments, the T 1 , T 2 , T 3 , T 4 or T 5are each independently selected from CH or N, one of which is selected from N and four of which are selected from CH.

[0028] In some embodiments, the T 1 , T 3 and T 5 is selected from N, and T 2 and T 4 is selected from CH.

[0029] In some embodiments, the T 1 and T 3 is selected from N, and T 2 , T 4 and T 5 is selected from CH.

[0030] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH.

[0031] In some embodiments, the T 2 and T 4 is selected from N, and T 1 , T 3 and T 5 is selected from CH.

[0032] In some embodiments, the T 1 and T 2 is selected from N, and T 3 , T 4 and T 5 is selected from CH.

[0033] In some embodiments, the T 2 and T 3 is selected from N, and T 1 , T 4 and T 5 is selected from CH.

[0034] In some embodiments, the T 1 and T4 is selected from N, and T 2 , T 3 and T 5 is selected from CH.

[0035] In some embodiments, the T 1 is selected from N, and T 2 , T 3 , T 4 and T 5 is selected from CH.

[0036] In some embodiments, the T 2 is selected from N, and T 1 , T 3 , T 4 and T 5 is selected from CH.

[0037] In some embodiments, the T 3 is selected from N, and T 1 , T 2 , T 4 and T 5 is selected from CH.

[0038] In some embodiments, ring A is C 3~8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6~10 It is selected from an aryl group or a 5- to 8-membered heteroaryl group.

[0039] In some embodiments, ring A is C 3~6 Cycloalkyl groups, 4- to 6-membered heterocyclyl groups, C 6~10 It is selected from an aryl group or a 5- to 6-membered heteroaryl group.

[0040] In some embodiments, ring A is C 3~6 a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; 6~10 It is selected from an aryl group or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0041] In some embodiments, ring A is C 3~8 Cycloalkyl group, 3- to 8-membered heterocycloalkyl group, 3- to 8-membered heterocycloalkenyl group, C 6~10 It is selected from an aryl group or a 5- to 8-membered heteroaryl group.

[0042] In some embodiments, ring A is C 3~8 Cycloalkyl group, 4- to 6-membered heterocycloalkyl group, 4- to 6-membered heterocycloalkenyl group, C 6~10 It is selected from an aryl group or a 5- to 8-membered heteroaryl group.

[0043] In some embodiments, ring A is C 3~6 a cycloalkyl group, a 4- to 6-membered heterocycloalkyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; a 4- to 6-membered heterocycloalkenyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; C 6~10 It is selected from an aryl group or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S.

[0044] In some embodiments, the ring A is selected from a 4- to 6-membered heterocycloalkyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; a 4- to 6-membered heterocycloalkenyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S.

[0045] In some embodiments, the ring A is selected from a 3- to 8-membered heterocycloalkenyl group or a 5- to 8-membered heteroaryl group.

[0046] In some embodiments, the ring A is selected from a 4- to 6-membered heterocycloalkenyl group or a 5- to 8-membered heteroaryl group.

[0047] In some embodiments, the ring A is selected from a 4- to 6-membered heterocycloalkenyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S.

[0048] In some embodiments, the ring A is selected from a 5-6 membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S.

[0049] In some embodiments, said ring A is selected from a 5-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S.

[0050] In some embodiments, said ring A is selected from a 5-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N and O.

[0051] In some embodiments, said ring A is selected from a 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N and O.

[0052] In some embodiments, said ring A is selected from a 5-membered heteroaryl group containing 1, 2, or 3 atoms selected from N.

[0053] In some embodiments, said ring A is selected from a 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from N.

[0054] In some embodiments, said ring A is selected from a 5-membered heteroaryl group containing 1 or 2 atoms selected from N.

[0055] In some embodiments, said ring A is selected from a 6-membered heteroaryl group containing 1 or 2 atoms selected from N.

[0056] In some embodiments, said ring A is selected from a 5-membered heteroaryl group containing two N's.

[0057] In some embodiments, said ring A is selected from a 6-membered heteroaryl group containing two N's.

[0058] In some embodiments, Ring A is chosen from an oxetanyl group, an azetidinyl group, a morpholinyl group, a dioxanyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a tetrahydropyrrolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, a dihydropyrimidinyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group.

[0059] In some embodiments, Ring A is selected from a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, a dihydropyrimidinyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group.

[0060] In some embodiments, Ring A is selected from a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group.

[0061] In some embodiments, Ring A is selected from a tetrazolyl group, a pyrazolyl group, or an imidazolyl group.

[0062] In some embodiments, said ring A is selected from a pyrazolyl group.

[0063] In some embodiments, ring A is C 5~10 Cycloalkyl groups, C 6~10 an aryl group, a 4-membered heterocycloalkyl group, a 5- to 6-membered heterocycloalkenyl group, or a 5- to 10-membered heteroaryl group; and T 1 and T 4 are not simultaneously selected from N and 2 and T 5are not simultaneously selected from N.

[0064] In some embodiments, ring A is C 5~6 Cycloalkyl groups, C 6~10 an aryl group, a 4-membered heterocycloalkyl group, a 5- to 6-membered heterocycloalkenyl group, or a 5- to 6-membered heteroaryl group; and T 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N.

[0065] In some embodiments, ring A is selected from a 5- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group, and T 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N.

[0066] In some embodiments, the ring A is selected from a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, a dihydropyrimidinyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group; 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N.

[0067] In some embodiments, the ring A is selected from a triazolyl group, a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group; 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N.

[0068] In some embodiments, the ring A is selected from a triazolyl group, a tetrazolyl group, a pyrazolyl group, or an imidazolyl group; 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N.

[0069] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from a 4- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group.

[0070] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from a 5- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group.

[0071] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from 5- to 6-membered heteroaryl groups.

[0072] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH and ring A is selected from 6-membered heteroaryl groups.

[0073] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4is selected from CH, and ring A is selected from 6-membered heteroaryl groups containing 1 or 2 nitrogen atoms.

[0074] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from a 6-membered heteroaryl group containing two nitrogen atoms.

[0075] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from 5-membered heteroaryl groups.

[0076] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from 5-membered heteroaryl groups containing 1 or 2 nitrogen atoms.

[0077] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, and ring A is selected from a 5-membered heteroaryl group containing two nitrogen atoms.

[0078] In some embodiments, X is selected from N and ring A is selected from a 5- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group.

[0079] In some embodiments, X is selected from N and ring A is selected from a 4- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group.

[0080] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH and X is selected from N.

[0081] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a 5- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group.

[0082] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a 4- to 6-membered heterocycloalkenyl group or a 5- to 6-membered heteroaryl group.

[0083] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from 5- to 6-membered heteroaryl groups.

[0084] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a 6-membered heteroaryl group.

[0085] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4is selected from CH, X is selected from N, and ring A is selected from 6-membered heteroaryl groups containing 1 or 2 nitrogen atoms.

[0086] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a 6-membered heteroaryl group containing two nitrogen atoms.

[0087] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a 5-membered heteroaryl group.

[0088] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from 5-membered heteroaryl groups containing 1 or 2 nitrogen atoms.

[0089] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a 5-membered heteroaryl group containing two nitrogen atoms.

[0090] In some embodiments, the T 1 and T 5 is selected from N, and T 2 , T 3 and T 4 is selected from CH, X is selected from N, and ring A is selected from a pyrazolyl group.

[0091] In some embodiments, Ring A is selected from an oxetanyl group, an azetidinyl group, a morpholinyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrrolyl group, a triazolyl group, a pyrazolyl group, a furyl group, a dihydropyrimidinyl group, an isoxazolyl group, or an imidazolyl group.

[0092] In some embodiments, Ring A is selected from an oxetanyl group, a morpholinyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrrolyl group, a triazolyl group, a pyrazolyl group, a furyl group, a dihydropyrimidinyl group, an isoxazolyl group, or an imidazolyl group.

[0093] In some embodiments, ring A is [ka] Selected from.

[0094] In some embodiments, ring A is [ka] Selected from.

[0095] In some embodiments, ring A is [ka] Selected from.

[0096] In some embodiments, ring A is [ka] Selected from.

[0097] In some embodiments, ring A is [ka] Selected from.

[0098] In some embodiments, ring A is [ka] Selected from.

[0099] In some embodiments, the ring A is selected from a 4- to 6-membered heterocycloalkyl group containing 1 or 2 atoms selected from the group consisting of N and O, a 4- to 6-membered heterocycloalkenyl group containing 1 or 2 atoms selected from N, or a 6-membered heteroaryl group containing 1 or 2 atoms selected from N.

[0100] In some embodiments, the ring A is selected from a 4- to 6-membered heterocyclyl group containing 1 or 2 atoms selected from the group consisting of N and O, or a 6-membered heteroaryl group containing 1 or 2 atoms selected from N.

[0101] In some embodiments, ring A is selected from an oxetanyl group, a morpholinyl group, a 1,2-dihydropyridinyl group, a pyridinyl group, or a pyrimidinyl group.

[0102] In some embodiments, ring A is [ka] Selected from.

[0103] In some embodiments, m is selected from 0, 1, 2, 3, or 4. In some embodiments, m is selected from 0, 1, 2, or 3. In some embodiments, m is selected from 0, 1, or 2.

[0104] In some embodiments, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C 6~10 Aryl group or C 1~6alkoxy groups, 1~6 Alkyl group, C 3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C 6~10 Aryl group or C 1~6 The alkoxy group may optionally be one or more R a is replaced by

[0105] In some embodiments, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~4 Alkyl group, C 3~6 Cycloalkyl group, 3- to 6-membered heterocycloalkyl group or C 1~4 alkoxy groups, 1~4 Alkyl group, C 3~6 Cycloalkyl group, 3- to 6-membered heterocycloalkyl group or C 1~4 The alkoxy group may optionally be one or more R a is replaced by

[0106] In some embodiments, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~3 Alkyl group, C 3~4 Cycloalkyl group or C 1~3 alkoxy groups, 1~3 Alkyl group, C 3~4 Cycloalkyl group or C 1~3 The alkoxy group may optionally be one or more R a is replaced by

[0107] In some embodiments, each R 3 are each ═O, fluorine, chlorine, a hydroxy group, an amino group, a cyano group, a cyclopropyl group, or a C optionally substituted by one or more fluorines; 1~3 alkyl groups.

[0108] In some embodiments, each R 3are each independently selected from ═O, fluorine, a hydroxy group, an amino group, a cyano group, a methyl group, a trifluoromethyl group, and a cyclopropyl group.

[0109] In some embodiments, each R 3 are each ═O, fluorine, chlorine, an amino group, a cyano group, a cyclopropyl group, or a C optionally substituted by one or more fluorines; 1~3 alkyl groups.

[0110] In some embodiments, each R 3 are each independently selected from ═O, fluorine, an amino group, a cyano group, a methyl group, a trifluoromethyl group, or a cyclopropyl group.

[0111] In some embodiments, each R 3 are each a cyano group, a cyclopropyl group or a C optionally substituted by one or more fluorines; 1~3 alkyl groups.

[0112] In some embodiments, each R 3 are each independently selected from a cyano group, a methyl group, a trifluoromethyl group, or a cyclopropyl group.

[0113] Also in some embodiments, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group or C 1~8 alkoxy groups, 1~8 Alkyl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by

[0114] In some embodiments, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~6 Alkyl group or C 1~6 alkoxy groups,1~6 Alkyl group or C 1~6 The alkoxy group may optionally be one or more R a is replaced by

[0115] In some embodiments, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~3 Alkyl group or C 1~3 alkoxy groups, 1~3 Alkyl group or C 1~3 The alkoxy group may optionally be one or more R a is replaced by

[0116] In some embodiments, each R 3 are each ═O, fluorine, chlorine, an amino group, a cyano group, or C optionally substituted by one or more fluorines; 1~3 alkyl groups.

[0117] In some embodiments, each R 3 are each independently selected from =O, fluorine, an amino group, a cyano group, a methyl group, or a trifluoromethyl group.

[0118] In some embodiments, each R 3 are respectively =O, fluorine, chlorine, bromine or C 1~3 alkyl group, 1~3 The alkyl group may optionally be one or more R a is replaced by

[0119] In some embodiments, each R 3 are each independently selected from =0, fluorine or a methyl group, said methyl group optionally being substituted with one or more fluorines.

[0120] In some embodiments, each R a are each independently selected from a halogen or a cyano group. aare each independently selected from fluorine, chlorine, or bromine. a are each independently fluorine.

[0121] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0122] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0123] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0124] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0125] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0126] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0127] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0128] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0129] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0130] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0131] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0132] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0133] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0134] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0135] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0136] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0137] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0138] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0139] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0140] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0141] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0142] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0143] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0144] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0145] In some embodiments, the structural unit [ka] teeth, [ka] Selected from TIFF0007818610000079.tif45169.

[0146] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0147] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0148] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0149] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0150] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0151] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0152] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0153] In some embodiments, the structural unit [ka] teeth, [ka] isn't it.

[0154] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0155] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0156] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0157] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0158] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0159] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0160] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0161] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0162] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0163] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0164] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0165] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0166] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0167] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0168] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0169] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0170] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0171] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0172] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0173] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0174] In some embodiments, the structural unit [ka] teeth, [ka] Selected from TIFF0007818610000138.tif73162.

[0175] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0176] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0177] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0178] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0179] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0180] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0181] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0182] In some embodiments, the structural unit [ka] teeth, [ka] Selected from TIFF0007818610000155.tif161165.

[0183] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0184] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0185] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0186] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0187] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0188] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from TIFF0007818610000168.tif117164.

[0189] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0190] In some embodiments, the structural unit [ka] teeth, [ka] Selected from TIFF0007818610000173.tif194166 and TIFF0007818610000174.tif79166.

[0191] In some embodiments, the structural unit [ka] teeth, [ka] Selected from TIFF0007818610000177.tif119170.

[0192] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0193] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0194] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0195] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0196] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0197] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0198] Also in some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0199] In a further aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1are each independently selected from halogens; q is selected from 0, 1 or 2; Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH, and T 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from N, Ring A is C 6~10 an aryl group, a 3- to 8-membered heterocycloalkenyl group, or a 5- to 8-membered heteroaryl group, wherein the 5- to 8-membered heteroaryl group is selected from a 5- to 8-membered heteroaryl group containing 1 or 2 atoms selected from the group consisting of N and O; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group or C 1~8 alkoxy groups, 1~8 Alkyl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1, 2, 3 or 4; Each R a are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group.

[0200] In a further aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R1 are each independently selected from halogens; q is chosen from 0, Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, among which T 1 and T 5 is selected from N and T 2 , T 3 and T 4 is selected from CH, Ring A is C 6~10 an aryl group, a 5- to 6-membered heterocycloalkenyl group, or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocycloalkenyl group is selected from a 5- to 6-membered heterocycloalkenyl group containing 1 or 2 N, and the 5- to 6-membered heteroaryl group is selected from a 5- to 6-membered heteroaryl group containing 1 or 2 N; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~3 Alkyl group or C 1~3 alkoxy groups, 1~3 Alkyl group or C 1~3 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1 or 2; Each R a are each independently selected from a halogen or a hydroxy group.

[0201] In a further aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is chosen from 0, Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, among which T 1 and T 5 is selected from N and T 2 , T 3 and T 4 is selected from CH, Ring A is selected from 5-membered heteroaryl groups, wherein the 5-membered heteroaryl groups are selected from 5-membered heteroaryl groups containing 1 or 2 N; Each R 3 are respectively =O, halogen, hydroxy group or C 1~3 alkyl group, 1~3 The alkyl group may optionally be one or more R a and preferably, each R 3 are respectively =O, fluorine, chlorine, bromine or C 1~3 alkyl group, 1~3 The alkyl group may optionally be one or more R a and more preferably, each R 3 are each independently selected from =0, fluorine or a methyl group, said methyl group optionally being substituted with one or more fluorines; m is selected from 0, 1 or 2; Each R a are each independently selected from halogens.

[0202] In a further aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is chosen from 0, Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH, and T 1 and T 4 are not simultaneously selected from N and 2 and T 5 are not simultaneously selected from CH, and preferably T 1 and T 5 is selected from N and T 2 , T 3 and T 4 is selected from CH, or T 1 or T 5 are selected from N, and the remaining four are selected from CH, Ring A is selected from 5-membered heteroaryl groups, wherein the 5-membered heteroaryl groups are selected from 5-membered heteroaryl groups containing 1, 2 or 3 N, preferably the 5-membered heteroaryl groups are selected from 5-membered heteroaryl groups containing 3 N; Each R 3 are respectively, C 3~6 cycloalkyl groups, wherein the C 3~6 The cycloalkyl group may optionally be one or more R a and preferably, each R 3 each optionally containing one or more R a cyclopropyl groups substituted by m is selected from 1 or 2; Each R aare each independently selected from halogens.

[0203] In some embodiments, the Formula I compound or a pharmaceutically acceptable salt thereof is selected from a Formula I-1 compound, a Formula I-2 compound, a Formula I-3 compound, a Formula I-4 compound, a Formula I-5 compound, a Formula I-6 compound, a Formula I-7 compound, or a pharmaceutically acceptable salt thereof; [ka] In the formula, T 6 is selected from C or N, and T 1 , T 2 , T 3 , T 4 , T 5 , X, R 3 , m, and ring A are defined as above, Said T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O, or a bond; [ka] represents a single bond or a double bond.

[0204] In some embodiments, the T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O, or a bond, one or two of which are selected from NH or N. In some embodiments, the T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, one or two of which are selected from NH or N, and one of which is selected from a bond.

[0205] In some embodiments, the T 7 , T 8 , T 9 , T 10 , T 11 are each independently selected from CH, C, NH, N, or O, and one or two of them are selected from NH or N.

[0206] In some embodiments, the T 7 , T 8 , T 9 , T 10 are each independently selected from CH, C, NH, N, or O, and one or two of them are selected from NH or N.

[0207] In some embodiments, the T 7 , T 8 , T 9 , T 10 are each independently selected from CH, C, NH, or N, and one or two of them are selected from NH or N.

[0208] In some embodiments, the [ka] is a heteroaromatic ring system.

[0209] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0210] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0211] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0212] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0213] In some embodiments, the structural unit [ka] The definition of is as described above.

[0214] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0215] In some embodiments, the structural unit [ka] teeth, [ka] In some embodiments, the structural unit [ka] teeth, [ka] Selected from.

[0216] In some embodiments, the structural unit [ka] teeth, [ka] In some embodiments, the structural unit [ka] teeth, [ka] In some embodiments, the structural unit [ka] teeth, [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] In some embodiments, the structural unit is selected from [ka] teeth, [ka] Selected from.

[0217] In some embodiments, the present disclosure includes the above-defined variables and embodiments thereof, and any combination thereof.

[0218] The heteroatoms in the heterocyclyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl groups are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are selected from carbon. In some embodiments, the number of heteroatoms is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms is selected from 1, 2, or 3. In some embodiments, the number of heteroatoms is selected from 1 or 2.

[0219] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or "one or more" refers to 1, 2, 3, 4, 5, or 6, or "one or more" refers to 1, 2, or 3.

[0220] In some embodiments, the compound of the present disclosure is not the compound below or a pharmaceutically acceptable salt thereof. [ka]

[0221] In some embodiments, the compound of the present disclosure is not the compound below or a pharmaceutically acceptable salt thereof. [ka] TIFF0007818610000226.tif132167

[0222] In another aspect, the disclosure provides the following compound or a pharmaceutically acceptable salt thereof: [ka] TIFF0007818610000228.tif179146TIFF0007818610000229.tif194146TIFF0007818610000230.tif230162TIFF00078186100 00231.tif248164TIFF0007818610000232.tif200163TIFF0007818610000233.tif187168TIFF0007818610000234.tif127165

[0223] In another aspect, the disclosure provides the following compound or a pharmaceutically acceptable salt thereof: [ka] TIFF0007818610000236.tif128155

[0224] In another aspect, the disclosure provides the following compound or a pharmaceutically acceptable salt thereof: [ka]

[0225] In another aspect, the disclosure provides the following compound or a pharmaceutically acceptable salt thereof: [ka] TIFF0007818610000239.tif128156TIFF0007818610000240.tif124151

[0226] In another aspect, the disclosure provides the following compound or a pharmaceutically acceptable salt thereof: [ka]

[0227] In another aspect, the present disclosure further provides a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0228] In another aspect, the present disclosure further provides a method for treating or preventing a disease associated with TYK2, comprising administering to a mammal, preferably a human, in need of treatment a therapeutically or prophylactically effective amount of said compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0229] In another aspect, the present disclosure further provides the use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease associated with TYK2.

[0230] In another aspect, the present disclosure further provides the use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a disease associated with TYK2.

[0231] In another aspect, the present disclosure further provides the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing a disease associated with TYK2.

[0232] In some embodiments, the TYK2 associated disease is selected from an inflammatory or autoimmune disease, hi some embodiments, the TYK2 associated disease is selected from colitis. [Effects of the Invention]

[0233] The compounds of the present disclosure have good in vitro enzymatic or cellular activity, metabolic stability (eg, metabolic stability to liver microsomes), pharmacokinetic properties, and pharmacodynamic activity (eg, in a colitis model).

[0234] "Definition" Unless otherwise specified, the terms used in this disclosure have the following meanings: Certain terms are to be understood in their ordinary sense in the art, and not as open or unclear, unless otherwise defined. When trade names are mentioned herein, they refer to the corresponding products or their active ingredients.

[0235] In this disclosure, when a covalent bond is not attached to a particular atom in a particular structural unit or group, it represents that the covalent bond can be attached to any atom of that structural unit or group, provided that valence bond law is not violated.

[0236] The term "substituted" refers to the replacement of any or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the resulting compound is stable. When the substituent is oxygen (=O), two hydrogen atoms are replaced. Oxygen substitution does not occur on aryl groups.

[0237] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, when an ethyl group is "optionally" substituted with a halogen, the ethyl group may be unsubstituted (-CHCH), monosubstituted (e.g., -CHCHF), polysubstituted (e.g., -CHFCHF, -CHCHF, etc.), or fully substituted (e.g., -CFCF). As will be understood by those skilled in the art, groups containing one or more substituents do not allow for substitution or forms of substitution that are spatially incompatible and / or synthetically impossible.

[0238] Herein, C m~n means that the moiety has an integer number of carbon atoms in the specified range. For example, "C 1~6 " means that the subject group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C 1~3means that the group in question may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0239] When a particular variable (e.g., R) occurs more than once in a compound composition or structure, each occurrence is independently defined. Thus, for example, if a subject group is substituted with two R, each R is independently selected.

[0240] When the number of a particular connecting group is 0, for example, -(CH2)0-, this indicates that the connecting group is a covalent bond.

[0241] When the number of substituents is 0, for example, -(R 1 )0 represents no substitution, e.g., [ka] teeth, [ka] Represents.

[0242] When one variable is selected from a covalent bond, it represents that the two groups connected by the variable are directly connected; for example, when L' in A-L'-Z represents a covalent bond, it represents that the structure is actually AZ.

[0243] When a bond of a substituent crosses two atoms of a ring, such a substituent can be bonded to any atom of the ring. For example, the structural unit [ka] or [ka] In the case of the formula (I), substitution can be performed at any position of the cyclohexyl group or the cyclohexadiene.

[0244] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0245] The term "alkyl group" refers to a C n H 2n+1 The alkyl group may be straight or branched. For example, the term "C 1~6 The term "alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl group moiety (i.e., alkyl group) of an alkoxy group, an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group has the same definition as above. For example, the term "C 1~3 The term "alkyl group" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, isopropyl).

[0246] The term "alkoxy" refers to an --O-alkyl group.

[0247] The term "cycloalkoxy" refers to an --O-cycloalkyl group.

[0248] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, such carbocyclic rings generally have 3 to 10 members. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3~4 The cycloalkyl group includes a cyclopropyl group and a cyclobutyl group.

[0249] The term "heterocyclyl group" refers to a non-aromatic ring that may be fully saturated or partially unsaturated (but not fully unsaturated heteroaryl groups) and may exist as a monocyclic, bridged, or spirocyclic ring, including, for example, heterocycloalkyl and heterocycloalkenyl groups. Unless otherwise specified, the heterocyclyl group is generally a 3- to 10-membered or 3- to 7-membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

[0250] The term "heterocycloalkyl group" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (including fused) or spirocyclic ring. Unless otherwise specified, the heterocycloalkyl group is generally a 3- to 10-membered, 3- to 7-membered, 3- to 6-membered, 4- to 6-membered, or 5- to 6-membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; and examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydrofuryl. Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups, and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

[0251] The term "heterocycloalkenyl group" refers to a non-aromatic cyclic group that is not fully saturated (but is not a fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, or spirocyclic ring; unless otherwise specified, the heterocycloalkenyl group generally contains 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Unless otherwise specified, the heterocycloalkenyl group generally is a 3- to 10-membered ring or a 4- to 8-membered ring. Specific examples of heterocycloalkenyl groups include, for example, [ka] is.

[0252] The term "aryl group" refers to an aromatic cyclic group having an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene, and the like.

[0253] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system having at least one ring atom selected from N, O, or S, the remaining ring atoms being C, and at least one aromatic ring. Heteroaryl groups have a 5- to 8-membered ring, or a single 5- to 6-membered ring, or multiple fused rings containing 6 to 14, and especially 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, and the like.

[0254] The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. Such compounds contemplated in the present disclosure include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic and other mixtures, e.g., mixtures enriched in enantiomers or diastereomers, all of which are included within the scope of the present disclosure. Substituents such as alkyl groups may also have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present disclosure.

[0255] Unless otherwise stated, solid wedge bonds ( [ka] ) and wedge-shaped dashed bond ( [ka] ) represents the absolute configuration of the chiral center, and the linear solid bond ( [ka] ) and linear dashed bond ( [ka] ) indicates the relative configuration of the chiral center, and the wavy line ( [ka] ) and solid wedge-shaped connection ( [ka] ) or wedge-shaped dashed bond ( [ka] ) or a wavy line ( [ka] ) and a straight solid line connection ( [ka] ) and linear dashed bond ( [ka] )

[0256] Unless otherwise specified, when a compound has a double bond structure such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and two different substituents are connected to each atom on the double bond (in a double bond containing a nitrogen atom, the lone electron pair on the nitrogen atom is considered to be the substituent connected to it), the atoms on the double bond and their substituents in the compound are shown with a wavy line ( [ka] ) represents the (Z)-isomer, the (E)-isomer, or a mixture of the two isomers of the compound.

[0257] The term "treatment" means administering a compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation, to improve or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) arresting the disease or disease state, i.e., arresting its progression; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to disappear.

[0258] The term "prevention" means administering a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation, to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when a mammal susceptible to the disease state has not been diagnosed with the disease state.

[0259] The term "therapeutically or prophylactically effective amount" refers to an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, 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. What constitutes a "therapeutically effective amount" of a compound of the present disclosure will vary depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal being treated, but can be determined by one of ordinary skill in the art based on their knowledge and the present disclosure.

[0260] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, are not toxic or irritating, and are not likely to cause an allergic reaction or other problem or complication, and for which the benefit-risk ratio is reasonable.

[0261] Pharmaceutically acceptable salts include, 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, and the like.

[0262] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof, with pharmaceutically acceptable excipients. The pharmaceutical composition facilitates administration of the compounds of the present disclosure to a living body.

[0263] The term "pharmaceutically acceptable additive" refers to an additive that does not cause obvious irritation to the living body and does not impair the biological activity and properties of the active compound. Suitable additives, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc., are well known to those skilled in the art.

[0264] The term "comprise" and similar terms, such as the English expressions "comprises" or "comprising," are to be understood as open and non-exclusive expressions, such as "including, but not limited to."

[0265] The compounds and intermediates of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as ketone-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety, where a proton can be transferred between two ring nitrogen atoms. Valence tautomers include interconversions via recombination of some bonding electrons.

[0266] The present disclosure further includes compounds of the present disclosure that are identical to the compounds described herein, but in which one or more atoms have been replaced by an atom whose atomic mass or mass number is different from the normal atomic mass or mass number occurring in nature, i.e., isotopically labeled. Examples of isotopes that can be attached to compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example: 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, 36 Cl, etc.

[0267] Certain isotopes (e.g., 3 H, 14 Compounds of the present disclosure labeled with deuterium isotopes (C) can be used for compound and / or substrate tissue distribution analysis. 3 H), carbon-14( 14 C) is particularly preferred because it is easily obtainable and detectable. Positron-emitting isotopes, e.g. 15 O. 13 N, 11 C. 18 F can be used to measure substrate occupancy in positron emission tomography (PET) studies. In general, isotopically labeled compounds of the present disclosure can be prepared by procedures analogous to the techniques and / or examples disclosed below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0268] Also, isotopes with larger mass numbers (e.g., deuterium (i.e., 2H)) may be preferred in some cases due to the therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced doses). However, deuterium substitution may be partial or full, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium. All such compounds are within the scope of the present disclosure.

[0269] The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise specified, all stereoisomers, including enantiomers and diastereomers, are included. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using asymmetric starting materials or reagents.

[0270] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure or a pharmaceutically acceptable salt thereof with suitable pharmaceutically acceptable additives, and can be prepared, for example, as a solid, semi-solid, liquid, or gaseous preparation, such as a tablet, pill, capsule, powder, granule, ointment, emulsion, suspension, suppository, injection, inhalant, gel, microsphere, aerosol, etc.

[0271] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous.

[0272] The pharmaceutical compositions of the present disclosure can be manufactured by conventional methods well known in the art, for example, mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0273] In some embodiments, the pharmaceutical composition is in a form for oral administration. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable additives well known in the art. From these additives, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be formulated as a tablet, pill, dragee, capsule, liquid, gel, syrup, suspension, etc. for oral administration to a patient.

[0274] Oral solid compositions can be prepared by conventional methods such as blending, filling, and tableting. For example, they can be prepared by blending an active compound with a solid additive, and optionally pulverizing the mixture. If necessary, other suitable additives can be added, and the mixture can then be granulated to obtain tablets or dragee cores. Suitable additives include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents, etc.

[0275] The pharmaceutical compositions are also suitable for parenteral administration, for example as appropriate unit dose sterile solutions, suspensions or lyophilized products.

[0276] The therapeutic dose of a compound of the present disclosure may be determined, for example, by the specific therapeutic use, the mode of administration of the compound, the patient's health condition, and the prescribing physician's judgment. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition is not necessarily constant and is determined by various factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. A compound of the present disclosure may be provided for parenteral administration, for example, in phosphate-buffered saline containing about 0.1-10% w / v of the compound. Some typical dose ranges are about 1 μg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dose range is about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dose may be determined by variables such as the type of disease or condition and its progression, the patient's general health, the relative bioavailability of the selected compound, the excipient composition, and its route of administration. Effective doses can be obtained by extrapolation to dose-response curves derived from in vitro or animal model test systems.

[0277] The compounds of the present disclosure can be prepared by various synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternatives familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0278] The chemical reactions of certain embodiments of the present disclosure are carried out in suitable solvents, which must be compatible with the chemical transformations of the present disclosure and the reagents and raw materials used. In order to obtain compounds of the present disclosure, one skilled in the art may need to select or modify synthetic steps or reaction processes based on existing embodiments.

[0279] In the art, one of the major factors to be considered when planning a synthetic route is the selection of an appropriate protecting group for a reactive functional group (e.g., an amino group in the present disclosure). In this regard, see, for example, "Greene's Protective Groups in Organic Synthesis" (4 th Ed.). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0280] In some embodiments, compounds of the present disclosure can be prepared by one skilled in the art of organic synthesis by reference to the routes described below. [ka] TIFF0007818610000259.tif51137In formula, X, R 1 , q, R 2 ,n,T 1 , T 2 , T 3 , T 4 , T 5 , ring A, m or R 3 The definition of is as described above.

[0281] The following abbreviations are used in this disclosure: DMF represents N,N-dimethylformamide, DIPEA represents diisopropylethylamine, LiHMDS represents bis(trimethylsilyl)aminolithium, Pd(dba)2 represents bis(dibenzylideneacetone)palladium(0), Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0), Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and DMSO represents dimethyl sulfoxide.

[0282] Next, the present disclosure will be further explained using examples to clarify the present disclosure, but the scope of the present disclosure is not limited to the examples. All of the reagents used in this disclosure are commercially available products and can be used without further purification.

[0283] Any patent, patent application, or previously established publication is expressly incorporated herein by reference in its entirety for purposes of illustration and disclosure. Reference to such publications herein does not constitute an admission that such publications are part of the common general knowledge in the art. DETAILED DESCRIPTION OF THE INVENTION

[0284] Example 1: Compound 1-j [ka]

[0285] 1) Preparation of Compound 1-a: 4,6-Dichloropyridazine-3-carboxylic acid lithium salt (50 g) was dissolved in dichloromethane (500 mL). A catalytic amount of DMF was added at 0°C, and then oxalyl chloride (96 g) was slowly added dropwise to the solution. After the addition was complete, the reaction was continued at room temperature with stirring for 2 hours to complete the reaction. The reaction solution was concentrated. Deuterated methylamine hydrochloride (18.6 g) and DIPEA (162 g) were dissolved in dichloromethane (200 mL) and stirred at -25°C to clarify the reaction. The concentrate was dissolved in 300 mL of dichloromethane and slowly added dropwise to the solution. After the addition was complete, the reaction was continued with stirring for 2 hours. Water (750 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (500 mL x 2). The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain compound 1-a (52 g). ESI-MS: m / z = 209.2 [M+H] + .

[0286] 2) Preparation of compound 1-c: Compound 1-a (2 g) and compound 1-b (2.3 g) were dissolved in tetrahydrofuran (40 mL), and 1 M LiHMDS in tetrahydrofuran (48 mL) was added dropwise at -10 °C. After the addition was complete, the mixture was cooled to room temperature and stirred overnight. Purified water and ethyl acetate were added, and the mixture was stirred and separated. The organic phase was washed with brine, dried, filtered, and rotary evaporated to give compound 1-c (3.5 g). ESI-MS: m / z = 373.90 [M+H] + .

[0287] 3) Preparation of Compound 1-e: Compound 1-c (1.8 g), compound 1-d (0.41 g), Pd2(dba)3 (0.88 g), Xantphos (0.56 g), and cesium carbonate (3.13 g) were dissolved in 50 mL of dioxane, in this order, and heated to 105 °C under nitrogen protection for 24 hours. The reaction mixture was concentrated and purified by column chromatography to give compound 1-e (1.6 g). ESI-MS: m / z = 422.97 [M+H]. + .

[0288] 4) Preparation of Compound 1-f: Compound 1-e (1.6 g), bis(pinacolato)diboron (4.8 g), Pd(dppf)Cl (1.38 g), and potassium acetate (1.12 g) were dissolved in dioxane (50 mL), in that order, and the mixture was heated to 100 °C under nitrogen protection for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated to an oil. Methanol and n-heptane were added, followed by stirring and separation. The methanol phase was rotary evaporated to give compound 1-f (1.3 g). ESI-MS: m / z = 471.09 [M+H] + .

[0289] 5) Preparation of Compound 1-h: Compound 1-f (1 g), compound 1-g (0.67 g), Pd(dppf)Cl (0.31 g), and potassium carbonate (0.59 g) were dissolved in dioxane (50 mL) and water (10 mL), in that order, and the mixture was heated to 80 °C under nitrogen protection and reacted for 8 hours. The reaction mixture was concentrated and purified by column chromatography to give compound 1-h (0.3 g). ESI-MS: m / z = 501.08 [M+H] + .

[0290] 6) Preparation of Compound 1-j: Compound 1-h (70 mg), 1-i (17 mg), Pd(dppf)Cl (10 mg), and potassium carbonate (38 mg) were dissolved in dioxane (6 mL) and 1 mL of water, in that order, and the mixture was heated to 110 °C under nitrogen protection for 8 hours. The reaction mixture was concentrated, purified, and separated to give compound 1-j (0.3 g). ESI-MS: m / z = 500.14 [M+H]. + .

[0291] Example 2: Compound 2-h [ka] Referring to the preparation method of compound 1-h in Example 1, in step 5), compound 1-g was replaced with compound 2-g to obtain compound 2-h. ESI-MS: m / z=479.10 [M+H] + .

[0292] Example 3: Compound 3-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 3-i to obtain compound 3-j. ESI-MS: m / z=518.10 [M+H] + .

[0293] Example 4: Compound 4-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 4-i to obtain compound 4-j. ESI-MS: m / z=518.09 [M+H] + .

[0294] Example 5: Compound 5-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 5-i to obtain compound 5-j. ESI-MS: m / z=518.10 [M+H] + .

[0295] Example 6: Compound 6-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 6-i to obtain compound 6-j. ESI-MS: m / z=568.09 [M+H] + .

[0296] Example 7: Compound 7-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 7-i to obtain compound 7-j. ESI-MS: m / z=568.11 [M+H] + .

[0297] Example 8: Compound 8-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 8-i to obtain compound 8-j. ESI-MS: m / z=568.10 [M+H] + .

[0298] Example 9: Compound 9-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 9-i to obtain compound 9-j. ESI-MS: m / z=516.06 [M+H] + .

[0299] Example 10: Compound 10-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 10-i to obtain compound 10-j. ESI-MS: m / z=501.13 [M+H] + .

[0300] Example 11: Compound 11-h [ka] Referring to the preparation method of compound 1-h in Example 1, in step 5), compound 1-g was replaced with compound 11-g to obtain compound 11-h. ESI-MS: m / z=507.08 [M+H] + .

[0301] Example 12: Compound 12-j [ka] Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-i was replaced with compound 12-i to obtain compound 12-j. ESI-MS: m / z=536.04 [M+H] + .

[0302] Examples 13 to 41: The target compounds were obtained by referring to the preparation method of compound 2-h in Example 2, and changing compound 2-g to the compounds shown as raw materials in the table below.

[0303] [ka] 2-Pyrrolidone (1.0 g), 5-iodo-2-bromopyrimidine (1.7 g), Pd2(dba)3 (1.88 g), Xantphos (1.1 g), and cesium carbonate (11 g) were dissolved in 50 mL of dioxane, in this order, and the mixture was heated to 105°C under nitrogen protection for 30 minutes. The reaction mixture was concentrated, and the compound (60 mg) was obtained after separation and purification. ESI-MS: m / z = 242.08 [M+H] + .

[0304] [ka] 1-Methyl-1H-pyrazole-5-pinacolatoboronic acid ester (2.0 g), 5-iodo-2-bromopyrimidine (2.8 g), Pd(dppf)Cl (1.4 g), and potassium carbonate (4.1 g) were dissolved in dioxane (30 mL), in that order, and the mixture was heated to 100 °C under nitrogen protection for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to an oil, which was then subjected to column chromatography to obtain the product (0.6 g). ESI-MS: m / z = 239.11 [M+H]. + .

[0305] [ka] Step 1: 3-Bromo-1-cyclopropyl-1H-1,2,4-triazole (5.0 g), bis(pinacolato)diboron (10.2 g), Pd(dppf)Cl (1.9 g), and potassium acetate (7.8 g) were dissolved in dioxane (50 mL), in this order, and the mixture was heated to 80° C. under nitrogen protection for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to an oil, which was then subjected to column chromatography to obtain Intermediate 1 (Int. 1, 1.2 g).

[0306] Step 2: Intermediate 1 (Int. 1, 1.2 g), 5-iodo-2-bromopyrimidine (0.7 g), Pd(dppf)Cl (0.7 g), and potassium carbonate (2.1 g) were dissolved in dioxane (20 mL), in that order, and the mixture was heated to 100 °C under nitrogen protection for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to an oil, which was then subjected to column chromatography to obtain Intermediate 2 (Int. 2, 0.2 g). ESI-MS: m / z = 266.23 [M+H]. + . [Table 1] TIFF0007818610000276.tif233167TIFF0007818610000277.tif236167TIFF0007818610000278.tif244168

[0307] Examples 42 to 55: The target compounds were obtained by referring to the preparation method of compound 1-j in Example 1, and changing compound 1-i to the compounds shown as raw materials in the table below. [Table 2] TIFF0007818610000280.tif218168

[0308] Example 57: Compound 57-j [ka]

[0309] 1) Preparation of compound 57-a: Referring to the preparation method of compound 1-a in Example 1, in step 1), 4,6-dichloropyridazine-3-carboxylic acid lithium salt was changed to 4,6-diclopyridine-3-carboxylic acid lithium salt to obtain compound 57-a.

[0310] 2) Preparation of compound 57-c: Referring to the preparation method of compound 1-c in Example 1, in step 2), compound 1-a was changed to 57-a to obtain compound 57-c.

[0311] 3) Preparation of compound 57-e: Referring to the preparation method of compound 1-e in Example 1, in step 3), compound 1-c was changed to 57-c to obtain compound 57-e.

[0312] 4) Preparation of compound 57-f: Referring to the preparation method of compound 1-f in Example 1, in step 4), compound 1-e was changed to 57-e to obtain compound 57-f.

[0313] 5) Preparation of compound 57-h: Referring to the preparation method of compound 1-h in Example 1, in step 5), compound 1-e was changed to 57-f to obtain compound 57-h.

[0314] 6) Preparation of compound 57-j: Referring to the preparation method of compound 1-j in Example 1, in step 6), compound 1-h was changed to compound 57-h, and compound 1-i was changed to compound 57-i to obtain compound 57-j. ESI-MS: m / z=517.46 [M+H] + .

[0315] Examples 58 to 60: The following compounds were produced by referring to the production method of Example 57, substituting compound 57-i for the starting compound. [Table 3]

[0316] Example 61: Compound 61-h [ka] Referring to the preparation method of compound 1-h in Example 1, in step 5), compound 1-g was changed to compound 63-g, and compound 1-f was replaced with compound 57-f to obtain compound 61-h. ESI-MS: m / z=488.21 [M+H] + . [Table 4] TIFF0007818610000285.tif245166TIFF0007818610000286.tif247166TIFF000 7818610000287.tif247166TIFF0007818610000288.tif247166TIFF00078186100 00289.tif247166TIFF0007818610000290.tif247166TIFF0007818610000291.t if247166TIFF0007818610000292.tif247166TIFF0007818610000293.tif121166

[0317] Experimental Example 1: Thermal stability test of TYK2 JH2 A 0.52 mg / mL TYK2 JH2 (Beijing Yiqiao Shenzhou) protein stock solution was diluted to 50 ng / μL in phosphate-buffered saline (PBS). Orange dye (5000x) was diluted to 20x in DMSO. 16 μL of the TYK2 JH2 protein dilution was added to each well. Different compounds dissolved in DMSO were then added to the wells using a nanoliter sampler to achieve final concentrations of 10 μM and 1 μM. A blank control well (without enzyme) and a negative control well (containing enzyme and DMSO) were also included. Runs in duplicate were performed. Finally, 4 μL of Orange dye was added to each well and mixed uniformly by centrifugation. Detection was performed using a Roche LightCycler 480 fluorescent quantitative PCR instrument. The run program was 20°C for 15 seconds, 30–90°C for 0.02°C / s, and 20°C for 15 seconds. Melting temperatures (Tm) were obtained by analysis using LightCycler Thermal Shift Analysis software.

[0318] The compounds of the present disclosure have a melting temperature (Tm) of greater than 40°C, preferably greater than 45°C, and more preferably greater than 55°C at a final concentration of 10 μM, and a melting temperature (Tm) of greater than 40°C, preferably greater than 45°C, and more preferably greater than 50°C at a final concentration of 1 μM.

[0319] Experimental Example 2: Method for detecting STAT3 phosphorylation using Jurkat cells 20 μL of Jurkat cells in the logarithmic growth phase were collected and counted to obtain the desired cell number (mL). The cells were centrifuged at 1300 rpm for 3 minutes, and phenol red-free 1640 basal medium (Hyclone) was added to adjust the cell density to approximately 1.7 × 10E 7The cell density was adjusted to cells / mL. Cells were plated at the above cell density (384-well small-volume white plate) at 8 μL per well. Samples were added using a nanoliter sampler, and the compound was incubated for 1.5 hours. IFN-α (Beijing Yiqiao Shenzhou) was diluted to 75 ng / mL (final concentration: 25 ng / mL) in phenol red-free 1640 basal medium. Subsequently, 4 μL of IFN-α (3x) was added to each well based on the plate distribution. The blank group contained cells without compound or IFN-α. The control group contained cells without compound or IFN-α and was incubated at 37°C for 30 minutes. Immediately, 4 μL of lysis solution (4x) supplemented with blocking solution was added, and the plate was lysed for 40 minutes with shaking at room temperature. 4 μL of premixed antibody (vol / vol) prepared in detection buffer was added, the plate was covered, centrifuged to mix uniformly, and incubated at room temperature overnight. The signal values ​​at 665 nm / 620 nm were measured using a PE Envision multimode plate reader, and IC values ​​were calculated using a four-parameter fit. 50 was calculated.

[0320] The results are shown in Table 1. [Table 5] TIFF0007818610000295.tif60165

[0321] Experimental Example 3: Evaluation of liver microsome stability in vitro The final incubation system (300 μL) contained 30 μL of liver microsomes (protein concentration 5 mg / mL), 30 μL of NADPH + MgCl2, 3 μL of test compound (prepared in acetonitrile), and 237 μL of PBS buffer (pH 7.4). The organic solvent (acetonitrile) was 1% (volume ratio). Two aliquots were prepared for each species, one containing 0.30 mL. Each tube contained a homogenous substrate-enzyme mixture (total volume 270 μL). Each tube was preincubated with NADPH at 37°C for 5 minutes, then 30 μL of NADPH + MgCl2 was added and mixed. 50 μL of each aliquot was removed at 0, 10, 30, and 60 minutes, and the reaction was stopped with 300 μL of ice-cold acetonitrile containing an internal standard.

[0322] 50 μL of the incubated sample was precipitated by adding 300 μL of ice-cold acetonitrile containing an internal standard (20 ng / mL), vortexing for 10 minutes, and then centrifuging for 10 minutes (13,000 rpm, 20°C). 70 μL of the supernatant was withdrawn, diluted with 70 μL of ultrapure water, mixed uniformly, and 0.5 μL was used for LC / MS / MS analysis. The experimental results are shown in Table 2. [Table 6] TIFF0007818610000297.tif46145

[0323] Experimental Example 4: In vivo pharmacokinetic evaluation in mice The ICR mice (Shanghai Planning and Development Institute, 6-8 weeks old) weighed 20-24 g and were allowed to adapt for 3-5 days. They were then randomly divided into groups (9 mice per group) and intragastrically administered with the test compound at a dose of 15 mg / kg or 30 mg / kg.

[0324] The test animals (ICR mice) were fasted for 12 hours before administration, fed 4 hours after administration, and allowed unlimited access to water before, during, and after the experiment.

[0325] After intragastric administration, each mouse was sampled at three or four time points: 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 10 hours. Each time point consisted of three mice. Approximately 0.1 mL of blood was collected via the orbit and anticoagulated with EDTA-K2. Within 30 minutes, the blood was transferred to 4°C and centrifuged at 4000 rpm for 10 minutes to separate the plasma. After collection, all plasma was immediately stored at -20°C for analysis.

[0326] 20 μL was withdrawn from the collected test plasma sample, and 400 μL of an acetonitrile solution containing an internal standard (20 ng / mL) was added. The mixture was shaken for 10 minutes to mix uniformly, and centrifuged at 13,000 rpm for 10 minutes. 50 μL was withdrawn from the supernatant, diluted with 100 μL of ultrapure water, mixed uniformly, and 0.5 μL was withdrawn for use in LC / MS / MS measurement. The chromatogram was recorded.

[0327] The oral exposure of compounds of the present invention was evaluated in an in vivo pharmacokinetic study in mice, and the results are shown in Table 3. [Table 7] TIFF0007818610000299.tif55170

[0328] Experimental Example 5: Pharmacodynamic evaluation in an anti-CD40 mAb antibody-induced murine colitis model SPF male CB17-SCID mice (6-8 weeks old) were divided into groups on the first day of the experiment. On the first day of the experiment, mice in the blank group were intraperitoneally injected with PBS, while model mice were intraperitoneally injected with anti-mouse CD40 antibody (containing 100 μg of model preparation solution diluted with PBS) to create a murine colitis model. The injection volume for mice in all groups was 0.1 mL. [Table 8]

[0329] The day of grouping was day 1, and intragastric administration began on the day of grouping. The administration volume was 2 mL / kg, and the administration was carried out twice daily for 6 consecutive days. The solvent for intragastric administration was DMSO:PEG400 = 5:95 (volume ratio).

[0330] The animal's weight was monitored daily during the experiment. The experimental endpoint was day 7, when all mice were harvested. Mice were killed by cervical dislocation, their abdominal cavities cut open, and their spleens removed, weighed, and photographed. The colorectum was separated from the small intestine from the cecum to the anus, and the entire colorectum was removed and photographed. Subsequently, the intestine was cut longitudinally along its longitudinal axis, and the intestinal contents were washed with pre-chilled saline. The washed intestinal mucosa was placed in a large Petri dish with the mucosa facing up. The saline above the colorectum was absorbed with filter paper, and the colon tissue was removed and weighed.

[0331] The formula for calculating the inhibition rate (%) was: inhibition rate % = (MT) / (MC) × 100% (T: treatment group, C: blank control group, M: model control group).

[0332] The results are shown in Table 5. [Table 9] The present invention includes, for example, the following embodiments. [Section 1] A compound of formula I or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X is selected from N or CH; Each R 1 are each independently selected from halogens; q is selected from 0, 1 or 2; Each R 2 are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T 1 , T 2 , T3 , T 4 or T 5 are each independently selected from CH or N, at least one of which is selected from CH; Ring A is C 3~10 Cycloalkyl groups, 3- to 10-membered heterocyclyl groups, C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; Each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 6~10 Aryl group or C 1~8 alkoxy groups, 1~8 Alkyl group, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C 6~10 Aryl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by m is selected from 0, 1, 2, 3 or 4; Each R a are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group, or a pharmaceutically acceptable salt thereof. [Section 2] wherein X is N; Item 2. The compound according to Item 1, wherein X is CH, or a pharmaceutically acceptable salt thereof. [Section 3] Each of the above R 1 are each independently selected from fluorine or chlorine; Or, each of the above R 1 and each independently represent fluorine; or a pharmaceutically acceptable salt thereof. [Section 4] wherein q is selected from 0 or 1; 4. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 3, wherein q is 0. [Section 5] Each of the above R 2 are each independently selected from fluorine, chlorine, or bromine; Or, each of the above R 2 are each independently selected from fluorine or chlorine; Or, each of the above R 2 and each independently represent fluorine, or a pharmaceutically acceptable salt thereof. [Section 6] The n is selected from 0 or 1, 6. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 5, wherein n is 0. [Section 7] Said T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, three of which are selected from N and two of which are selected from CH; Or, the T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, two of which are selected from N and three of which are selected from CH; Or, the T 1 , T 2 , T 3 , T 4 or T 5 are each independently selected from CH or N, one of which is selected from N and four of which are selected from CH; Optionally, the T 1 , T 3 and T 5 is selected from N, and T 2 and T 4 is selected from CH, Or, the T 1 and T 3 is selected from N, and T 2 , T 4 and T 5 is selected from CH, or 1 and T 5is selected from N, and T 2 , T 3 and T 4 is selected from CH, or 2 and T 4 is selected from N, and T 1 , T 3 and T 5 is selected from CH, or 1 and T 2 is selected from N, and T 3 , T 4 and T 5 is selected from CH, or 2 and T 3 is selected from N, and T 1 , T 4 and T 5 is selected from CH, or 1 and T 4 is selected from N, and T 2 , T 3 and T 5 is selected from CH, or 2 and T 3 is selected from N, and T 1 , T 4 and T 5 is selected from CH, or 1 is selected from N, and T 2 , T 3 , T 4 and T 5 is selected from CH, Or, the T 2 is selected from N, and T 1 , T 3 , T 4 and T 5 is selected from CH, Or, the T 3 is selected from N, and T 1 , T 2 , T 4 and T 5 or CH. The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof. [Section 8] The ring A is C 3~8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C6~10 an aryl group or a 5- to 8-membered heteroaryl group; Or, the ring A is C 3~6 Cycloalkyl groups, 4- to 6-membered heterocyclyl groups, C 6~10 selected from an aryl group or a 5- to 6-membered heteroaryl group, Or, the ring A is C 3~6 a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; 6~10 an aryl group or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; Or, the ring A is C 3~8 Cycloalkyl group, 3- to 8-membered heterocycloalkyl group, 3- to 8-membered heterocycloalkenyl group, C 6~10 an aryl group or a 5- to 8-membered heteroaryl group; Or, the ring A is C 3~8 Cycloalkyl group, 4- to 6-membered heterocycloalkyl group, 4- to 6-membered heterocycloalkenyl group, C 6~10 an aryl group or a 5- to 8-membered heteroaryl group; Optionally, said ring A is C 3~6 a cycloalkyl group, a 4- to 6-membered heterocycloalkyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; a 4- to 6-membered heterocycloalkenyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; C 6~10 an aryl group or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; or the ring A is selected from a 4- to 6-membered heterocycloalkyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S, a 4- to 6-membered heterocycloalkenyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; or the ring A is selected from an oxetanyl group, an azetidinyl group, a morpholinyl group, a dioxanyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a tetrahydropyrrolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, a dihydropyrimidinyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group; or the ring A is selected from an oxetanyl group, an azetidinyl group, a morpholinyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrrolyl group, a triazolyl group, a pyrazolyl group, a furyl group, a dihydropyrimidinyl group, an isoxazolyl group, or an imidazolyl group; or said ring A is selected from an oxetanyl group, a morpholinyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrrolyl group, a triazolyl group, a pyrazolyl group, a furyl group, a dihydropyrimidinyl group, an isoxazolyl group, or an imidazolyl group; or said ring A is selected from [ka] Selected from Optionally, the ring A is selected from a 4- to 6-membered heterocyclyl group containing 1 or 2 atoms selected from the group consisting of N and O, or a 6-membered heteroaryl group containing 1 or 2 atoms selected from N; Alternatively, the ring A is selected from a 4- to 6-membered heterocycloalkyl group containing 1 or 2 atoms selected from the group consisting of N and O, a 4- to 6-membered heterocycloalkenyl group containing 1 or 2 atoms selected from N, or a 6-membered heteroaryl group containing 1 or 2 atoms selected from N, 8. The compound according to any one of items 1 to 7, wherein ring A is selected from an oxetanyl group, a morpholinyl group, a 1,2-dihydropyridinyl group, a pyridinyl group, and a pyrimidinyl group, or a pharmaceutically acceptable salt thereof. [Section 9] wherein m is selected from 0, 1, 2, or 3; Item 9. The compound according to any one of items 1 to 8, wherein m is optionally selected from 0, 1, and 2, or a pharmaceutically acceptable salt thereof. [Section 10] Each of the above R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C 6~10 Aryl group or C 1~6 alkoxy groups, 1~6 Alkyl group, C 3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C 6~10 Aryl group or C 1~6 The alkoxy group may optionally be one or more R a is replaced by Or, each of the above R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~4 Alkyl group, C 3~6 Cycloalkyl group, 3- to 6-membered heterocycloalkyl group or C 1~4 alkoxy groups, 1~4 Alkyl group, C 3~6 Cycloalkyl group, 3- to 6-membered heterocycloalkyl group or C 1~4 The alkoxy group may optionally be one or more R a is replaced by Or, each of the above R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~3 Alkyl group, C 3~4 Cycloalkyl group or C 1~3 alkoxy groups, 1~3 Alkyl group, C 3~4 Cycloalkyl group or C 1~3 The alkoxy group may optionally be one or more R a is replaced by Or, each of the above R 3 are each ═O, fluorine, chlorine, a hydroxy group, an amino group, a cyano group, a cyclopropyl group, or a C optionally substituted by one or more fluorines; 1~3independently selected from alkyl groups, Or, each of the above R 3 are each independently selected from =O, fluorine, a hydroxy group, an amino group, a cyano group, a methyl group, a trifluoromethyl group, and a cyclopropyl group; Optionally, each R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~8 Alkyl group or C 1~8 alkoxy groups, 1~8 Alkyl group or C 1~8 The alkoxy group may optionally be one or more R a is replaced by Or, each of the above R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~6 Alkyl group or C 1~6 alkoxy groups, 1~6 Alkyl group or C 1~6 The alkoxy group may optionally be one or more R a is replaced by Or, each of the above R 3 are respectively =O, halogen, hydroxy group, amino group, cyano group, nitro group, C 1~3 Alkyl group or C 1~3 alkoxy groups, 1~3 Alkyl group or C 1~3 The alkoxy group may optionally be one or more R a is replaced by Or, each of the above R 3 are respectively =O, fluorine, chlorine, bromine or C 1~3 alkyl group, 1~3 The alkyl group may optionally be one or more R a is replaced by Or, each of the above R 3 are each independently selected from =O, fluorine, or a methyl group, and the methyl group is optionally substituted with one or more fluorine atoms. [Section 11] Each of the above R a are each independently selected from a halogen or a cyano group; Or, each of the above R a are each independently selected from fluorine, chlorine, or bromine; Or, each of the above R a and each independently represent fluorine, or a pharmaceutically acceptable salt thereof. [Section 12] Structural Unit [ka] teeth, [ka] Selected from Or, structural unit [ka] teeth, [ka] Selected from Or, structural unit [ka] teeth, [ka] Selected from TIFF0007818610000310.tif53167 Or, structural unit [ka] teeth, [ka] TIFF0007818610000313.tif45169 or a pharmaceutically acceptable salt thereof according to any one of items 1 to 11. [Section 13] Structural Unit [ka] teeth, [ka] Selected from TIFF0007818610000316.tif78169 Or, structural unit [ka] teeth, [ka] Selected from Or, structural unit [ka] teeth, [ka] Selected from Or, structural unit [ka] teeth, [ka] Selected from Or, structural unit [ka] teeth, [ka] Selected from TIFF0007818610000325.tif82165, Or, structural unit [ka] teeth, [ka] 13. The compound according to any one of items 1 to 12, selected from TIFF0007818610000328.tif194167 and TIFF0007818610000329.tif79167, or a pharmaceutically acceptable salt thereof. [Section 14] selected from the group consisting of compounds of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, or a pharmaceutically acceptable salt thereof; [ka] In the formula, T 6 is selected from CH or N, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O, or a bond; [ka] represents a single bond or a double bond, Or, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, one or two of which are selected from NH or N; Or, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, one or two of which are selected from NH or N, and one of which is selected from a bond; Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] Selected from Optionally, a structural unit [ka] teeth, [ka] 14. The compound according to any one of items 1 to 13, selected from the group consisting of: [Section 15] The compound below or a pharmaceutically acceptable salt thereof. [ka] TIFF0007818610000353.tif246168TIFF0007818610000354.tif228167TIFF0007818610000 355.tif249168TIFF0007818610000356.tif245168TIFF0007818610000357.tif118169[Section 16] 16. A pharmaceutical composition comprising the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof. [Section 17] Use of the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 16, in the manufacture of a medicament for treating or preventing a disease associated with TYK2. [Section 18] Item 18. The use according to Item 17, wherein the TYK2-associated disease is selected from autoimmune diseases.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, X is selected from N or CH; Each R １ are each independently selected from halogens; q is selected from 0, 1 or 2; Each R ２ are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, or a nitro group; n is selected from 0, 1 or 2; T １ , T ２ , T ３ , T ４ or T ５ are each independently selected from CH or N, at least one of which is selected from CH; Ring A is C ３～１０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６～１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; Each R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～８ Alkyl group, C ３～１０ Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C ６～１０ Aryl group or C １～８ alkoxy groups, １～８ Alkyl group, C ３～１０ Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 5- to 10-membered heteroaryl groups, C ６～１０ Aryl group or C １～８ The alkoxy group may optionally be one or more R ａ is replaced by m is selected from 0, 1, 2, 3 or 4; Each R ａ are each independently selected from a halogen, a hydroxy group, an amino group, or a cyano group; However, the compound is the following compound: 【Chemistry 2】 【change】 or a pharmaceutically acceptable salt thereof, which is not

2. X is N, Or, the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH.

3. Each of the R １ are each independently selected from fluorine or chlorine; Or, each of the R １ and each independently represent fluorine, or a pharmaceutically acceptable salt thereof.

4. The q is selected from 0 or 1, Alternatively, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein q is 0.

5. Each of the R ２ are each independently selected from fluorine, chlorine, or bromine; Or, each of the R ２ are each independently selected from fluorine or chlorine; Or, each of the R ２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each of

6. The n is selected from 0 or 1, Alternatively, the compound according to any one of claims 1 to 5, wherein n is 0, or a pharmaceutically acceptable salt thereof.

7. Said T １ , T ２ , T ３ , T ４ or T ５ are each independently selected from CH or N, three of which are selected from N and two of which are selected from CH; Or, the T １ , T ２ , T ３ , T ４ or T ５ are each independently selected from CH or N, two of which are selected from N and three of which are selected from CH; Or, the T １ , T ２ , T ３ , T ４ or T ５ are each independently selected from CH or N, one of which is selected from N and four of which are selected from CH; Optionally, the T １ , T ３ and T ５ is selected from N, and T ２ and T ４ is selected from CH, Or, the T １ and T ３ is selected from N, and T ２ , T ４ and T ５ is selected from CH, or １ and T ５ is selected from N, and T ２ , T ３ and T ４ is selected from CH, or ２ and T ４ is selected from N, and T １ , T ３ and T ５ is selected from CH, or １ and T ２ is selected from N, and T ３ , T ４ and T ５ is selected from CH, or ２ and T ３ is selected from N, and T １ , T ４ and T ５ is selected from CH, or １ and T ４ is selected from N, and T ２ , T ３ and T ５ is selected from CH, or ２ and T ３ is selected from N, and T １ , T ４ and T ５ is selected from CH, or １ is selected from N, and T ２ , T ３ , T ４ and T ５ is selected from CH, Or, the T ２ is selected from N, and T １ , T ３ , T ４ and T ５ is selected from CH, Or, the T ３ is selected from N, and T １ , T ２ , T ４ and T ５ The compound according to any one of claims 1 to 6, wherein is selected from CH, or a pharmaceutically acceptable salt thereof.

8. The ring A is C ３～８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６～１０ selected from an aryl group or a 5- to 8-membered heteroaryl group; Or, the ring A is C ３～６ Cycloalkyl group, 4- to 6-membered heterocyclyl group, C ６～１０ selected from an aryl group or a 5- to 6-membered heteroaryl group; Or, the ring A is C ３～６ a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; ６～１０ an aryl group or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S; Or, the ring A is C ３～８ Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, 3- to 8-membered heterocycloalkenyl groups, C ６～１０ selected from an aryl group or a 5- to 8-membered heteroaryl group; Or, the ring A is C ３～８ Cycloalkyl groups, 4- to 6-membered heterocycloalkyl groups, 4- to 6-membered heterocycloalkenyl groups, C ６～１０ selected from an aryl group or a 5- to 8-membered heteroaryl group; Optionally, said ring A is C ３～６ a cycloalkyl group, a 4- to 6-membered heterocycloalkyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; a 4- to 6-membered heterocycloalkenyl group containing 1, 2, or 3 atoms selected from the group consisting of N, O, and S; C ６～１０ an aryl group or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S; or the ring A is selected from a 4- to 6-membered heterocycloalkyl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, a 4- to 6-membered heterocycloalkenyl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 atoms selected from the group consisting of N, O and S; or the ring A is selected from an oxetanyl group, an azetidinyl group, a morpholinyl group, a dioxanyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a tetrahydropyrrolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a furyl group, a thienyl group, a dihydropyrimidinyl group, an oxazolyl group, an isoxazolyl group, or an imidazolyl group; or the ring A is selected from an oxetanyl group, an azetidinyl group, a morpholinyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrrolyl group, a triazolyl group, a pyrazolyl group, a furyl group, a dihydropyrimidinyl group, an isoxazolyl group, and an imidazolyl group; or said ring A is selected from an oxetanyl group, a morpholinyl group, a dihydropyridinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrrolyl group, a triazolyl group, a pyrazolyl group, a furyl group, a dihydropyrimidinyl group, an isoxazolyl group, or an imidazolyl group; or said ring A is selected from 【Transformation 3】 Selected from Optionally, said ring A is selected from a 4- to 6-membered heterocyclyl group containing 1 or 2 atoms selected from the group consisting of N and O, or a 6-membered heteroaryl group containing 1 or 2 atoms selected from N; Alternatively, the ring A is selected from a 4- to 6-membered heterocycloalkyl group containing 1 or 2 atoms selected from the group consisting of N and O, a 4- to 6-membered heterocycloalkenyl group containing 1 or 2 atoms selected from N, or a 6-membered heteroaryl group containing 1 or 2 atoms selected from N, Alternatively, the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the ring A is selected from an oxetanyl group, a morpholinyl group, a 1,2-dihydropyridinyl group, a pyridinyl group, and a pyrimidinyl group.

9. wherein m is selected from 0, 1, 2, or 3; 9. The compound according to any one of claims 1 to 8, wherein m is optionally selected from 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

10. Each of the R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～６ Alkyl group, C ３～６ Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C ６～１０ Aryl group or C １～６ alkoxy groups, １～６ Alkyl group, C ３～６ Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 5- to 6-membered heteroaryl groups, C ６～１０ Aryl group or C １～６ The alkoxy group may optionally be one or more R ａ is replaced by Or, each of the R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～４ Alkyl group, C ３～６ a cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or C １～４ alkoxy groups, １～４ Alkyl group, C ３～６ a cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or C １～４ The alkoxy group may optionally be one or more R ａ is replaced by Or, each of the R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～３ Alkyl group, C ３～４ Cycloalkyl group or C １～３ alkoxy groups, １～３ Alkyl group, C ３～４ Cycloalkyl group or C １～３ The alkoxy group may optionally be one or more R ａ is replaced by Or, each of the R ３ are each ═O, fluorine, chlorine, a hydroxy group, an amino group, a cyano group, a cyclopropyl group, or a C optionally substituted by one or more fluorines; １～３ independently selected from alkyl groups, Or, each of the R ３ are each independently selected from ═O, fluorine, a hydroxy group, an amino group, a cyano group, a methyl group, a trifluoromethyl group, and a cyclopropyl group; Optionally, each R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～８ Alkyl group or C １～８ alkoxy groups, １～８ Alkyl group or C １～８ The alkoxy group may optionally be one or more R ａ is replaced by Or, each of the R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～６ Alkyl group or C １～６ alkoxy groups, １～６ Alkyl group or C １～６ The alkoxy group may optionally be one or more R ａ is replaced by Or, each of the R ３ are ═O, halogen, a hydroxy group, an amino group, a cyano group, a nitro group, and C １～３ Alkyl group or C １～３ alkoxy groups, １～３ Alkyl group or C １～３ The alkoxy group may optionally be one or more R ａ is replaced by Or, each of the R ３ are each ═O, fluorine, chlorine, bromine or C １～３ alkyl groups, １～３ The alkyl group may optionally be one or more R ａ is replaced by Or, each of the R ３ are each independently selected from =O, fluorine, or a methyl group, and the methyl group is optionally substituted with one or more fluorines, or a pharmaceutically acceptable salt thereof.

11. Each of the R ａ are each independently selected from a halogen or a cyano group; Or, each of the R ａ are each independently selected from fluorine, chlorine, or bromine; Or, each of the R ａ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each of

12. Structural Unit 【Chemistry 4】 teeth, 【Transformation 5】 Selected from Or, structural unit 【Transformation 6】 teeth, 【Transformation 7】 Selected from Or, structural unit 【Transformation 8】 teeth, 【Chemistry 9】 【change】 Selected from Or, structural unit 【Chemistry 10】 teeth, 【Chemistry 11】 【change】 12. The compound according to any one of claims 1 to 11, selected from the group consisting of:

13. Structural Unit 【Chemistry 12】 teeth, 【Chemistry 13】 【change】 Selected from Or, structural unit 【Chemistry 14】 teeth, 【Chemistry 15】 Selected from Or, structural unit 【Chemistry 16】 teeth, 【Chemistry 17】 Selected from Or, structural unit [Chemistry 18] teeth, 【Chemistry 19】 Selected from Or, structural unit 【Chemistry 20】 teeth, 【Chemistry 21】 【change】 Selected from Or, structural unit 【Chemistry 22】 teeth, 【Chemistry 23】 【change】 【change】 The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

14. selected from the group consisting of compounds of formula I-1, I-2, I-3, I-4, I-5, I-6, and I-7, or pharmaceutically acceptable salts thereof; 【Chemistry 24】 In the ceremony, T ６ is selected from CH or N, T ７ , T ８ , T ９ , T １０ , T １１ , T １２ are each independently selected from CH, C, NH, N, O, or a bond; 【Chemistry 25】 represents a single bond or a double bond, Or, T ７ , T ８ , T ９ , T １０ , T １１ , T １２ are each independently selected from CH, C, NH, N, O, or a bond, one or two of which are selected from NH or N; Or, T ７ , T ８ , T ９ , T １０ , T １１ , T １２ are each independently selected from CH, C, NH, N, O or a bond, one or two of which are selected from NH or N, and one of which is selected from a bond; Optionally, a structural unit 【Chemistry 26】 teeth, 【Chemistry 27】 Selected from Optionally, a structural unit 【Chemistry 28】 teeth, 【Chemistry 29】 Selected from Optionally, a structural unit 【Transformation 30】 teeth, 【Chemistry 31】 Selected from Optionally, a structural unit 【Chemistry 32】 teeth, 【Transformation 33】 Selected from Optionally, a structural unit 【Transformation 34】 teeth, 【Chemistry 35】 Selected from Optionally, a structural unit 【Transformation 36】 teeth, 【Chemistry 37】 Selected from Optionally, a structural unit 【Transformation 38】 teeth, 【Chemistry 39】 Selected from Optionally, a structural unit 【Chemistry 40】 teeth, 【Chemistry 41】 Selected from Optionally, a structural unit 【Chemistry 42】 teeth, 【Chemistry 43】 Selected from Optionally, a structural unit 【Chemistry 44】 teeth, 【Chemistry 45】 The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

15. The compound below or a pharmaceutically acceptable salt thereof. 【Chemistry 46】 【change】 【change】 【change】 【change】 【change】

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for treating or preventing a disease associated with TYK2.

18. The use according to claim 17, wherein the TYK2-related disease is selected from autoimmune diseases.

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