Heterocyclic compound, and pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a heterocyclic compound, and a pharmaceutical composition thereof and the use thereof. Specifically, disclosed in the present invention are a compound as shown in formula (I), and a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention has an excellent inhibitory activity on TYK2, has, in particular, an excellent inhibitory activity on TYK2-E957D and / or TYK2 JH2, and can significantly inhibit the proliferation of cells carrying TYK2-E957D mutations.

Description

Heterocyclic compounds, pharmaceutical compositions and applications thereof

[0001] This application claims priority to Chinese patent application No. 2024101762909, filed on February 7, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to heterocyclic compounds, pharmaceutical compositions and applications thereof. Background Art

[0003] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and II cytokine receptors and interferon type I and III receptors and is activated by these receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons and interleukins. Cytokine activation of the TYK2 signaling pathway promotes the phosphorylation and activation of signal transducers and activators of transcription (STATs), which then transduce to the nucleus and participate in the production of specific proteins. This pathway is involved in the function of Th17, Th1, B cells, and myeloid cells, all of which play a key role in the pathology of autoimmune diseases such as psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, and atopic dermatitis.

[0004] At the same time, TYK2 has been shown to play an important role in maintaining tumor surveillance, with TYK2 knockout mice showing impaired cytotoxic T cell responses and accelerated tumor development. Studies on T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 through TYK2, which maintains cancer cell survival by upregulating the anti-apoptotic protein BCL2 through STAT-mediated signaling. Knockdown of TYK2 (but not other JAK family members) reduces cell growth. TYK2-specific activating mutations that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V73II), and kinase domain (E957D and R1027H). However, the kinase function of TYK2 has also been found to be required for increased cancer cell survival, as the TYK2 enzyme has kinase-dead mutations (M978Y or M978F) in addition to the activating mutation (E957D) that causes transformation failure.

[0005] TYK2 inhibitors reported in the prior art include deucravacitinib and zasocitinib, but the variety is still relatively limited. Considering that TYK2 plays an important role in the pathological processes of various diseases, there is still a need to provide more novel compounds with TYK2 inhibitory effects to meet the needs of disease treatment. Summary of the Invention

[0006] The present invention addresses the technical problem of insufficient TYK2 inhibitors in the prior art by providing novel heterocyclic compounds, pharmaceutical compositions thereof, and their uses. The compounds of the present invention exhibit excellent inhibitory activity against TYK2, particularly TYK2-E957D and / or TYK2 JH2, and can significantly inhibit the proliferation of cells carrying the TYK2-E957D mutation.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] represents a single bond or a double bond;

[0011] X 1 C or N;

[0012] X 2 C or N;

[0013] R 1 is H, C1-C6 alkyl, or C1-C6 alkyl substituted by one or more deuteriums;

[0014] R 2 C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C1-C6 alkyl, one or more R 2-2 Substituted C1-C6 alkoxy, one or more R 2-3 Substituted C3-C 12 Cycloalkyl or one or more R 2-4 substituted 3-12 membered heterocycloalkyl;

[0015] R 2-1 and R 2-2 Each independently represents halogen, OH, C3-C 12Cycloalkyl or 3-12 membered heterocycloalkyl;

[0016] Or, two adjacent R 2-1 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C5-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl;

[0017] Alternatively, two R 2-1 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C5-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl;

[0018] Or, two adjacent R 2-2 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C5-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl;

[0019] Alternatively, two R 2-2 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C5-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl;

[0020] R 2-3 and R 2-4 Each is independently halogen, OH, C1-C6 alkyl or C1-C6 alkoxy;

[0021] Or, two adjacent R 2-3 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0022] Alternatively, two R2-3 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0023] Or, two adjacent R 2-4 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0024] Alternatively, two R 2-5 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0025] Ring A, Ring B and Ring C are each independently a benzene ring, a 5-6 membered heteroaromatic ring, a C5-C6 cycloalkene or a 5-6 membered heterocycloalkene;

[0026] Ring A and Ring B share a bond, which is a single bond or a double bond;

[0027] Ring B and Ring C share a bond, which is a single bond or a double bond;

[0028] R 3 is a substituent on Ring A, Ring B or Ring C;

[0029] R 3 are independently halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-1 Substituted C1-C6 alkyl or one or more R 3-2 Substituted C1-C6 alkoxy;

[0030] R 3-1 and R 3-2 are each independently halogen;

[0031] n is 0, 1, 2, or 3;

[0032] The "3-12 membered heterocycloalkyl" and " 2-4 In the "substituted 3-12 membered heterocycloalkyl", "substituted 5-6 membered heterocycloalkene", "3-8 membered heterocycloalkyl", "3-7 membered monocyclic heterocycloalkyl", "5-12 membered cyclic heterocycloalkyl", "5-12 membered bridged heterocycloalkyl", "5-12 membered spirocyclic heterocycloalkyl" and "3-7 membered heterocycloalkyl", the type of heteroatom or heteroatom group is independently selected from one or more of N, O, S, C(=O), S(=O)2, and the number of heteroatoms or heteroatom groups is independently one or more;

[0033] In the “5-6 membered heteroaromatic ring”, the types of heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently one or more.

[0034] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I), its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0035] In one embodiment of the present invention, the "3-12 membered heterocycloalkyl" or "substituted by one or more R 2-4 In the "substituted 3-12 membered heterocycloalkyl", "substituted 5-6 membered heterocycloalkene", "3-8 membered heterocycloalkyl", "3-7 membered monocyclic heterocycloalkyl", "5-12 membered cyclic heterocycloalkyl", "5-12 membered bridged heterocycloalkyl", "5-12 membered spirocyclic heterocycloalkyl" and "3-7 membered heterocycloalkyl", the types of heteroatoms or heteroatomic groups are each independently selected from 1, 2 or 3 of N, O, S, C(=O), S(=O)2, and the number of heteroatoms or heteroatomic groups is each independently 1, 2 or 3.

[0036] In one embodiment of the present invention, in the "5-6 membered heteroaromatic ring", the types of heteroatoms are independently selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0037] In one embodiment of the present invention, each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH(C2H5)CH2CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2 or -CH2C(CH3)3, for example, methyl, isopropyl, isobutyl or -CH2C(CH3)3.

[0038] In one embodiment of the present invention, each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.

[0039] In one embodiment of the present invention, each "C3-C 12 "Cycloalkyl" are each independently C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl or spiro[2.3]hexyl, further such as

[0040] In one embodiment of the present invention, each "3-12 membered heterocycloalkyl" is independently a 3-6 membered heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms, such as azetidinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl or piperidinyl, and further such as

[0041] In one embodiment of the present invention, each "halogen" is independently F, Cl, Br or I, such as F.

[0042] In one embodiment of the present invention, each "5-6 membered heteroaromatic ring" is a 5-6 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms, such as a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrazine ring, a pyridazine ring or a pyrimidine ring.

[0043] In one embodiment of the present invention, each "5-6 membered heterocyclic alkene" is For example

[0044] In one embodiment of the present invention, for

[0045] in,

[0046] X 3-1 is CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 3-2 、X 3-3 、X 3-4 、X 3-5 、X 3-6 、X 3-7 、X 3-8 and X 3- 9 are each independently CH or N;

[0047] X 4-1 、X 4-2 、X 4-3 、X 4-4 、X 4-5 、X 4-6 、X 4-7 、X 4-8 、X 4-9 and X 4-10are each independently CH or N;

[0048] X 5-1 、X 5-2 、X 5-3 、X 5-4 、X 5-5 、X 5-6 、X 5-7 、X 5-8 、X 5-9 and X 5-10 are each independently CH or N;

[0049] X 6-1 、X 6-7 and X 6-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 6-2 、X 6-3 、X 6-4 、X 6- 5 、X 6-6 and X 6-9 are each independently CH or N;

[0050] X 7-1 and X 7-5 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 7-2 、X 7-3 、X 7-4 、X 7-6 、X 7- 7 、X 7-8 、X 7-9 and X 7-10 are each independently CH or N;

[0051] X 8-1 、X 8-5 and X 8-7 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 8-2 、X 8-3 、X 8-4 、X 8- 6 、X 8-8 and X 8-9 are each independently CH or N;

[0052] X 9-1 and X 9-3 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 9-2 、X 9-4 、X9-5 、X 9-6 、X 9- 7 、X 9-8 、X 9-9 and X 9-10 are each independently CH or N;

[0053] X 10-1 、X 10-2 、X 10-3 、X 10-4 、X 10-5 、X 10-6 、X 10-7 、X 10-8 、X 10-9 and X 10-10 are each independently CH or N;

[0054] X 11-1 and X 11-7 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 11-2 、X 11-3 、X 11-4 、X 11- 5 、X 11-8 and X 11-9 are each independently CH or N;

[0055] X 12-1 and X 12-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 12-2 、X 12-3 、X 12-4 、X 12- 5 、X 12-7 and X 12-9 are each independently CH or N;

[0056] X 13-1 、X 13-5 and X 13-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 13-2 、X 13-3 、X 13- 4 、X 13-6 、X 13-7 and X 13-9 are each independently CH or N;

[0057] X 14-1 、X 14-6 、X 14-7 and X14-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 14-2 、X 14- 3 、X 14-4 and X 14-5 are each independently CH or N;

[0058] X 15-1 、X 15-3 and X 15-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 15-2 、X 15-4 、X 15- 5 、X 15-6 、X 15-7 and X 15-9 are each independently CH or N;

[0059] X 16-1 、X 16-2 and X 16-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 16-3 、X 16-4 、X 16- 5 、X 16-6 、X 16-7 and X 16-9 are each independently CH or N.

[0060] In one embodiment of the present invention, for

[0061] in,

[0062] X 3-1 is CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 3-2 、X 3-3 、X 3-4 、X 3-6 、X 3-7 、X 3-8 and X 3-9 are each independently CH or N;

[0063] X 4-1 、X 4-2 、X 4-3 、X 4-4 、X 4-5 、X 4-7 、X 4-8 、X4-9 and X 4-10 are each independently CH or N;

[0064] X 6-1 、X 6-7 and X 6-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 6-2 、X 6-3 、X 6-4 、X 6- 6 and X 6-9 are each independently CH or N;

[0065] X 7-1 and X 7-5 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 7-2 、X 7-3 、X 7-6 、X 7-7 、X 7- 8 、X 7-9 and X 7-10 are each independently CH or N;

[0066] X 8-1 、X 8-5 and X 8-7 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 8-2 、X 8-3 、X 8-6 、X 8- 8 and X 8-9 are each independently CH or N;

[0067] X 9-1 and X 9-3 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 9-2 、X 9-4 、X 9-5 、X 9-6 、X 9- 7 、X 9-8 、X 9-9 and X 9-10 are each independently CH or N;

[0068] X 10-1 、X 10-2 、X 10-3 、X 10-4 、X 10-5 、X10-7 、X 10-8 、X 10-9 and X 10-10 are each independently CH or N;

[0069] X 12-1 and X 12-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 12-2 、X 12-3 、X 12-4 、X 12- 7 and X 12-9 are each independently CH or N;

[0070] X 14-1 、X 14-6 、X 14-7 and X 14-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 14-2 、X 14- 3 and X 14-4 are each independently CH or N;

[0071] X 15-1 、X 15-3 and X 15-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 15-2 、X 15-4 、X 15- 5 、X 15-6 、X 15-7 and X 15-9 are each independently CH or N;

[0072] X 16-1 、X 16-2 and X 16-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 16-3 、X 16-4 、X 16- 5 、X 16-7 and X 16-9 are each independently CH or N.

[0073] In one embodiment of the present invention, Any of the following:

[0074] Case 1:

[0075] Case 2:

[0076] In one embodiment of the present invention, R 3 is independently F, CN, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkyl substituted with one or more F, such as F, CN, CH3, CF3, OCH3 or

[0077] In one embodiment of the present invention, n is 0, 1 or 2.

[0078] In one embodiment of the present invention, Any of the following:

[0079] Case 1:

[0080] Case 2:

[0081] In one embodiment of the present invention, R 1 is a C1-C3 alkyl group, such as a methyl group.

[0082] In one embodiment of the present invention, R 2 is C1-C5 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 2-1 Substituted C1-C5 alkyl, one or more R 2-3 Substituted C3-C6 cycloalkyl, or one or more R 2-4 substituted 3-6 membered heterocycloalkyl;

[0083] R 2-1 are independently OH or 3-6 membered heterocycloalkyl;

[0084] R 2-3 are independently F, OH or OCH3;

[0085] R 2-4 are independently OH or OCH3.

[0086] In one embodiment of the present invention, R 2 for

[0087] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1) or (I-2):

[0088] R 1 、R 2 、R3 , n, Ring A, Ring B and Ring C are as defined in any embodiment of the present invention.

[0089] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (I-3) or (I-4):

[0090] R 1 、R 3 , n, Ring A, Ring B and Ring C are as defined in any embodiment of the present invention.

[0091] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0092] The present invention also provides a pharmaceutical composition comprising the compound of formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0093] The present invention also provides a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a use of the above pharmaceutical composition in the preparation of a TYK2 inhibitor. Preferably, the TYK2 is TYK2-E957D.

[0094] The present invention also provides a use of a compound as represented by formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease associated with TYK2. Preferably, the disease associated with TYK2 is a disease associated with TYK2-E957D and / or TYK2 JH2.

[0095] In one embodiment of the present invention, the TYK2-related disease is an autoimmune disease, such as psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus or atopic dermatitis.

[0096] The present invention also provides a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition for use in the preparation of a medicament for preventing and / or treating autoimmune diseases, such as psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, or atopic dermatitis.

[0097] Unless otherwise specified, the groups in the present invention can be interpreted as follows.

[0098] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0099] In the present invention, The structure only represents that ring A and ring B are mutually annealed, ring B and ring C are mutually annealed, ring A and ring B share a bond, denoted as bond i, then bond i can be a single bond or a double bond, ring B and ring C share a bond, denoted as bond ii, then bond ii can be a single bond or a double bond, The relative positions of key i and key ii are not limited in the structure.

[0100] When any variable (such as R 3 ) occurs more than once in a compound's composition or structure, its definition is independent on each occurrence. Thus, for example, if a group is represented by 0-3 R 3 substituted, then the group may optionally be replaced by up to three R 3 is replaced, and in each case R 3 Also, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0101] In the present invention, the "C1-C6 alkyl" in each "C1-C6 alkyl" refers not only to an independent C1-C6 alkyl group, but also to a "C1-C6 alkyl" in a substituted C1-C6 alkyl group; for example, the "3-12 membered heterocycloalkyl" in each "3-12 membered heterocycloalkyl" refers not only to an independent 3-12 membered heterocycloalkyl group, but also to a "3-12 membered heterocycloalkyl" in a substituted 3-12 membered heterocycloalkyl group; the same applies to other expressions involving "each".

[0102] The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group having a specified number of carbon atoms, for example, a C1-C6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0103] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0104] The term "cycloalkyl" refers to a group having the specified number of ring carbon atoms (e.g., C3-C12 ), a saturated monocyclic, fused, bridged or spirocyclic group whose ring atoms consist only of carbon atoms.

[0105] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (e.g., 1, 2, or 3 of N, O, S, C(=O), S(=O), and S(=O)2), which is monocyclic, bridged, or spirocyclic, and each ring is saturated.

[0106] The term "halogen" refers to F, Cl, Br, I.

[0107] The term "heteroaromatic ring" refers to a cyclic, unsaturated aromatic ring having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (e.g., 1, 2, or 3 of N, O, and S). The heteroaromatic ring is attached to the rest of the molecule through a carbon atom or a heteroatom.

[0108] The term "cycloalkene" refers to a cyclic, partially unsaturated ring having a specified number of carbon atoms (e.g., C5-C6) with one or more (e.g., 1 or 2) carbon-carbon sp 2 Double bond, which is not aromatic.

[0109] The term "heterocyclene" refers to a cyclic, partially unsaturated ring having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (1, 2, or 3 of N, O, S, C(=O), S(=O), or S(=O)2), having one or more (e.g., 1 or 2) carbon-carbon sp 2 Double bond, which is not aromatic.

[0110] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds discovered herein with specific substituents with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.

[0111] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances, other than the active ingredient, contained in a pharmaceutical preparation. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0112] The term "solvate" refers to a substance formed by the combination of a compound and a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0113] The term "pharmaceutically acceptable salt solvate" refers to a compound formed by combining with a pharmaceutically acceptable acid or base and a solvent, wherein the amount of the solvent may be stoichiometric or non-stoichiometric.

[0114] In the aforementioned applications, the TYK2 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example, as a standard or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of TYK2 inhibitory effects.

[0115] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0116] The reagents and raw materials used in the present invention are commercially available.

[0117] The positive and progressive effects of the present invention are that the compounds of the present invention have excellent inhibitory activity against TYK2, in particular, have excellent inhibitory activity against TYK2-E957D and / or TYK2 JH2, and can significantly inhibit the proliferation of cells carrying the TYK2-E957D mutation. DETAILED DESCRIPTION

[0118] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0119] Example T01

[0120] Step 1: Synthesis of Compounds 1-3

[0121] Dissolve 1-1 (50 g, 322 mmol) and diethyl malonate (103 g, 645 mmol) in 1000 mL of ethanol and cool to 0°C in an ice-water bath. Add sodium ethoxide (65.8 g, 0.97 mol) in portions, maintaining the system temperature below 10°C. Heat the reaction system to 80°C and stir overnight. After completion of the reaction, concentrate the reaction system to obtain a yellow solid, which is suspended in 2 L of water and adjusted to pH 4 with 6 M HCl (77 g). Filter and wash the filter cake with 150 mL of water. After draining, dry the filter cake at 50°C overnight to obtain 1-3 (68 g, 94.6% yield). MS m / z: 224 [M+H] + .

[0122] Step 2: Synthesis of Compounds 1-4

[0123] 1-3 (10 g, 44.8 mmol) and N,N-diethylaniline (10 mL, 62.7 mmol) were added to a 250 mL three-necked flask. POCl3 (45 mL, 479.4 mmol) was slowly added under an ice-water bath. After the addition was complete, the reaction system was heated to 80°C and stirred for 3 h. After the reaction was completed, the reaction system was cooled to room temperature and quenched by slowly adding ice water. The pH was adjusted to 6.4 with saturated NaHCO3. Extraction was performed with ethyl acetate (200 mL x 3). The organic phases were combined, dried over sodium sulfate, and then spin-dried to obtain the crude product. Purification by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) afforded product 1-4 (10 g, 86% yield). MS m / z: 260 [M+H] + .

[0124] Step 3: Synthesis of compound INT01

[0125] 1-3 (1.0 g, 3.84 mmol) was dissolved in 20 mL of ethanol and added to a 250 mL three-necked flask. 1-5 (639 mg, 4.2 mmol) and potassium carbonate (585 mg, 4.2 mmol) were then added. The reaction system was stirred at room temperature overnight. The reaction system was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. The resulting concentrate was dissolved in ethyl acetate (50 mL) and washed with water (30 mL). The organic phase was washed with 10% citric acid, saturated NaHCO3 solution, and saturated brine, respectively, dried over sodium sulfate, and then spin-dried to obtain the crude product. Purification by preparative TLC (petroleum ether:ethyl acetate = 5:1) gave the product INT01 (1.2 g, 83% yield). MS m / z: 375 [M+H] + .

[0126] Step 4: Synthesis of Compounds 1-7

[0127] INT01 (1.19 g, 3.2 mmol) was dissolved in 15 mL of THF. 1-6 (611 mg, 3.3 mmol) and potassium tert-butoxide (713 mg, 6.4 mmol) were added at 0°C. The reaction system was stirred at room temperature overnight. After completion of the reaction, 10% aqueous citric acid was slowly added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over sodium sulfate, and then spin-dried to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 2:1) was used to isolate the product 1-7 (1 g, 60% yield). MS m / z: 522 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.55 (d, J=8.0Hz, 1H), 8.39 (s, 1H), 7.96 (dt, J=7.6, 1. 0Hz, 1H), 7.66 (dd, J=7.8, 1.1Hz, 1H), 7.59-7.52 (m, 1H), 7.51-7.42 (m, 1H), 7 .47-7.30(m, 3H), 7.16-7.09(m, 2H), 6.86-6.79(m, 2H), 5.66(s, 1H), 5.08(s , 2H), 4.45 (q, J=7.1Hz, 2H), 3.77 (s, 3H), 2.99 (s, 3H), 1.51 (t, J=7.1Hz, 3H).

[0128] Step 5: Synthesis of Compound 1-8

[0129] 1-7 (611.8 mg, 1.17 mmol) was dissolved in 10 mL of THF, 10 mL of ethanol, and 5 mL of water, and LiOH (281 mg, 11.7 mmol) was added. The reaction system was stirred at room temperature overnight. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the resulting concentrate was suspended in 20 mL of water and the pH was adjusted to 4-5 with 0.5 N hydrochloric acid. Filter, and transfer the filter cake to a single-necked flask with ethyl acetate, dry, and concentrate to obtain product 1-8 (542 mg, 94% yield), which was used directly in the next reaction. MS m / z: 494 [M+H] + .

[0130] Step 6: Synthesis of compound INT02

[0131] 1-8 (542 mg, 1.1 mmol) was suspended in 5 mL of ethyl acetate and 5 mL of 4 M HCl in ethyl acetate was added. The reaction system was stirred at room temperature overnight. After completion of the reaction, the reaction system was concentrated under reduced pressure to obtain the crude product INT02 (411 mg, 100% yield), which was used directly in the next reaction. MS m / z: 374 [M+H] + .

[0132] Step 7: Synthesis of compound T01

[0133] INT02 (20 mg, 53.57 μmol) was dissolved in 3 mL of DMF, and HATU (40.74 mg, 107.13 μmol) was added. After stirring at room temperature for 15 minutes, DIEA (34.62 mg, 267.83 μmol) and isopropylamine (6.33 mg, 107.13 μmol) were added. The reaction system was stirred at room temperature overnight. After completion of the reaction, the reaction system was dispersed in ethyl acetate and washed with 0.5 M HCl and then water. The organic phase was dried over sodium sulfate and spin-dried to obtain the crude product. Preparative TLC (petroleum ether:ethyl acetate = 2:1) was used to isolate the product T01 (18 mg, 82% yield). MS m / z: 415 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.17 (d, J=7.4Hz, 1H), 8.11 (s, 1H), 7.97-7.87 (m, 2H), 7.84 (dd, J=7.8, 1.1Hz, 1H) , 7.71 (d, J = 8.2Hz, 1H), 7.58-7.36 (m, 4H), 5.82 (s, 1H), 3.93-3.75 (m, 1H), 2.94 (d, J = 4.8Hz, 3H), 0.75 (d, J = 6.6Hz, 6H).

[0134] The synthesis methods of Examples T02-T14 are similar to those of T01, using INT02 and different amines or amine salts condensed under the same conditions. The identification data of Examples T02-T14 are shown in Table 1.

[0135] Table 1 Identification data of Examples T02-T14

[0136] Example T16

[0137] Step 1: Synthesis of compound 16-2

[0138] 16-1 (4.0 g, 21.9 mmol), o-hydroxyphenylboronic acid (3.33 g, 24.1 mmol), sodium carbonate (4.65 g, 43.8 mmol), and triphenylphosphine (2.3 g, 0.4 mmol) were mixed in toluene (64 mL) and water (16 mL). The mixture was purged with nitrogen five times. Palladium acetate (492 mg, 2.19 mmol) was then added under nitrogen, and the mixture was purged with nitrogen three times. The mixture was stirred at 80°C overnight. LCMS confirmed the reaction was complete. The reaction mixture was cooled, water was added, and extraction with EtOAc was performed until the aqueous phase was free of product. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to yield 16-2 (1.8 g, 62% yield). MS m / z: 240 [M+H] + .

[0139] Step 2: Synthesis of compound 16-3

[0140] To a 50 mL single-necked flask, 16-2 (127 mg, 0.53 mmol) and DMA (7 mL) were added. The atmosphere was purged with nitrogen three times. Under nitrogen protection, cuprous thiophene-2-carboxylate (121 mg, 0.63 mmol) was added to the reaction flask. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 120°C for 30 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (PE:EtOAc = 10:1) to afford 16-3 (50 mg, 46% yield). MS m / z: 204 [M+H] + .

[0141] Step 3: Synthesis of compound 16-4

[0142] To a 25 mL Schlenk flask were added 16-4 (61 mg), tert-butyl carbamate (61 mg), potassium phosphate (80 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-11′-biphenyl (12 mg), and tert-butanol (10 mL). The atmosphere was purged with nitrogen three times. Trisdibenzylideneacetone dipalladium (10 mg) was added to the reaction flask under nitrogen protection, and the atmosphere was purged with nitrogen three times. The reaction was stirred at 90°C for 4 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (PE:EtOAc = 6:1) to afford 16-4 (67 mg). MS m / z: 285 [M+H] + .

[0143] Step 4: Synthesis of compound 16-5

[0144] To a solution of 16-4 (193 mg, 0.068 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to afford 16-5 (257 mg, 100% yield), which was used directly in the next step. MS m / z: 185 [M+H] + .

[0145] Step 5: Synthesis of compound 16-6

[0146] To a 50 mL single-necked reaction flask were added 16-5 (41.28 mg, 0.224 mmol), INTO1 (70 mg, 0.187 mmol), cesium carbonate (304 mg, 0.994 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-11′-biphenyl (20 mg, 0.037 mmol), and 1,4-dioxane (5 mL). The atmosphere was purged with nitrogen three times. Under nitrogen protection, BrettPhos Pd G3 (17 mg, 0.019 mmol) was added to the reaction flask. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 100°C for 3 h. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (PE:EtOAc = 2:1) to afford 16-6 (80.2 mg, 82% yield). MS m / z: 523 [M+H] + .

[0147] Step 6 and Step 7: Synthesis of Compound 16-7

[0148] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 16-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 375 [M+H] + .

[0149] Step 8: Synthesis of compound T16

[0150] The same protocol as in Example T01 was used to prepare 16-7. MS m / z: 432 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.24 (s, 1H), 8.47 (d, J = 5.4Hz, 1H), 8.29 (s, 1H), 8.21- 8.10(m, 2H), 7.86-7.75(m, 1H), 7.71-7.64(m, 1H), 7.56-7.48(m, 1H), 7.47-7.4 0 (m, 1H), 7.34-7.24 (m, 1H), 6.12 (s, 1H), 4.79-4.53 (m, 1H), 3.25 (d, J=4.9Hz, 3 H), 2.62 (dqd, J=9.1, 5.1, 4.3, 1.7Hz, 1H), 1.13-0.94 (m, 1H), 0.90-0.75 (m, 1H).

[0151] Example T17

[0152] Step 1: Synthesis of compound INT03

[0153] Dissolve 17-1 (250 mg, 0.96 mmol) in 5 mL of acetonitrile, add 17-2 (160 mg, 1.06 mmol) and potassium carbonate (146 mg, 1.06 mmol). Stir the reaction system at room temperature overnight. Filter and concentrate. The resulting product is slurried with 5 mL of PE:EtOAc = 2:1 and filtered to obtain pure INT03 (300 mg, 83% yield). MS m / z: 375 [M+H] + .

[0154] Step 2: Synthesis of compound 17-4

[0155] The same protocol as in Example T16 was used to couple INT03 with 17-3. MS m / z: 522 [M+H] + .

[0156] Step 3 and Step 4: Synthesis of Compound INT04

[0157] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 17-4 with LiOH and HCl / EtOAc, respectively. MS m / z: 374 [M+H] + .

[0158] Step 5: Synthesis of compound T17

[0159] The same protocol as in Example T01 was used to prepare the product using INT04. MS m / z: 431 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.60 (d, J = 4.1Hz, 1H), 8.18 (d, J = 7.2Hz, 1H), 7.92 (dd, J=7.7, 1.2Hz, 1H), 7.85 (s, 1H), 7.70 (t, J=7.4Hz, 2H), 7.58-7.4 8(m, 2H), 7.47-7.34(m, 2H), 6.05(s, 1H), 4.64-4.45(m, 1H), 2.91(d, J=4.9Hz , 3H), 2.05-1.95 (m, 1H), 0.84 (dq, J=14.8, 8.2, 7.2Hz, 1H), 0.35-0.22 (m, 1H).

[0160] The syntheses of Examples T18-T19 were similar to those of Example T17, using INT04 and different amines or amine salts condensed under the same conditions. The identification data of Examples T18-T19 are shown in Table 2.

[0161] Table 2 Identification data of Examples T18-T19

[0162] Example T20

[0163] Step 1: Synthesis of compound 20-2

[0164] The same protocol as in Example T16 was used to couple 20-1 (same as 16-5) with INT03. MS m / z: 523 [M+H] + .

[0165] Step 2 and Step 3: Synthesis of Compound 20-3

[0166] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 20-2 with LiOH and HCl / EtOAc, respectively. MS m / z: 375 [M+H] + .

[0167] Step 4: Synthesis of compound T20

[0168] The same protocol as in Example T01 was used to prepare 20-3. MS m / z: 432 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 8.47 (d, J=5.5Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=5.5Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.68 (s, 1H), 7.45-7.33 (m, 1H), 7.26 (d, J=8. 7Hz, 1H), 6.87 (s, 1H), 6.64 (s, 1H), 6.25 (s, 1H), 4.63-4.44 (m, 1H), 2.91 (d, J=4. 9Hz, 3H), 2.05-1.95 (m, 1H), 0.84 (dq, J=14.8, 8.2, 7.2Hz, 1H), 0.35-0.22 (m, 1H).

[0169] Example T21

[0170]

[0171] Step 1: Synthesis of compound 21-2

[0172] The same protocol as in Example T16 was used to couple INT03 with 21-1. MS m / z: 538 [M+H] + .

[0173] Step 2 and Step 3: Synthesis of Compound 21-3

[0174] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 21-2 with LiOH and HCl / EtOAc, respectively. MS m / z: 390 [M+H] + .

[0175] Step 4: Synthesis of compound T21

[0176] The same protocol as in Example T01 was used to prepare 21-3. MS m / z: 473 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.52 (d, J = 9.4Hz, 1H), 8.45 (s, 1H), 8.34 (d, J=7.8Hz, 1H), 8.01 (d, J=6.2Hz, 1H), 7.76 (s, 1H), 7.66-7.44 (m, 6H), 5.89 (s, 1H), 3.86-3.77 (m, 1H), 2.94 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.02 (dd, J=15 .5, 7.7Hz, 1H), 1.44 (d, J=9.9Hz, 1H), 1.05-0.95 (m, 1H), -0.05--0.15 (m, 1H).

[0177] Example T22

[0178] Step 1: Synthesis of compound 22-2

[0179] 22-1 (1.0 g, 3.52 mmol) was dissolved in THF (80 mL), followed by the addition of 3-bromo-2-methoxyphenylboronic acid (813.2 mg, 3.52 mmol). The atmosphere was purged with nitrogen five times. Cesium carbonate (2.3 g, 7.04 mmol) and Pd(dppf)Cl (285.3 mg, 0.352 mmol) were then added under nitrogen, purged three times, and stirred in an oil bath at 65°C for 3 h. LCMS confirmed the reaction was complete. The reaction mixture was cooled, water was added, and extraction with DCM was performed until the aqueous phase was free of product. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 22-2 (855 mg, 70% yield). MS m / z: 344 [M+H] + .

[0180] Step 2: Synthesis of compound 22-3

[0181] 22-2 (850 mg, 2.48 mmol) was dissolved in DCM (30 mL), and BBr3 (3.7 g, 14.87 mmol) was added. The mixture was stirred at room temperature for 1 h. LCMS confirmed the complete reaction. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc until the aqueous phase was free of product. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 22-3 (610 mg, 75% yield). MS m / z: 330 [M+H] + .

[0182] Step 3: Synthesis of compound 22-4

[0183] The same protocol as in Example T16 was used to prepare 22-3. MS m / z: 248, 250 [M+H] + .

[0184] Step 4: Synthesis of compound 22-5

[0185] The same protocol as in Example T16 was used to prepare 22-4. MS m / z: 285 [M+H] + .

[0186] Step 5: Synthesis of compound 22-6

[0187] The same protocol as in Example T16 was used to prepare 22-5. MS m / z: 185 [M+H] + .

[0188] Step 6: Synthesis of compound 22-7

[0189] Prepared in the same manner as in Example T16 using INT03 and amine 22-6. MS m / z: 523 [M+H] + .

[0190] Step 7 and Step 8: Synthesis of Compound 22-8

[0191] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 22-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 375 [M+H] + .

[0192] Step 9: Synthesis of compound T22

[0193] The same protocol as in Example T01 was used to prepare 22-8. MS m / z: 458 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.68 (dd, J=4.8, 1.3Hz, 1H), 8.58 (d, J=9 .0Hz, 1H), 8.23-8.16(m, 2H), 8.06(d, J=7.6Hz, 1H), 7.81-7.71(m, 2H), 7.57(d d, J=8.1, 5.3Hz, 3H), 5.97 (s, 1H), 3.99-3.88 (m, 1H), 2.90 (d, J=4.8Hz, 3H), 2. 81 (s, 3H), 2.44-2.22 (m, 1H), 1.63 (dd, J=16.6, 9.2Hz, 2H), 0.29-0.06 (m, 1H).

[0194] Example T23

[0195] Step 1: Synthesis of compound 23-3

[0196] The same protocol as in Example T22 was used to prepare the product using 23-1 and 23-2. MS m / z: 272 [M+H] + .

[0197] Step 2: Synthesis of compound 23-4

[0198] The same protocol as in Example T22 was used to prepare 23-3. MS m / z: 258 [M+H] + .

[0199] Step 3: Synthesis of compound 23-5

[0200] Similar to the corresponding step of Example T16, 23-4 was used to prepare the product in NMP at 110°C. MS m / z: 222 [M+H] + .

[0201] Step 4: Synthesis of compound 23-6

[0202] The same protocol as in Example T16 was used to prepare 23-5. MS m / z: 303 [M+H] + .

[0203] Step 5: Synthesis of compound 23-7

[0204] The same protocol as in Example T16 was used to prepare 23-6. MS m / z: 203 [M+H] + .

[0205] Step 6: Synthesis of compound 23-8

[0206] Prepared in the same manner as in Example T16 using INT03 and amine 23-7. MS m / z: 541 [M+H] + .

[0207] Step 7 and Step 8: Synthesis of Compound 23-9

[0208] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 23-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 393 [M+H] + .

[0209] Step 9: Synthesis of compound T23

[0210] The same protocol as in Example T01 was used to prepare 23-9. MS m / z: 476 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 8.74 (dd, J=2.5, 1.3Hz, 1H), 8.58 (d, J=9.0Hz, 1H), 8 .35 (dd, J=9.2, 2.5Hz, 1H), 8.30-8.20 (bs, 1H), 8.03 (dd, J=7.8, 1.2Hz, 1H), 7.79 (s, 1H), 7 .74 (d, J=7.8Hz, 1H), 7.58 (t, J=7.7Hz, 2H), 5.96 (s, 1H), 3.94 (p, J=8.9Hz, 1H), 2.93 (d, J =4.9Hz, 3H), 2.84 (s, 3H), 2.47-2.38 (m, 1H), 1.65 (t, J = 9.1Hz, 2H), 0.19 (q, J = 9.9Hz, 1H).

[0211] Example T24

[0212] Step 1: Synthesis of compound 24-3

[0213] To a 50 mL three-necked flask were added 24-1 (1.0 g, 6.71 mmol), 24-2 (1.26 g, 6.76 mmol), triphenylphosphine (265.0 mg, 1.01 mmol), potassium phosphate (4.28 g, 20.18 mmol), acetonitrile (20 mL), and water (5 mL). The atmosphere was purged with nitrogen three times. Palladium acetate (126.0 mg, 0.56 mmol) was added to the reaction flask under nitrogen protection. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 60°C for 3 h. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 24-3 (1.53 g, 87.7% yield). MS m / z: 255 [M+H] + .

[0214] Step 2: Synthesis of compound 24-4

[0215] The same protocol as in Example T22 was used to prepare 24-3. MS m / z: 241 [M+H] + .

[0216] Step 3: Synthesis of compound 24-5

[0217] Similar to the corresponding step of Example T16, 24-4 was used to prepare the product in DMF at 100°C. MS m / z: 205 [M+H] + .

[0218] Step 4: Synthesis of compound 24-6

[0219] The same protocol as in Example T16 was used to prepare 24-5. MS m / z: 286 [M+H] + .

[0220] Step 5: Synthesis of compound 24-7

[0221] The same protocol as in Example T16 was used to prepare 24-6. MS m / z: 186 [M+H] + .

[0222] Step 6: Synthesis of compound 24-8

[0223] Prepared in the same manner as in Example T16 using INT03 and amine 24-7. MS m / z: 524 [M+H] + .

[0224] Step 7 and Step 8: Synthesis of Compound 24-9

[0225] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 24-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 376 [M+H] + .

[0226] Step 9: Synthesis of compound T24

[0227] The same protocol as in Example T01 was used to prepare 24-9. MS m / z: 459 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 8.81 (d, J = 2.8Hz, 1H), 8.65 (d, J = 9.1Hz, 1H), 8. 56 (d, J=2.7Hz, 1H), 8.45-8.25 (bs, 1H), 8.08 (dd, J=7.8, 1.2Hz, 1H), 7.95 (dd, J=7.9 , 1.1Hz, 1H), 7.82 (s, 1H), 7.67-7.58 (m, 2H), 6.05 (s, 1H), 4.01 (p, J=8.8Hz, 1H), 2.9 7-2.86 (m, 6H), 2.65 (q, J=7.5Hz, 1H), 1.71 (t, J=9.3Hz, 2H), 0.37 (p, J=10.0Hz, 1H).

[0228] Example T25

[0229] Step 1: Synthesis of compound 25-3

[0230] 25-1 (500 mg, 1.91 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and K3PO4 (815 mg, 3.82 mmol) and 25-2 (357 mg, 1.91 mmol) were added. The nitrogen atmosphere was replaced three times, and then Pd(dppf)Cl2 (140 mg, 0.19 mmol) was added. The nitrogen atmosphere was replaced three times, and the mixture was reacted at 60°C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by preparative TLC (petroleum ether:ethyl acetate = 10:1) to obtain 25-3 (384 mg, yield 62%). MS m / z: 322 [M+H] + .

[0231] Step 2: Synthesis of compound 25-4

[0232] The same protocol as in Example T22 was used to prepare 25-3. MS m / z: 308 [M+H] + .

[0233] Step 3: Synthesis of compound 25-5

[0234] The same protocol as in Example T24 was used to prepare 25-4. MS m / z: 272 [M+H] + .

[0235] Step 4: Synthesis of compound 25-6

[0236] The same protocol as in Example T16 was used to prepare 25-5. MS m / z: 353 [M+H] + .

[0237] Step 5: Synthesis of compound 25-7

[0238] The same protocol as in Example T16 was used to prepare 25-6. MS m / z: 253 [M+H] + .

[0239] Step 6: Synthesis of compound 25-8

[0240] Prepared in the same manner as in Example T16 using INT03 and amine 25-7. MS m / z: 591 [M+H] + .

[0241] Step 7 and Step 8: Synthesis of Compound 25-9

[0242] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 25-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 443 [M+H] + .

[0243] Step 9: Synthesis of compound T25

[0244] The same protocol as in Example T01 was used to prepare 25-9. MS m / z: 526 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 9.09 (dd, J=2.0, 0.9Hz, 1H), 8.78 (d, J=1.9Hz, 1 H), 8.52 (d, J=9.0Hz, 1H), 8.328.20 (bs, 1H), 8.23 ​​(s, 1H), 7.84 (dd, J=7.8, 1.2Hz, 1H ), 7.80 (s, 1H), 7.69-7.57 (m, 2H), 5.99 (s, 1H), 3.91 (p, J=8.7Hz, 1H), 2.94 (d, J=4.9 Hz, 3H), 2.79 (s, 3H), 2.37-2.27 (m, 1H), 1.61 (t, J=9.9Hz, 2H), 0.12 (p, J=9.9Hz, 1H).

[0245] Example T26

[0246] Step 1: Synthesis of compound 26-2

[0247] The same protocol as in Example T24 was used to prepare 26-1. MS m / z: 268 [M+H] + .

[0248] Step 2: Synthesis of compound 26-3

[0249] The same protocol as in Example T22 was used to prepare 26-2. MS m / z: 254 [M+H] + .

[0250] Step 3: Synthesis of compound 26-4

[0251] 26-3 (100 mg, 0.40 mmol) was dissolved in DMF (5 mL), followed by the addition of KOH (44.35 mg, 0.79 mmol) and Cu (30 mg, 0.47 mmol). The mixture was stirred and refluxed in an oil bath at 85°C overnight. EDTA was added for complexation, and the mixture was extracted with DCM. The organic phase was concentrated under reduced pressure to afford 26-4 (30 mg, 35% yield). MS m / z: 218 [M+H] + .

[0252] Step 4: Synthesis of compound 26-5

[0253] The same protocol as in Example T16 was used to prepare 26-4. MS m / z: 299 [M+H] + .

[0254] Step 5: Synthesis of compound 26-6

[0255] The same protocol as in Example T16 was used to prepare 26-5. MS m / z: 199 [M+H] + .

[0256] Step 6: Synthesis of compound 26-7

[0257] Prepared in the same manner as in Example T16 using INT03 and amine 26-6. MS m / z: 537 [M+H] + .

[0258] Step 7 and Step 8: Synthesis of Compound 26-8

[0259] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 26-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0260] Step 9: Synthesis of compound T26

[0261] The same protocol as in Example T01 was used to prepare 26-8. MS m / z: 472 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.63-8.53 (m, 2H), 8.27-8.10 (bs, 1H), 8.05 -7.97 (m, 1H), 7.82 (d, J=7.2Hz, 1H), 7.78 (s, 1H), 7.69 (d, J=7.7Hz, 1H), 7.53 (p, J =7.3Hz, 2H), 5.96 (s, 1H), 3.94 (p, J = 8.1Hz, 1H), 2.93 (d, J = 4.8Hz, 3H), 2.81 (s, 3 H), 2.48 (s, 3H), 2.08-1.90 (m, 1H), 1.63 (q, J=9.8Hz, 2H), 0.17 (t, J=10.3Hz, 1H).

[0262] Example T27

[0263] Step 1: Synthesis of compound 27-3

[0264] The same protocol as in Example T24 was used to prepare 27-1. MS m / z: 283 [M+H] + .

[0265] Step 2: Synthesis of compound 27-4

[0266] The same protocol as in Example T22 was used to prepare 27-3. MS m / z: 269 [M+H] + .

[0267] Step 3: Synthesis of compound 27-5

[0268] The same steps as in Example T24 were used to prepare 27-4. MS m / z: 233 [M+H] + .

[0269] Step 4: Synthesis of compound 27-6

[0270] The same protocol as in Example T16 was used to prepare 27-5. MS m / z: 314 [M+H] + .

[0271] Step 5: Synthesis of compound 27-7

[0272] The same protocol as in Example T16 was used to prepare 27-6. MS m / z: 214 [M+H] + .

[0273] Step 6: Synthesis of compound 27-8

[0274] Prepared in the same manner as in Example T16 using INT03 and amine 27-7. MS m / z: 552 [M+H] + .

[0275] Step 7 and Step 8: Synthesis of Compound 27-9

[0276] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 27-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 404 [M+H] + .

[0277] Step 9: Synthesis of compound T27

[0278] The same protocol as in Example T01 was used to prepare 27-9. MS m / z: 487 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 8.59 (dd, J=19.7, 8.4Hz, 2H), 8.04-7.97 (m, 1H), 7.84-7.77 (m, 2H), 7.63-7.51 (m, 2H), 6.01 (s, 1 H), 4.02-3.93 (m, 1H), 2.96-2.83 (m, 6H), 2.70 (s, 3H), 2.55 (s, 3H), 2.65-2.51 (m, 1H), 1.68 (q, J=9.6Hz, 2H), 0.31 (t, J=10.1Hz, 1H).

[0279] Example T28

[0280] Step 1: Synthesis of compound 28-2

[0281] Dissolve 1 (1.0 g, 10.41 mmol) in DMAP (100 mL), then add thionyl chloride (4 mL). Then, dissolve BTC (6.17 g, 20.82 mmol) in another 8 mL of thionyl chloride and slowly add the mixture dropwise. Stir in an 80°C oil bath for 12 h. Cool and quench with water, then adjust the pH to 8 with saturated sodium carbonate solution. Extract with DCM until the aqueous phase is free of product. Concentrate under reduced pressure, and the crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to yield 28-2 (46 mg). MS m / z: 149 [M+H] + .

[0282] Step 2: Synthesis of compound 28-3

[0283] The same protocol as in Example T24 was used to prepare 28-2. MS m / z: 255 [M+H]+ .

[0284] Step 3: Synthesis of compound 28-4

[0285] The same protocol as in Example T22 was used to prepare 28-3. MS m / z: 241 [M+H] + .

[0286] Step 4: Synthesis of compound 28-5

[0287] The same protocol as in Example T26 was used to prepare 28-4. MS m / z: 205 [M+H] + .

[0288] Step 5: Synthesis of compound 28-6

[0289] The same protocol as in Example T16 was used to prepare 28-5. MS m / z: 286 [M+H] + .

[0290] Step 6: Synthesis of compound 28-7

[0291] The same protocol as in Example T16 was used to prepare 28-6. MS m / z: 186 [M+H] + .

[0292] Step 7: Synthesis of compound 28-8

[0293] Prepared in the same manner as in Example T16 using INT03 and amine 28-7. MS m / z: 524 [M+H] + .

[0294] Steps 8 and 9: Synthesis of Compounds 28-9

[0295] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 28-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 376 [M+H] + .

[0296] Step 10: Synthesis of compound T28

[0297] The same protocol as in Example T01 was used to prepare 28-9. MS m / z: 459 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 9.37 (d, J=6.0Hz, 1H), 8.78-8.70 (bs, 1H), 8.57 (d, J=8.9Hz, 1H), 8.26 (dd, J=7.8, 1.2Hz, 1H), 8.13 (d, J=5.9Hz, 1H), 7.92 (dd, J=7.9, 1.2Hz, 1H), 7.81 (s, 1H), 7.68 (t, J=7.8Hz, 2H), 5.99 (s, 1H), 3.96 (p, J=8.9Hz, 1H), 2.93 (d, J=4. 8Hz, 3H), 2.84 (s, 3H), 2.60-2.52 (m, 1H), 1.67 (t, J=10.8Hz, 2H), 0.27 (t, J=10.1Hz, 1H).

[0298] Example T29

[0299] Step 1: Synthesis of compound 29-2

[0300] 29-1 (50 mg, 209 μmol) was dissolved in 1 mL of concentrated sulfuric acid, followed by the addition of fuming nitric acid (130 mg, 2.09 mmol). The mixture was stirred at room temperature for 40 minutes. LC-MS analysis revealed complete conversion of the starting material, with hydrolysis of the product as a side reaction. The mixture was slowly added dropwise to a saturated sodium carbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 29-2 (30 mg). MS m / z: 266 [M+H] + .

[0301] Step 2: Synthesis of compound 29-3

[0302] 29-2 (814 mg, 3.06 mmol) was dissolved in POCl3 (8 mL). The reaction system was incubated at 120°C for 5 h, then the reaction solution was slowly added to ice water. Extraction was performed with ethyl acetate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 29-3 (572 mg). MS m / z: 284 [M+H] + .

[0303] Step 3: Synthesis of compound 29-4

[0304] 29-4 (385 mg, 1.35 mmol) was dissolved in methanol (5 mL), and aqueous ammonia (5 mL) and Pd / C (35 mg) were added. The reaction system was reacted under 5 MPa hydrogen pressure for 15 h. The reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM:methanol = 10:1) to obtain 29-4 (54 mg). MS m / z: 186 [M+H] + .

[0305] Step 4: Synthesis of compound 29-5

[0306] Prepared in the same manner as in Example T16 using INT03 and amine 29-4. MS m / z: 524 [M+H] + .

[0307] Step 5 and Step 6: Synthesis of Compound 29-6

[0308] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 29-5 with LiOH and HCl / EtOAc, respectively. MS m / z: 376 [M+H] + .

[0309] Step 7: Synthesis of compound T29

[0310] The same protocol as in Example T01 was used to prepare 29-6. MS m / z: 459 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 9.30 (s, 1H), 9.11 (s, 1H), 8.61 (d, J=8.8Hz, 1H), 8.25 (bs, 1H), 7.89-7.74 (m, 3H), 7.64 (t, J=6.0H z, 2H), 6.11 (s, 1H), 4.04 (p, J=8.8Hz, 1H), 3.23-2.93 (m, 6H), 1.95-1.79 (m, 2H), 1.41 (dt, J=19.2, 9.5Hz, 1H), 0.70 (t, J=10.1Hz, 1H).

[0311] Example T30

[0312] Step 1: Synthesis of compound 30-3

[0313] The same protocol as in Example T24 was used to prepare 30-1. MS m / z: 326 [M+H] + .

[0314] Step 2: Synthesis of compound 30-4

[0315] The same protocol as in Example T22 was used to prepare 30-3. MS m / z: 312 [M+H] + .

[0316] Step 3: Synthesis of compound 30-5

[0317] The same protocol as in Example T26 was used to prepare 30-4. MS m / z: 232 [M+H] + .

[0318] Step 4: Synthesis of compound 30-6

[0319] The same protocol as in Example T16 was used to prepare 30-5. MS m / z: 313 [M+H] + .

[0320] Step 5: Synthesis of compound 30-7

[0321] The same protocol as in Example T16 was used to prepare 30-6. MS m / z: 213 [M+H] + .

[0322] Step 6: Synthesis of compound 30-8

[0323] Prepared in the same manner as in Example T16 using INT03 and amine 30-7. MS m / z: 551 [M+H] + .

[0324] Step 7 and Step 8: Synthesis of Compound 30-9

[0325] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 30-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 403 [M+H] + .

[0326] Step 9: Synthesis of compound T30

[0327] The same protocol as in Example T01 was used to prepare the compound 30-9. MS m / z: 486 [M+H] + . 1H N-MR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.58 (d, J = 9.1Hz, 1H), 8.25 (bs, 1H), 7.97 (dd , J=7.7, 1.1Hz, 2H), 7.66 (d, J=7.7Hz, 1H), 8.80 (s, 1H), 7.59-7.45 (m, 2H), 5.96 (s, 1H), 3.93 (q, J=8.7Hz, 1H), 2.93 (d, J=4.9Hz, 3H), 2.82 (s, 3H), 2.59 (s, 3H), 2.55-2 .50 (m, 1H), 2.41 (s, 3H), 1.64 (dq, J=19.2, 9.3Hz, 2H), 0.25 (q, J=10.1, 9.7Hz, 1H).

[0328] Example T31

[0329] Step 1: Synthesis of compound 31-3

[0330] The same protocol as in Example T24 was used to prepare 31-1. MS m / z: 253 [M+H] + .

[0331] Step 2: Synthesis of compound 31-4

[0332] The same protocol as in Example T22 was used to prepare 31-3. MS m / z: 239 [M+H] + .

[0333] Step 3: Synthesis of compound 31-5

[0334] The same protocol as in Example T26 was used to prepare 31-4. MS m / z: 219 [M+H] + .

[0335] Step 4: Synthesis of compound 31-6

[0336] The same protocol as in Example T16 was used to prepare 31-5. MS m / z: 300 [M+H] + .

[0337] Step 5: Synthesis of compound 31-7

[0338] The same protocol as in Example T16 was used to prepare 31-6. MS m / z: 200 [M+H] + .

[0339] Step 6: Synthesis of compound 31-8

[0340] Prepared in the same manner as in Example T16 using INT03 and amine 31-7. MS m / z: 538 [M+H] + .

[0341] Step 7 and Step 8: Synthesis of Compounds 31-9

[0342] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 31-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 390 [M+H] + .

[0343] Step 9: Synthesis of compound T31

[0344] The same protocol as in Example T01 was used to prepare 31-9. MS m / z: 473 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 9.21 (s, 1H), 8.57 (d, J=9.0Hz, 1H), 8.25 (bs , 1H), 8.09 (dd, J=7.9, 1.2Hz, 1H), 7.94 (dd, J=7.8, 1.2Hz, 1H), 7.81 (s, 1H), 7.66- 7.57(m, 2H), 6.00(s, 1H), 4.05-3.92(m, 1H), 2.93(d, J=4.9Hz, 3H), 2.87(s, 3H), 2.80 (s, 3H), 2.61 (q, J=7.6Hz, 1H), 1.69 (q, J=9.8Hz, 2H), 0.34 (t, J=10.0Hz, 1H).

[0345] Example T32

[0346] Step 1: Synthesis of compound 32-2

[0347] The same protocol as in Example T24 was used to prepare 32-1. MS m / z: 268 [M+H] + .

[0348] Step 2: Synthesis of compound 32-3

[0349] The same protocol as in Example T22 was used to prepare 32-2. MS m / z: 254 [M+H] + .

[0350] Step 3: Synthesis of compound 32-4

[0351] The same protocol as in Example T26 was used to prepare 32-3. MS m / z: 218 [M+H] + .

[0352] Step 4: Synthesis of compound 32-5

[0353] The same protocol as in Example T16 was used to prepare 32-4. MS m / z: 299 [M+H] + .

[0354] Step 5: Synthesis of compound 32-6

[0355] The same protocol as in Example T16 was used to prepare 32-5. MS m / z: 199 [M+H] + .

[0356] Step 6: Synthesis of compound 32-7

[0357] Prepared in the same manner as in Example T16 using INT03 and amine 32-6. MS m / z: 537 [M+H] + .

[0358] Step 7 and Step 8: Synthesis of Compound 32-8

[0359] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 32-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0360] Step 9: Synthesis of compound T32

[0361] The same protocol as in Example T01 was used to prepare 32-8. MS m / z: 472 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.66 (d, J = 8.2Hz, 1H), 8.54 (d, J = 4.8Hz, 1H), 8.18 (d, J=8.4Hz, 1H), 8.01 (d, J=7.5Hz, 1H), 7.81 (s, 1H), 7.76 (d, J=7.9Hz, 1H), 7.54 (s, 1H) , 7.43 (s, 1H), 7.22 (s, 1H), 6.00 (s, 1H), 4.053.92 (m, 1H), 2.94 (d, J=4.6Hz, 3H), 2.85 ( s, 3H), 2.72 (s, 3H), 2.67 (q, J=7.6Hz, 1H), 1.62 (q, J=9.8Hz, 2H), 0.85 (d, J=7.0Hz, 1H).

[0362] Example T33

[0363] Step 1: Synthesis of compound 33-2

[0364] The same protocol as in Example T24 was used to prepare 33-1. MS m / z: 268 [M+H] + .

[0365] Step 2: Synthesis of compound 33-3

[0366] The same protocol as in Example T22 was used to prepare 33-2. MS m / z: 254 [M+H] + .

[0367] Step 3: Synthesis of compound 33-4

[0368] The same protocol as in Example T26 was used to prepare 33-3. MS m / z: 218 [M+H] + .

[0369] Step 4: Synthesis of compound 33-5

[0370] The same protocol as in Example T16 was used to prepare 33-4. MS m / z: 299 [M+H] + .

[0371] Step 5: Synthesis of compound 33-6

[0372] The same protocol as in Example T16 was used to prepare 33-5. MS m / z: 199 [M+H] + .

[0373] Step 6: Synthesis of compound 33-7

[0374] Prepared in the same manner as in Example T16 using INT03 and amine 33-6. MS m / z: 537 [M+H] + .

[0375] Step 7 and Step 8: Synthesis of Compound 33-8

[0376] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 33-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0377] Step 9: Synthesis of compound T33

[0378] The same protocol as in Example T01 was used to prepare 33-8. MS m / z: 472 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.58 (d, J=9.0Hz, 1H), 8.25 (bs, 1H), 8.10 -7.98 (m, 2H), 7.79 (s, 1H), 7.72 (dd, J=7.7, 1.2Hz, 1H), 7.60-7.48 (m, 2H), 7.4 2 (d, J=8.7Hz, 1H), 5.97 (s, 1H), 3.95 (p, J=8.9Hz, 1H), 2.93 (d, J=4.9Hz, 3H), 2 .83 (s, 3H), 2.65 (s, 3H), 1.65 (dd, J=15.2, 9.2Hz, 2H), 0.26 (q, J=10.0Hz, 1H).

[0379] Example T35

[0380] Step 1: Synthesis of compound 35-2

[0381] The same protocol as in Example T24 was used to prepare 35-1. MS m / z: 322 [M+H] + .

[0382] Step 2: Synthesis of compound 35-3

[0383] The same protocol as in Example T22 was used to prepare 35-2. MS m / z: 308 [M+H] + .

[0384] Step 3: Synthesis of compound 35-4

[0385] The same protocol as in Example T26 was used to prepare 35-3. MS m / z: 272 [M+H] + .

[0386] Step 4: Synthesis of compound 35-5

[0387] The same protocol as in Example T16 was used to prepare 35-4. MS m / z: 353 [M+H] + .

[0388] Step 5: Synthesis of compound 35-6

[0389] The same protocol as in Example T16 was used to prepare 35-5. MS m / z: 253 [M+H] + .

[0390] Step 6: Synthesis of compound 35-7

[0391] Prepared in the same manner as in Example T16 using INT03 and amine 35-6. MS m / z: 591 [M+H] + .

[0392] Step 7 and Step 8: Synthesis of Compound 35-8

[0393] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 35-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 443 [M+H] + .

[0394] Step 9: Synthesis of compound T35

[0395] The same protocol as in Example T01 was used to prepare 35-8. MS m / z: 526 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 8.31 (dd, J=20.2, 8.8Hz, 2H), 8.01 (s, 1H), 7.96 (d, J=7.8Hz, 1H), 7.91 (d, J=8.7Hz, 1H), 7.67 (d, J=7.7Hz, 1H), 7.62 (s, 1H) ,7.52-7.37(m,2H),5.80(s,1H),3.75(p,J=8.8Hz,1H),2.75(d,J=4.8Hz,3H),2 .63 (s, 3H), 2.25 (q, J=7.8Hz, 1H), 1.44 (d, J=9.6Hz, 2H), -0.00 (p, J=9.8Hz, 1H).

[0396] Example T36

[0397] Step 1: Synthesis of compound 36-2

[0398] 36-1 (274 mg, 1.45 mmol) was dissolved in 1,4-dioxane (8 mL), followed by the addition of 3-chloro-2-methoxyphenylboronic acid (270.17 mg, 1.45 mmol). The atmosphere was purged with nitrogen five times. Potassium phosphate (923.01 mg, 4.34 mmol), Pd(OAc)2 (24.41 mg, 0.11 mmol), and triphenylphosphine (57.026 mg, 0.22 mmol) were then added under nitrogen. The mixture was purged with nitrogen three times and stirred at 70°C overnight. LCMS confirmed the reaction was complete. The reaction mixture was cooled, water was added, and extraction with DCM was performed until the aqueous phase was free of product. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 36-2 (174 mg, 65.8% yield). MS m / z: 295 [M+H] + .

[0399] Step 2: Synthesis of compound 36-3

[0400] The same protocol as in Example T22 was used to prepare 36-2. MS m / z: 281 [M+H] + .

[0401] Step 3: Synthesis of compound 36-4

[0402] The same protocol as in Example T26 was used to prepare 36-3. MS m / z: 245 [M+H] + .

[0403] Step 4: Synthesis of compound 36-5

[0404] The same protocol as in Example T16 was used to prepare 36-4. MS m / z: 326 [M+H] + .

[0405] Step 5: Synthesis of compound 36-6

[0406] The same protocol as in Example T16 was used to prepare 36-5. MS m / z: 226 [M+H] + .

[0407] Step 6: Synthesis of compound 36-7

[0408] Prepared in the same manner as in Example T16 using INT03 and amine 36-6. MS m / z: 564 [M+H] + .

[0409] Step 7 and Step 8: Synthesis of Compound 36-8

[0410] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 36-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 416 [M+H] + .

[0411] Step 9: Synthesis of compound T36

[0412] The same protocol as in Example T01 was used to prepare 36-8. MS m / z: 499 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 1H), 8.92 (s, 1H), 8.30 (d, J = 8.9Hz, 1H), 7.84 (d, J = 7.8Hz, 1H), 7.67 (d, J=7.9Hz, 1H), 7.57 (s, 1H), 7.37 (dd, J=10.0, 6.1Hz, 2H), 5.75 (s, 1H), 3.74 (q, J=8.6Hz , 1H), 2.69 (d, J=4.9Hz, 3H), 2.61 (s, 3H), 2.22-2.13 (m, 1H), 1.84-1.70 (m, 1H), 1.45 (p, J=10.0 Hz, 2H), 1.20 (d, J=15.9Hz, 1H), 0.88-0.80 (m, 2H), 0.62 (t, J=6.9Hz, 1H), 0.02 (t, J=9.9Hz, 1H).

[0413] Example T37

[0414] Step 1: Synthesis of compound 37-2

[0415] 37-1 (200 mg, 1.05 mmol) was dissolved in toluene (6 mL) and water (1 mL), followed by the addition of 3-chloro-2-methoxyphenylboronic acid (215.82 mg, 1.16 mmol). The atmosphere was purged with nitrogen five times. Potassium carbonate (436.4 mg, 3.16 mmol) and Pd(dppf)Cl (38.51 mg, 0.05 mmol) were then added under nitrogen. The mixture was purged with nitrogen three times and stirred at 110°C overnight. LCMS confirmed the reaction was complete. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 37-2 (12.7 mg, 5% yield). MS m / z: 252 [M+H] + .

[0416] Step 2: Synthesis of compound 37-3

[0417] The same protocol as in Example T22 was used to prepare 37-2. MS m / z: 238 [M+H] + .

[0418] Step 3: Synthesis of compound 37-4

[0419] The same protocol as in Example T26 was used to prepare 37-3. MS m / z: 218 [M+H] + .

[0420] Step 4: Synthesis of compound 37-5

[0421] The same protocol as in Example T16 was used to prepare 37-4. MS m / z: 299 [M+H] + .

[0422] Step 5: Synthesis of compound 37-6

[0423] The same protocol as in Example T16 was used to prepare 37-5. MS m / z: 199 [M+H] + .

[0424] Step 6: Synthesis of compound 37-7

[0425] Prepared in the same manner as in Example T16 using INT03 and amine 37-6. MS m / z: 537 [M+H] + .

[0426] Step 7 and Step 8: Synthesis of Compound 37-8

[0427] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 37-7 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0428] Step 9: Synthesis of compound T37

[0429] The same protocol as in Example T01 was used to prepare 37-8. MS m / z: 472 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 8.73-8.56 (m, 1H), 8.34 (d, J=4.9Hz, 1H) , 8.02 (d, J = 7.7Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.9Hz, 1H), 7.65-7.47 (m, 2H) , 7.37 (s, 1H), 6.01 (s, 1H), 4.09-3.89 (m, 1H), 2.93 (d, J=4.6Hz, 3H), 2.85 (s, 3H), 2.84 (s, 3H), 2.57-2.55 (m, 1H), 1.66 (d, J=9.5Hz, 2H), 0.40-0.22 (m, 1H).

[0430] Example T38

[0431] Step 1: Synthesis of compound 38-2

[0432] Dissolve 38-1 (1.0 g, 4.81 mmol) in THF and stir in an ice-water bath for 0.5 h. Then, add NaOH solution (3.2 mL, 3 M) and H₂O₂ (1.09 g, 9.6 mmol, 30%) and stir at 25°C for 3 h. LCMS confirmed the reaction was complete. The reaction solution was cooled to 0°C and the pH was adjusted to 7-8 with concentrated hydrochloric acid. Extraction was performed with a 10:1 dichloromethane:methanol mixture, and the organic phase was concentrated under reduced pressure to yield 38-2 (382.3 mg, 81.1% yield). MS m / z: 99 [M+H] + .

[0433] Step 2: Synthesis of compound 38-3

[0434] 38-2 (382.3 mg, 2.41 mmol) was dissolved in DMF (5.0 mL) and stirred in an ice-water bath for 20 minutes. NaH (192.2 mg, 4.81 mmol) was added under nitrogen and stirred in an ice-water bath for 0.5 h. 2-Fluoro-3-bromonitrobenzene (793.0 mg, 3.61 mmol) was dissolved in DMF and slowly added dropwise, stirring at 25°C for 20 minutes. LCMS confirmed the complete reaction of the starting material. The reaction mixture was quenched with aqueous solution and extracted with ethyl acetate until the aqueous phase was free of product. The organic phase was concentrated under reduced pressure and dissolved in dichloromethane. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 38-3 (280.1 mg, 24.1% yield). MS m / z: 298 [M+H] + .

[0435] Step 3: Synthesis of compound 38-4

[0436] 38-3 (100.0 mg, 0.22 mmol) and Na2CO3 (34.7 mg, 0.33 mmol) were dissolved in DMF (2.5 mL) and the nitrogen atmosphere was replaced three times. Palladium acetate (4.9 mg, 0.022 mmol) was then added under nitrogen protection, and the mixture was replaced with nitrogen six times and stirred in an oil bath at 135°C for 3 h. LCMS determined that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and dissolved in DCM. The crude product was purified by silica gel column chromatography (dichloromethane) to obtain 38-4 (51.0 mg, yield 70%). MS m / z: 218 [M+H] + .

[0437] Step 4: Synthesis of compound 38-5

[0438] 38-4 (51.0 mg, 0.23 mmol) was dissolved in MeOH (4.0 mL) and palladium on carbon (5 mg) was added. The mixture was replaced with hydrogen three times and stirred in an oil bath at 25°C for 1.5 h. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to afford 38-5 (40.0 mg, 91.1% yield). MS m / z: 188 [M+H] + .

[0439] Step 5: Synthesis of compound 38-6

[0440] Prepared in the same manner as in Example T16 using INT03 and amine 38-5. MS m / z: 526 [M+H] + .

[0441] Step 6 and Step 7: Synthesis of Compound 38-7

[0442] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 38-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 378 [M+H] + .

[0443] Step 8: Synthesis of compound T38

[0444] The same protocol as in Example T01 was used to prepare 38-7. MS m / z: 461 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 8.65 (d, J = 9.1Hz, 1H), 8.58 (s, 1H), 7. 89 (d, J=7.7Hz, 1H), 7.79 (s, 1H), 7.59-7.52 (m, 2H), 7.43 (t, J=7.9Hz, 1H), 5 .94(s, 1H), 4.17(s, 3H), 4.08-3.94(m, 1H), 2.92(d, J=4.6Hz, 3H), 2.90(s, 3H), 2.63 (q, J=7.7Hz, 1H), 1.73 (dq, J=19.6, 9.4Hz, 2H), 0.42-0.32 (m, 1H).

[0445] Example T39

[0446] Step 1: Synthesis of compound 39-3

[0447] To a 15 mL Schlenk flask, 39-1 (100 mg, 0.77 mmol) was added and the atmosphere was purged with nitrogen three times. Under nitrogen protection, 39-2 (1 mL) was added to the reaction flask and the atmosphere was purged with nitrogen three times. The reaction was stirred at 50°C for 2 h. Samples were taken and LCMS control showed that approximately 42% of the starting material had not reacted completely. The temperature was raised to 80°C and the reaction was stirred for 5 h. Samples were taken and LCMS control showed that approximately 6% of the starting material had not reacted completely. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative TLC (DCM:MeOH = 20:1) to obtain 39-3 (21.5 mg, yield 13.6%). MS m / z: 205 [M+H] + .

[0448] Step 2: Synthesis of compound 39-4

[0449] The same protocol as in Example T16 was used to prepare 39-3. MS m / z: 286 [M+H] + .

[0450] Step 3: Synthesis of compound 39-5

[0451] The same protocol as in Example T16 was used to prepare 39-4. MS m / z: 186 [M+H] + .

[0452] Step 4: Synthesis of compound 39-6

[0453] Prepared in the same manner as in Example T16 using INT03 and amine 39-5. MS m / z: 524 [M+H] + .

[0454] Step 5 and Step 6: Synthesis of Compound 39-7

[0455] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 39-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 376 [M+H] + .

[0456] Step 7: Synthesis of compound T39

[0457] The same protocol as in Example T01 was used to prepare 39-7. MS m / z: 459 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 9.49 (d, J = 8.0Hz, 1H), 9.15 (s, 1H), 8.81 (d, J = 8.9Hz, 1H), 8.68 (d, J=6.7Hz, 1H), 8.32 (s, 2H), 8.21 (d, J=7.4Hz, 1H), 7.89 (s, 1H), 7.62 (d, J=5.4 Hz, 1H), 7.16 (t, J=7.1Hz, 1H), 6.48 (s, 1H), 4.41-4.17 (m, 1H), 3.51 (q, J=7.7Hz, 1H), 3.14 (s, 3H), 2.92 (d, J=5.0Hz, 3H), 2.02 (dt, J=17.8, 9.4Hz, 2H), 1.46 (dt, J=21.9, 10.9Hz, 1H).

[0458] Example T40

[0459] Step 1: Synthesis of compound 40-2

[0460] 40-1 (200 mg, 1.07 mmol) was dissolved in toluene, and 3-bromo-4-iodopyridine (364 mg, 1.28 mmol), Cs2CO3 (1.05 g, 3.21 mmol), and 1,10-phenanthroline (77 mg, 0.43 mmol) were added. The nitrogen atmosphere was purged three times. CuI (68 mg, 0.21 mmol) was then added, and the nitrogen atmosphere was purged three times. The mixture was stirred at 110°C overnight. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. Dissolved in DCM, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford 40-2 (182 mg, 65% yield). MS m / z: 262 [M+H] + .

[0461] Step 2: Synthesis of compound 40-3

[0462] The same protocol as in Example T16 was used to prepare the product using 40-2. MS m / z: 299 [M+H] + .

[0463] Step 3: Synthesis of compound 40-4

[0464] The same protocol as in Example T16 was used to prepare the product using 40-3. MS m / z: 199 [M+H] + .

[0465] Step 4: Synthesis of compound 40-5

[0466] Prepared in the same manner as in Example T16 using INT03 and amine 40-4. MS m / z: 537 [M+H] + .

[0467] Step 5 and Step 6: Synthesis of Compound 40-6

[0468] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 40-5 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0469] Step 7: Synthesis of compound T40

[0470] The same protocol as in Example T01 was used to prepare the product using 40-6. MS m / z: 472 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 9.29 (bs, 1H), 9.28 (s, 1H), 8.94 (s, 1H), 8.67 (d, J = 4.4Hz, 1H), 8. 49 (dd, J=22.2, 8.7Hz, 2H), 8.18 (d, J=8.6Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=5.1Hz, 1H), 7.52 (d, J=8.6Hz, 1H), 7.45 (dd, J=8.5, 4.4Hz, 1H), 6.02 (s, 1H), 3.99 (dd, J=16.9, 8.3Hz, 1H), 2.93 (d, J=4.8Hz, 3H), 2.8 6 (s, 3H), 2.68 (s, 3H), 2.62 (dt, J=15.4, 7.6Hz, 1H), 1.67 (p, J=9.1, 8.7Hz, 2H), 0.33 (p, J=10.3Hz, 1H).

[0471] Example T41

[0472] Step 1: Synthesis of compound 41-2

[0473] Compound 41-1 (500 mg, 2.69 mmol) was dissolved in DCM (10 mL), and boron tribromide (809 mg, 3.23 mmol) was added. The mixture was stirred at 25°C for 3 h. 2 mL of methanol was added to quench the reaction, and the reaction solution was concentrated under reduced pressure to afford compound 41-2 (440 mg, 95% yield). MS m / z: 173 [M+H] + .

[0474] Step 2: Synthesis of compound 41-4

[0475] 41-3 (3 g, 20.8 mmol) was dissolved in DMA (10 mL), the atmosphere was replaced with nitrogen three times, the temperature was lowered to 0°C, phosphorus oxychloride (10 mL) was added, and the mixture was stirred at 25°C for 3 h. The reaction mixture was quenched by adding ice water, extracted with EtOAc (50 mL × 3), washed with 2N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 41-4 (1.3 g, yield 31%). MS m / z: 163 [M+H] + .

[0476] Step 3: Synthesis of compound 41-5

[0477] 41-2 (440 mg, 2.55 mmol) was dissolved in acetonitrile (10 mL), and sodium carbonate (676 mg, 6.38 mmol), 41-4 (414 mg, 2.55 mmol), and water (5 mL) were added. The atmosphere was purged with nitrogen three times, and bis(triphenylphosphine)palladium chloride (179 mg, 0.255 mmol) was added, followed by purging with nitrogen three times. The mixture was stirred at 75°C for 5 h. 2 mL of water was added to quench the reaction, and the mixture was extracted with EtOAc (15 mL x 3). The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain 41-5 (420 mg, 65% yield). MS m / z: 255 [M+H] + .

[0478] Step 4: Synthesis of compound 41-6

[0479] The same protocol as in Example T26 was used to prepare the product using 41-5. MS m / z: 235 [M+H] + .

[0480] Step 5: Synthesis of compound 41-7

[0481] The same protocol as in Example T16 was used to prepare 41-6. MS m / z: 316 [M+H] + .

[0482] Step 6: Synthesis of compound 41-8

[0483] The same protocol as in Example T16 was used to prepare 41-7. MS m / z: 216 [M+H] + .

[0484] Step 7: Synthesis of compound 41-9

[0485] Prepared in the same manner as in Example T16 using INT03 and amine 41-8. MS m / z: 554 [M+H] + .

[0486] Steps 8 and 9: Synthesis of compounds 41-10

[0487] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 41-9 with LiOH and HCl / EtOAc, respectively. MS m / z: 406 [M+H] + .

[0488] Step 10: Synthesis of compound T41

[0489] The same protocol as in Example T01 was used to prepare the compound 41-10. MS m / z: 489 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 9.36 (bs, 1H), 8.58 (d, J = 9.0Hz, 1H), 8.04 (d, J = 7.8Hz, 1H), 7.93 (d, J = 7.7Hz, 1H), 7.60 (dd, J = 10.7, 5.7Hz, 2H), 6 .01 (s, 1H), 4.03 (s, 3H), 3.98 (p, J = 8.3Hz, 1H), 2.93 (d, J = 4.8Hz, 3H), 2.88 (s, 3H), 2.62 (q, J=7.7Hz, 1H), 1.72 (t, J=9.7Hz, 2H), 0.33 (q, J=9.9Hz, 1H).

[0490] Example T42

[0491] Step 1: Synthesis of compound 42-3

[0492] 42-1 (460 mg, 4.21 mmol) was dissolved in acetonitrile (5 mL), and K3CO3 (582 mg, 8.42 mmol) and 42-2 (1000 mg, 4.21 mmol) were added. The nitrogen atmosphere was replaced three times, and the mixture was reacted at 50°C for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by preparative TLC (dichloromethane:methanol = 20:1) to obtain 42-3 (1171 mg, 90% yield). MS m / z: 310 [M+H] + .

[0493] Step 2: Synthesis of compound 42-4

[0494] The same protocol as in Example T38 was used to prepare the product using 42-3. MS m / z: 230 [M+H] + .

[0495] Step 3: Synthesis of compound 42-5

[0496] The same protocol as in Example T38 was used to prepare 42-4. MS m / z: 200 [M+H] + .

[0497] Step 4: Synthesis of compound 42-6

[0498] Prepared in the same manner as in Example T16 using INT03 and amine 42-5. MS m / z: 538 [M+H] + .

[0499] Step 5 and Step 6: Synthesis of Compound 42-7

[0500] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 42-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 390 [M+H] + .

[0501] Step 7: Synthesis of compound T42

[0502] The same protocol as in Example T01 was used to prepare 42-7. MS m / z: 473 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 9.28 (s, 1H), 8.94 (s, 1H), 8.67 (d, J=4.4Hz, 1H), 8.49 (dd, J=2 2.2, 8.7Hz, 2H), 8.18 (d, J=8.6Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=5.1Hz, 1H), 7.52 (d, J=8.6Hz, 1H), 7. 45 (dd, J=8.5, 4.4Hz, 1H), 6.02 (s, 1H), 3.99 (dd, J=16.9, 8.3Hz, 1H), 2.93 (d, J=4.8Hz, 3H), 2.86 (s , 3H), 2.68 (s, 3H), 2.62 (dt, J=15.4, 7.6Hz, 1H), 1.67 (p, J=9.1, 8.7Hz, 2H), 0.33 (p, J=10.3Hz, 1H).

[0503] Example T43

[0504] Step 1: Synthesis of compound 43-2

[0505] 43-1 (1.0 g, 4.93 mmol) and di-tert-butyl dicarbonate (1.29 g, 5.91 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred at 100°C for 7 h. TLC monitoring indicated that the reaction was incomplete, so additional di-tert-butyl dicarbonate (2.6 g, 11.93 mmol) was added. After allowing the reaction to proceed overnight, TLC indicated that the reaction was complete. The reaction solution was concentrated, added to water, and extracted with dichloromethane. The organic phase was concentrated to yield 43-2, which was used directly in the next reaction. MS m / z: 303 [M+H] + .

[0506] Step 2: Synthesis of compound 43-3

[0507] 43-2 (0.50 g, 1.65 mmol), o-formylphenylboronic acid (0.247 g, 1.65 mmol), palladium acetate (0.011 g, 0.05 mmol), XantPhos (0.048 g, 0.09 mmol), and potassium carbonate (0.456 g, 3.30 mmol) were dissolved in tetrahydrofuran (15 mL) and water (3 mL). The atmosphere was replaced with nitrogen three times, and the mixture was stirred in an oil bath at 75°C overnight. The reaction solution was concentrated and the crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give 43-3 (0.16 g, yield 30%). MS m / z: 329 [M+H] + .

[0508] Step 3: Synthesis of compound 43-4

[0509] 43-3 (0.16 g, 0.61 mmol) was dissolved in anhydrous methanol (5 mL) and sodium borohydride (0.038 g, 1.0 mmol) was added. The mixture was reacted at room temperature for 0.5 h. The reaction was quenched with aqueous citric acid until neutral. The reaction solution was concentrated and extracted with dichloromethane. The organic phase was concentrated and redissolved with chloroform (5 mL), diisopropylethylamine (0.2 mL) was added, nitrogen was replaced three times and cooled to 0°C, and methanesulfonyl chloride (0.1 mL) was added. The mixture was stirred at room temperature for 1 h and then heated to 55°C for half an hour. After concentrating the reaction solution, the crude product was purified by preparative TLC plate (dichloromethane) to obtain 43-4 (0.15 g, yield 100%). MS m / z: 299 [M+H] + .

[0510] Step 4: Synthesis of compound 43-5

[0511] The same protocol as in Example T16 was used to prepare 43-4. MS m / z: 199 [M+H] + .

[0512] Step 5: Synthesis of compound 43-6

[0513] Prepared in the same manner as in Example T16 using INT03 and amine 45-5. MS m / z: 537 [M+H] + .

[0514] Step 6: Synthesis of compound 43-7

[0515] The same protocol as in Example T01 was used to remove PMB using 43-6 and HCl / EtOAc. MS m / z: 417 [M+H] + .

[0516] Step 7: Synthesis of compound T43

[0517] (1R,2R)-2-Methoxycyclobutane-1-amine hydrochloride (13 mg, 95 μmol) was dissolved in 1,2-dichloromethane (1.5 mL), and 60 μL of a 1.6 M AlMe3 solution in toluene was added. The reaction was stirred at room temperature for 1 h. Compound 43-7 (20 mg, 0.048 mmol) was added to the reaction solution and allowed to react at room temperature for 3 h. The mixture was quenched by dropwise addition of 2 mL of water, followed by extraction with 2 mL of DCM:MeOH (10:1). The organic phase was dried and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH = 20:1) to afford T43 (5 mg, 22% yield). MS m / z: 472 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ8.93 (d, J=9.0Hz, 1H), 8.67 (s, 1H), 8.21 (d, J=7.7Hz, 1H), 8. 03 (d, J=6.9Hz, 1H), 7.86 (s, 1H), 7.70 (d, J=6.9Hz, 1H), 7.51 (td, J=11.4, 9.8, 6.0Hz, 3H), 7.06 (d, J=7.6Hz, 1H), 6.36 (s, 1H), 5.22 (s, 2H), 3.98 (p, J=8.7Hz, 1H), 3.16 (s, 3 H), 2.88 (d, J=4.8Hz, 3H), 2.67 (q, J=7.7Hz, 1H), 2.00-1.97 (m, 2H), 0.87-0.84 (m, 1H).

[0518] Example T44

[0519] Step 1: Synthesis of compound 44-2

[0520] The same protocol as in Example T42 was used to prepare the product using 44-1. MS m / z: 325 [M+H] + .

[0521] Step 2: Synthesis of compound 44-3

[0522] The same protocol as in Example T22 was used to prepare the product using 44-2. MS m / z: 311 [M+H] + .

[0523] Step 3: Synthesis of compound 44-4

[0524] 44-3 (190 mg, 0.61 mmol) was dissolved in anhydrous methanol (4 mL), acetic acid (2 mL) was added, and the atmosphere was replaced with nitrogen three times. Iron powder (170 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 1 h and filtered through celite to obtain 44-4 (120 mg, yield 70%). HRMS m / z: 280.9916, 282.9895 [M+H] + .

[0525] Step 4: Synthesis of compound 44-5

[0526] 44-4 (495 mg, 1.77 mmol), potassium carbonate (489 mg, 3.54 mmol), and DMEDA (62.3 mg, 0.71 mmol) were dissolved in 1,4-dioxane (15 mL), the atmosphere was purged with nitrogen three times, and cuprous iodide (67.3 mg, 0.35 mmol) was added. The mixture was stirred at 110°C for 1 h. The reaction solution was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 44-5 (70 mg, yield 20%). HRMS m / z: 201.0657 [M+H] + .

[0527] Step 5: Synthesis of compound 44-6

[0528] The same protocol as in Example T16 was used to prepare the product using 44-5. MS m / z: 539 [M+H] + .

[0529] Step 6: Synthesis of compound 44-7

[0530] The same protocol as in Example T01 was used to remove PMB using 44-6 and HCl / EtOAc. MS m / z: 419 [M+H] + .

[0531] Step 7: Synthesis of compound T44

[0532] Same as the corresponding step protocol in Example T43, prepared using 44-7. MS m / z: 474 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.96 (d, J=9.2Hz, 1H), 8.55 (s, 1H), 8.11 (d, J=8.1Hz, 1H), 8.08(d, J=8.3Hz, 1H), 7.81-7.78(m, 2H), 7.60-7.50(m, 2H), 7.22-7.19( m, 2H), 6.60-6.53 (m, 1H), 6.01 (s, 1H), 4.22 (p, J=8.7Hz, 1H), 3.25-3.10 (m, 1 H), 2.97 (s, 3H), 2.89 (d, J=4.7Hz, 3H), 2.08-2.00 (m, 2H), 0.86-0.83 (m, 1H).

[0533] Example T45

[0534]

[0535] Step 1: Synthesis of compound 45-2

[0536] The same protocol as in Example T42 was used to prepare the product using 45-1. MS m / z: 326 [M+H] + .

[0537] Step 2: Synthesis of compound 45-3

[0538] The same protocol as in Example T22 was used to prepare the product using 45-2. MS m / z: 312 [M+H] + .

[0539] Step 3: Synthesis of compound 45-4

[0540] The same protocol as in Example T44 was used to prepare 45-3. HRMS m / z: 281.9894, 283.9874 [M+H] + .

[0541] Step 4: Synthesis of compound 45-5

[0542] The same protocol as in Example T44 was used to prepare 45-4. HRMS m / z: 202.0602 [M+H] + .

[0543] Step 5: Synthesis of compound 45-6

[0544] The same protocol as in Example T16 was used to prepare 45-5. HRMS m / z: 540.1978 [M+H] + .

[0545] Step 6 and Step 7: Synthesis of Compound 45-7

[0546] Similar to the corresponding step of Example T01, 45-6 was used with HCl / EtOAc and LiOH to remove PMB and ethyl ester. MS m / z: 392 [M+H] + .

[0547] Step 8: Synthesis of compound T45

[0548] The same protocol as in Example T01 was used to prepare 45-7. MS m / z: 475 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.96 (d, J=9.2Hz, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8. 17 (d, J=8.1Hz, 1H), 8.08 (d, J=8.3Hz, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 7.45 (s , 1H), 6.53 (d, J=8.1Hz, 1H), 6.10 (s, 1H), 4.22 (p, J=8.7Hz, 1H), 3.03 (s, 3H ), 2.89 (d, J=4.7Hz, 3H), 2.60-2.50 (m, 1H), 2.00 (s, 2H), 0.86-0.83 (m, 1H).

[0549] Example T46

[0550] Step 1: Synthesis of compound T46

[0551] T41 (10 mg, 20.5 μmol) was dissolved in dichloromethane (1 mL). Boron tribromide (20 mg, 82 μmol) was slowly added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 7 with sodium bicarbonate, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 15:1) to obtain T46 (7 mg, 72% yield). HRMS m / z: 475.1811 [M+H] + .

[0552] Example T47

[0553] Step 1: Synthesis of compound 47-2

[0554] The same protocol as in Example T42 was used to prepare the product using 47-1. MS m / z: 325.25, 327.25 [M+H] + .

[0555] Step 2: Synthesis of compound 47-3

[0556] 47-2 (200 mg, 0.615 mmol) was dissolved in HBr (33 wt% in AcOH) and heated at 50°C overnight. The reaction was quenched with water, the pH was adjusted to 7 with sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 47-3 (135 mg, 71% yield). MS m / z: 311.25, 313.25 [M+H] + .

[0557] Step 3: Synthesis of compound 47-4

[0558] 47-3 (130 mg, 0.42 mmol) was dissolved in anhydrous methanol (4 mL). Acetic acid (2 drops) was added and the atmosphere was purged with nitrogen three times. Pt / Fe / C (13 mg) was added and the atmosphere was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred at room temperature under 1 atm of hydrogen for one hour. Filtration and concentration afforded 47-4, which was used directly in the next step. HRMS m / z: 280.9905, 282.9883 [M+H] + .

[0559] Step 4: Synthesis of compound 47-5

[0560] The same protocol as in Example T44 was used to prepare compound 47-4. HRMS m / z: 201.0652 [M+H] + .

[0561] Step 5: Synthesis of compound 47-6

[0562] The same protocol as in Example T16 was used to prepare 47-5. MS m / z: 539.55 [M+H] + .

[0563] Step 6 and Step 7: Synthesis of Compound 47-7

[0564] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 47-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 391 [M+H] + .

[0565] Step 8: Synthesis of compound T47

[0566] The same protocol as in Example T01 was used to prepare compound 47-7. HRMS m / z: 474.1874 [M+H] + .

[0567] Example T48

[0568] Step 1: Synthesis of compound T48

[0569] T21 (5 mg, 10.6 μmol) was suspended in dichloromethane (1 mL), and mCPBA (5.5 mg, 31.7 μmol) was added at room temperature. The mixture was stirred at room temperature for 16 h. The crude reaction solution was purified by preparative TLC (DCM:MeOH = 15:1) to afford T48 (2 mg, 37% yield). HRMS m / z: 505.1630 [M+H] + .

[0570] Example T49

[0571] Step 1: Synthesis of compound 49-2

[0572] The same protocol as in Example T16 was used to couple INT03 with 49-1. HRMS m / z: 534.2108 [M+H] + Step 2 and Step 3: Synthesis of Compound 49-3

[0573] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 49-2 with LiOH and HCl / EtOAc, respectively. MS m / z: 386 [M+H] + .

[0574] Step 4: Synthesis of compound T49

[0575] The same protocol as in Example T01 was used to prepare the product using 49-3. MS m / z: 469 [M+H] + . 1 H NMR (600MHz, DMSO-d6) 59.33 (s, 1H), 8.75 (d, J=7.8Hz, 1H), 7.84 (s, 1H), 7.82-7.78 (m, 2H), 7. 68-7.64 (m, 1H), 7.58-7.53 (m, 3H), 7.42 (d, J=7.8Hz, 1H), 7.37-7.33 (m, 1H), 6.05 (s, 1H), 4.20 -4.16 (m, 1H), 3.45-3.41 (m, 1H), 2.91 (d, J=4.8Hz, 3H), 2.86 (s, 3H), 1.98-1.81 (m, 2H), 1.12-1.03 (m, 1H).

[0576] Example T50

[0577] Step 1: Synthesis of compound 50-3

[0578] 50-1 (1 g, 3.7 mmol) was dissolved in THF (3 mL), cooled to -78°C under nitrogen, and n-BuLi (5.4 mL, 8.1 mmol) was added and stirred for 0.5 h. 50-2 (350 mg, 2.25 mmol) was added at this temperature, and the mixture was allowed to warm to room temperature. After completion, saturated aqueous ammonium chloride was added to quench the reaction. After slowly cooling to room temperature, the mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 3:1) to afford 50-3 (400 mg, 28% yield). MS m / z: 381.10 [M+H] + .

[0579] Step 2: Synthesis of compound 50-4

[0580] 50-3 (450 mg, 1.18 mmol) was dissolved in DCM (3 mL), cooled to 0°C under nitrogen, and Dess-Martin periodinane (1 g, 2.3 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 0.5 h. After the reaction was complete, saturated aqueous sodium sulfite solution was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure, and the crude product was purified by preparative TLC (PE / EtOAc = 3:1) to give 50-4 (380 mg, yield 86%). MS m / z: 379.00 [M+H] + .

[0581] Step 3: Synthesis of compound 50-5

[0582] 50-4 (300 mg, 0.8 mmol) was dissolved in THF (5 mL), and triethylamine (304 mg, 3 mmol), Boc2O (394 mg, 1.8 mmol), and DMAP (88 mg, 0.72 mmol) were added. The mixture was heated to 50°C and stirred for 3 h. After completion of the reaction, 10 mL of H2O was added to the reaction solution to quench the reaction. The mixture was extracted with DCM (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 3:1) to give 50-5 (300 mg, yield 79%). MS m / z: 479.05 [M+H] + .

[0583] Step 4: Synthesis of compound 50-6

[0584] 50-5 (200 mg, 0.43 mmol) was dissolved in DMF (3 mL). Potassium acetate (68 mg, 0.68 mmol) was added under nitrogen protection. The nitrogen atmosphere was replaced three times, and palladium acetate (15 mg, 0.06 mmol) was added. The mixture was heated to 85°C and stirred for 3 h. After completion of the reaction, 20 mL of H2O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 3:1) to obtain 50-6 (90 mg, 54% yield). MS m / z: 397.15 [M+H] + .

[0585] Step 5: Synthesis of compound 50-7

[0586] The same protocol as in Example T16 was used to prepare 50-6. MS m / z: 197.15 [M+H] + .

[0587] Step 6: Synthesis of compound 50-8

[0588] The same protocol as in Example T16 was used to prepare 50-7. MS m / z: 535.10 [M+H] + .

[0589] Step 7 and Step 8: Synthesis of Compound 50-9

[0590] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 50-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 387 [M+H] + .

[0591] Step 9: Synthesis of compound T50

[0592] The same protocol as in Example T01 was used to prepare the compound using 50-9. MS m / z: 470 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.70-8.60 (m, 2H), 7.98-7.88 (m, 3H), 7.70-7.60 (m, 2H), 7.48-7.38 (m, 2H), 6.05 ( s, 1H), 4.15-4.10 (m, 1H), 3.02 (s, 3H), 2.87 (d, J=4.8Hz, 3H), 2.64-2.60 (m, 1H), 1.88-1.84 (m, 2H), 0.77-0.74 (m, 1H).

[0593] Example T51

[0594] Step 1: Synthesis of compound 51-2

[0595] 3-Nitrophthalimide 51-1 (2.16 g, 11.3 mmol) was dissolved in DMF (5 mL), and potassium carbonate (1.43 g, 10 mmol) was added. The reaction solution was stirred at room temperature for 1 h. 4-Chloro-2-butanone (1 g, 9.4 mmol) and sodium iodide (70.3 mg, 0.5 mmol) were added under nitrogen, and the mixture was reacted at 40°C. TLC indicated that the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure to obtain 51-2 (the crude product was directly used in the next step). MS m / z: 263.20 [M+H] + .

[0596] Step 2: Synthesis of compound 51-3

[0597] 51-2 (1.4 g, 5.3 mmol) was weighed into a 250 mL three-necked flask, and toluene (60 mL) was used as the solvent. Trifluoromethanesulfonic acid (1.6 g, 10.7 mmol) was added under nitrogen. The reaction solution was stirred at 90°C for 10 h. TLC indicated the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc = 6 / 1) to afford 51-3 (585 mg, 45%). MS m / z: 245.15 [M+H] + .

[0598] Step 3: Synthesis of compound 51-4

[0599] The same protocol as in Example T44 was used to prepare 51-4. MS m / z: 215.25 [M+H] + .

[0600] Step 4: Synthesis of compound 51-5

[0601] 51-4 (65 mg, 0.3 mmol), INTO3 (148 mg, 0.39 mmol), potassium carbonate (105 mg, 0.76 mmol), and H2O (1d) were added to tert-butanol. XPhos (89.7 mg, 0.12 mmol), palladium acetate (13.6 mg, 0.06 mmol), and cuprous iodide (28.9 mg, 0.15 mmol) were added under nitrogen. The mixture was stirred at 110°C overnight. TLC analysis revealed a small amount of product remaining. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 1 / 1) to afford 51-5 (18 mg, 11%). MS m / z: 553.20 [M+H] + .

[0602] Step 5 and Step 6: Synthesis of Compound 51-6

[0603] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 51-5 with LiOH and HCl / EtOAc, respectively. MS m / z: 405 [M+H] + .

[0604] Step 7: Synthesis of compound T51

[0605] The same protocol as in Example T01 was used to prepare 51-6. MS m / z: 488 [M+H] + .

[0606] Example T52

[0607] Step 1: Synthesis of compound 52-3

[0608] 52-1 (300 mg, 1.43 mmol) was dissolved in ACN (4 mL) and water (1 mL). Sodium carbonate (380 mg, 3.6 mmol) and 52-2 (267 mg, 1.43 mmol) were added. The atmosphere was purged with nitrogen three times, and Pd(PPh3)2Cl2 (106 mg, 0.15 mmol) was added. The mixture was heated to 75°C and stirred for 3 h. After completion, 10 mL of H2O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 5:1) to afford 52-3 (200 mg, 52% yield). MS m / z: 272.00 [M+H] + .

[0609] Step 2: Synthesis of compound 52-4

[0610] The same protocol as in Example T22 was used to prepare 52-3. MS m / z: 258 [M+H] + .

[0611] Step 3: Synthesis of compound 52-5

[0612] The same protocol as in Example T26 was used to prepare 52-4. MS m / z: 222 [M+H] + .

[0613] Step 4: Synthesis of compound 52-6

[0614] The same protocol as in Example T16 was used to prepare 52-5. MS m / z: 303.10 [M+H] + .

[0615] Step 5: Synthesis of compound 52-7

[0616] The same protocol as in Example T16 was used to prepare 52-6. MS m / z: 203.20 [M+H] + .

[0617] Step 6: Synthesis of compound 52-8

[0618] The same protocol as in Example T16 was used to prepare 52-7. MS m / z: 541.15 [M+H] + .

[0619] Step 7 and Step 8: Synthesis of Compound 52-9

[0620] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 52-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 393 [M+H] + .

[0621] Step 9: Synthesis of compound T52

[0622] The same protocol as in Example T01 was used to prepare 52-9. MS m / z: 476 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.71 (d, J = 7.8Hz, 1H), 8.67-8.58 (m, 1H), 8.48 (s, 1H), 8.04 (d, J = 7.3Hz, 1H), 7.79-7.75 (m, 2H), 7.59-5.53 (m, 2H), 5.99 (s, 1H), 3.98 (dd, J=16.9, 8.3Hz, 1H), 2.91 (d, J=4.8Hz, 3H ), 2.86 (s, 3H), 2.63-2.59 (m, 1H), 1.79-1.58 (m, 2H), 0.34-0.30 (m, 1H).

[0623] Example T53

[0624] Step 1: Synthesis of compound 53-3

[0625] The same protocol as in Example T42 was used to prepare 53-1. MS m / z: 309, 311 [M+H] + .

[0626] Step 2: Synthesis of compound 53-4

[0627] 53-3 (200 mg, 0.65 mmol) was dissolved in DMF (3 mL). Potassium carbonate (90 mg, 0.65 mmol) was added under nitrogen protection. The atmosphere was replaced with nitrogen three times, and Pd(OAc)2 (23 mg, 0.1 mmol) was added. The mixture was heated to 75°C and stirred for 3 h. After completion of the reaction, 10 mL of H2O was added to quench the reaction. The mixture was extracted with DCM (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative plate chromatography (PE / EtOAc = 2:1) to afford 53-4 (34 mg, 23% yield). MS m / z: 229.15 [M+H] + .

[0628] Step 3: Synthesis of compound 53-5

[0629] The same protocol as in Example T47 was used to prepare 53-4. MS m / z: 199.40 [M+H] + .

[0630] Step 4: Synthesis of compound 53-6

[0631] The same protocol as in Example T16 was used to prepare 53-5. MS m / z: 537 [M+H] + .

[0632] Step 5 and Step 6: Synthesis of Compound 53-7

[0633] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 53-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0634] Step 7: Synthesis of compound T53

[0635] The same protocol as in Example T01 was used to prepare 53-7. MS m / z: 472 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 8.08-8.04 (m, 2H), 7.77-7.73 (m, 2H), 7.55-7.51 (m, 2H), 5.94 (s, 1H), 3. 93 (dd, J=16.9, 8.3Hz, 1H), 2.89 (d, J=4.8Hz, 3H), 2.78 (s, 3H), 2.59 (s, 3H), 2.53-2.50 (m, 1H), 1.83-1.55 (m, 2H), 0.26 (p, J=9.9Hz, 1H).

[0636] Example T54

[0637] Step 1: Synthesis of compound 54-3

[0638] The same protocol as in Example T52 was used to prepare 54-1. MS m / z: 252.05 [M+H] + .

[0639] Step 2: Synthesis of compound 54-4

[0640] The same protocol as in Example T22 was used to prepare 54-3. MS m / z: 238.00 [M+H] + .

[0641] Step 3: Synthesis of compound 54-5

[0642] The same protocol as in Example T26 was used to prepare 54-4. MS m / z: 218.00 [M+H] + .

[0643] Step 4: Synthesis of compound 54-6

[0644] The same protocol as in Example T16 was used to prepare 54-5. MS m / z: 299.30 [M+H] + .

[0645] Step 5: Synthesis of compound 54-7

[0646] The same protocol as in Example T16 was used to prepare 54-6. MS m / z: 199.15 [M+H] + .

[0647] Step 6: Synthesis of compound 54-8

[0648] The same protocol as in Example T16 was used to prepare 54-7. MS m / z: 537.40 [M+H]+ .

[0649] Step 7 and Step 8: Synthesis of Compound 54-9

[0650] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 54-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 389 [M+H] + .

[0651] Step 9: Synthesis of compound T54

[0652] The same protocol as in Example T01 was used to prepare 54-9. MS m / z: 472 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.64 (d, J = 7.8Hz, 1H), 8.49 (s, 1H), 8.28 (s, 1 H), 7.99 (d, J=7.8Hz, 1H), 7.78 (s, 1H), 7.68 (d, J=7.8Hz, 1H), 7.56-7.52 (m, 1H), 7. 50-7.46 (m, 1H), 5.98 (s, 1H), 3.96 (dd, J=16.9, 8.3Hz, 1H), 2.91 (d, J=4.8Hz, 3H), 2.83(s, 3H), 2.58-2.54(m, 1H), 2.45(s, 3H), 1.72-1.59(m, 2H), 0.38-0.22(m, 1H).

[0653] Example T55

[0654] Step 1: Synthesis of compound 55-3

[0655] The same protocol as in Example T50 was used to prepare 55-1. MS m / z: 393 [M+H] + .

[0656] Step 2: Synthesis of compound 55-4

[0657] The same protocol as in Example T50 was used to prepare 55-3. MS m / z: 391 [M+H] + .

[0658] Step 3: Synthesis of compound 55-5

[0659] The same protocol as in Example T50 was used to prepare 55-4. MS m / z: 491 [M+H] + .

[0660] Step 4: Synthesis of compound 55-6

[0661] The same protocol as in Example T50 was used to prepare 55-5. MS m / z: 411.10 [M+H] + .

[0662] Step 5: Synthesis of compound 55-7

[0663] The same protocol as in Example T16 was used to prepare 55-6. MS m / z: 211.15 [M+H] + .

[0664] Step 6: Synthesis of compound 55-8

[0665] The same protocol as in Example T16 was used to prepare 55-7. MS m / z: 549.15 [M+H] + .

[0666] Step 7 and Step 8: Synthesis of Compound 55-9

[0667] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 55-8 with LiOH and HCl / EtOAc, respectively. MS m / z: 401 [M+H] + .

[0668] Step 9: Synthesis of compound T55

[0669] The same protocol as in Example T01 was used to prepare 55-9. MS m / z: 484 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 8.72 (d, J = 7.8Hz, 1H), 8.26 (s, 1H), 7.92 (d , J=7.8Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 7.69-7.56 (m, 2H), 7.42 (d, J=4.4Hz, 1H), 7.21(d, J=7.4Hz, 1H), 6.07(s, 1H), 4.18-4.14(m, 1H), 3.50-3.34(m, 1H), 3.04( s, 3H), 2.89 (d, J=4.8Hz, 3H), 2.54 (s, 3H), 1.92-1.88 (m, 2H), 1.12-1.08 (m, 1H).

[0670] Example T56

[0671] Step 1: Synthesis of compound INT05

[0672] INT03 (200 mg, 0.53 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (2 mL). Lithium hydroxide (51 mg, 2.14 mmol) was added in H2O (2 mL), and the mixture was stirred at room temperature. TLC monitored the reaction completion. The reaction solution was concentrated to remove methanol and tetrahydrofuran. The remaining phase was adjusted to pH 4-5 with 1N hydrochloric acid solution. The aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo on a rotary evaporator to obtain INT05 (the crude product was directly used in the next step). MS m / z: 347.20 [M+H] + .

[0673] Step 2: Synthesis of compound INT06

[0674] INT05 (200 mg, 0.58 mmol) and 1-hydroxybenzotriazole (220 mg, 1.16 mmol) were dissolved in DMF (10 mL). Ten minutes later, N,N-diisopropylethylamine (112 mg, 1.73 mmol) was added. Half an hour later, a DMF solution of (1R,2R)-2-methoxycyclobutylamine hydrochloride (40 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature. The reaction was monitored for completion by TLC. The reaction solution was concentrated, and the crude product was purified by preparative TLC to obtain INT06 (196 mg, 79%). MS m / z: 430.25 [M+H] + .

[0675] Step 3: Synthesis of compound 56-3

[0676] The same protocol as in Example T42 was used to prepare 56-2. MS m / z: 320 [M+H] + .

[0677] Step 4: Synthesis of compound 56-4

[0678] The same protocol as in Example T38 was used to prepare 56-3. MS m / z: 240.15 [M+H] + .

[0679] Step 5: Synthesis of compound 56-5

[0680] The same protocol as in Example T47 was used to prepare 56-4. MS m / z: 210.25 [M+H] + .

[0681] Step 6: Synthesis of compound 56-6

[0682] 56-5 (40 mg, 0.19 mmol) was dissolved in dioxane (3 mL), and cesium carbonate (66 mg, 0.2 mmol) and Brettphos (12 mg, 0.02 mmol) were added. INT06 (90 mg, 0.2 mmol) were added, and the atmosphere was purged with nitrogen three times. Brettphos G3 Pd (10 mg, 0.01 mmol) was added, and the mixture was heated to 75°C and stirred for 3 h. After completion of the reaction, 10 mL of H2O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure, and the crude product was purified by preparative TLC (D / M = 20:1) to give 56-6 (55 mg, 48% yield). MS m / z: 603.25 [M+H] + .

[0683] Step 7: Synthesis of compound T56

[0684] 56-6 (16 mg, 0.027 mmol) was dissolved in 2M HCl / EtOAc (4 mL) and the mixture was incubated at room temperature for 4.3 h. After the reaction was complete, 10 mL of EtOAc*3 was added to the reaction mixture under reduced pressure and dried three times. The crude product was purified by preparative TLC (D / M = 17:1) to afford T56 (5.8 mg, 45% yield). MS m / z: 483 [M+H] + .1H NMR (400 / MHz, DMSO-d6) δ9.43 (s, 1H), 9.30 (d, J = 4.4Hz, 1H), 8.97 (d, J = 4.4Hz, 1 H), 8.65 (d, J=7.8Hz, 1H), 8.06 (d, J=8.6Hz, 1H), 7.87 (d, J=8.6Hz, 1H), 7.80 (s, 1H), 7.61-7.57 (m, 2H), 6.02 (s, 1H), 4.00 (dd, J=16.9, 8.3Hz, 1H), 2.91 (d, J=4. 8Hz, 3H), 2.88 (s, 3H), 2.70-2.66 (m, 1H), 1.75-1.71 (m, 2H), 0.51-0.33 (m, 1H).

[0685] Example T57

[0686] Step 1: Synthesis of compound 57-3

[0687] The same protocol as in Example T42 was used to prepare 57-1. MS m / z: 314.90 [M+H] + .

[0688] Step 2: Synthesis of compound 57-4

[0689] The same protocol as in Example T53 was used to prepare 57-3. MS m / z: 233.05 [M+H] + .

[0690] Step 3: Synthesis of compound 57-5

[0691] The same protocol as in Example T47 was used to prepare 57-4. MS m / z: 203 [M+H] + .

[0692] Step 4: Synthesis of compound 57-6

[0693] The same protocol as in Example T16 was used to prepare 57-5. MS m / z: 541.25 [M+H] + .

[0694] Step 5 and Step 6: Synthesis of Compound 57-7

[0695] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 57-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 393 [M+H] + .

[0696] Step 7: Synthesis of compound T57

[0697] The same protocol as in Example T01 was used to prepare 57-7. MS m / z: 476 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 8.71 (s, 1H), 8.60-8.56 (m, 1H), 8.13-8.10 (m, 2H), 8.08 (s, 1H), 7.80-7.77 (m, 1H), 7.77 (s, 1H), 7.58 -7.53 (m, 1H), 5.95 (s, 1H), 3.97-3.85 (m, 1H), 2.87 (s, 3H), 2.79 (d, J=4.8Hz, 3H), 2.55-2.51 (m, 1H), 1.60-1.56 (m, 2H), 0.26-0.20 (m, 1H).

[0698] Example T58

[0699] Step 1: Synthesis of compound 58-2

[0700] 58-1 (200 mg, 0.97 mmol) was dissolved in concentrated sulfuric acid (2 mL) and water (1 mL). NaNO2 (217 mg, 3.18 mmol) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, 10 mL of aqueous ammonia was added to the reaction solution to quench the reaction. The mixture was washed with water (10 mL × 3) and filtered under reduced pressure. The filter cake was retained as the crude product and purified by preparative TLC (PE / EtOAc = 1:1) to obtain 58-2 (190 mg, yield 96%). MS m / z: 208 [M+H] + .

[0701] Step 2: Synthesis of compound 58-3

[0702] 58-2 (190 mg, 0.91 mmol) was dissolved in DMF (3 mL), and cesium carbonate (163 mg, 0.5 mmol) was added. The mixture was cooled to 0°C, and iodomethane (71 mg, 0.5 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 0.5 h. After the reaction was completed, 10 mL of H2O was added to the reaction solution to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 1:1) to give 58-3 (160 mg, 80% yield). MS m / z: 222 [M+H] + .

[0703] Step 3: Synthesis of compound 58-5

[0704] 58-3 (200 mg, 0.7 mmol) was dissolved in ACN (4 mL) and water (1 mL). Sodium carbonate (190 mg, 1.8 mmol) and 58-4 (267 mg, 1.43 mmol) were added. The atmosphere was purged with nitrogen three times, and Pd(dtbpf)Cl2 (66 mg, 0.1 mmol) was added. The mixture was heated to 75°C and stirred for 3 h. After completion, 10 mL of H2O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 1:1) to afford 58-5 (100 mg, 40% yield). MS m / z: 285.95 [M+H] + .

[0705] Step 4: Synthesis of compound 58-6

[0706] The same protocol as in Example T22 was used to prepare 58-5. MS m / z: 270 [M+H] + .

[0707] Step 5: Synthesis of compound 58-7

[0708] The same protocol as in Example T26 was used to prepare 58-6. MS m / z: 234 [M+H] + .

[0709] Step 6: Synthesis of compound 58-8

[0710] The same protocol as in Example T16 was used to prepare 58-7. MS m / z: 315.10 [M+H] + .

[0711] Step 7: Synthesis of Compound 58-9

[0712] The same protocol as in Example T16 was used to prepare 58-8. MS m / z: 215 [M+H] + .

[0713] Step 8: Synthesis of compound 58-10

[0714] The same protocol as in Example T56 was used to prepare 58-9. MS m / z: 608.15 [M+H] + .

[0715] Step 9: Synthesis of compound T58

[0716] The same protocol as in Example T56 was used to prepare 58-10. MS m / z: 488 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.78 (s, 1H), 8.71 (d, J=7.8Hz, 1H), 7.7 7 (s, 1H), 7.67 (d, J = 7.8Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.34 (d, J = 7.8Hz, 1 H), 6.40 (s, 1H), 5.90 (s, 1H), 4.06-4.00 (m, 1H), 3.54 (s, 3H), 2.91 (d, J=4.8H z, 3H), 2.87 (s, 3H), 1.79-1.75 (m, 2H), 1.31-1.27 (m, 1H), 0.68-0.46 (m, 1H).

[0717] Example T59

[0718] Step 1: Synthesis of compound 59-3

[0719] The same protocol as in Example T42 was used to prepare 59-1. MS m / z: 328.90, 330.90 [M+H] + .

[0720] Step 2: Synthesis of compound 59-4

[0721] The same protocol as in Example T53 was used to prepare 59-3. MS m / z: 249.35 [M+H] + .

[0722] Step 3: Synthesis of compound 59-5

[0723] The same protocol as in Example T47 was used to prepare 59-4. MS m / z: 219 [M+H] + .

[0724] Step 4: Synthesis of compound 59-6

[0725] The same protocol as in Example T16 was used to prepare 59-5. MS m / z: 557.10 [M+H] + .

[0726] Step 5 and Step 6: Synthesis of Compound 59-7

[0727] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 59-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 409 [M+H] + .

[0728] Step 7: Synthesis of compound T59

[0729] The same protocol as in Example T01 was used to prepare 59-7. MS m / z: 492 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.14 (s, 1H), 8.69 (s, 1H), 8.32 (d, J=7.8Hz, 1H), 8. 24 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 7.8Hz, 1H), 7.59 (d, J = 7.8Hz, 1H), 7.55 ( s, 1H), 7.35-7.31 (m, 1H), 5.73 (s, 1H), 3.72-3.66 (m, 1H), 2.68 (d, J=4.8Hz , 3H), 2.60 (s, 3H), 2.27-2.23 (m, 1H), 1.46-1.42 (m, 2H), 0.03-0.00 (m, 1H).

[0730] Example T60

[0731] Step 1: Synthesis of compound 60-3

[0732] The same protocol as in Example T42 was used to prepare 60-1. MS m / z: 321.90 [M+H] + .

[0733] Step 2: Synthesis of compound 60-4

[0734] The same protocol as in Example T53 was used to prepare 60-3. MS m / z: 240.05 [M+H] + .

[0735] Step 3: Synthesis of compound 60-5

[0736] The same protocol as in Example T47 was used to prepare 60-4. MS m / z: 210.15 [M+H] + .

[0737] Step 4: Synthesis of compound 60-6

[0738] The same protocol as in Example T56 was used to prepare 60-5. MS m / z: 603.30 [M+H] + .

[0739] Step 5: Synthesis of compound T60

[0740] The same protocol as in Example T56 was used to prepare 60-6. MS m / z: 483 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.24 (s, 1H), 9.04 (s, 1H), 8.52 (d, J = 7.8Hz, 1H), 8.13 (d, J = 7.8Hz, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.75 (s, 1H), 7.60-7.56(m, 2H), 5.94(s, 1H), 3.96-3.90(m, 1H), 2.87(s, 3H), 2.80(d , J=4.8Hz, 3H), 2.55-2.51(m, 1H), 1.75-1.56(m, 2H), 0.28-0.24(m, 1H).

[0741] Example T61

[0742] Step 1: Synthesis of compound 61-3

[0743] Compound 61-1 (100 mg, 0.52 mmol) was dissolved in ACN (3 mL), and cesium carbonate (172 mg, 0.52 mmol) and 61-2 (142 mg, 1.5 mmol) were added. The mixture was heated to 75°C and stirred for 6 h. After completion, 10 mL of H2O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 3:1) to give 61-3 (90 mg, 55% yield). MS m / z: 313.10, 315.10 [M+H] + .

[0744] Step 2: Synthesis of compound 61-4

[0745] Compound 61-3 (90 mg, 0.3 mmol) was dissolved in DMF (3 mL). Cesium carbonate (147 mg, 0.45 mmol) was added under nitrogen protection. The atmosphere was replaced with nitrogen three times, and Pd(OAc)2 (23 mg, 0.1 mmol) was added. The mixture was heated to 75°C and stirred for 3 h. After completion, 10 mL of H2O was added to quench the reaction. The mixture was extracted with DCM (30 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 3:1) to obtain 61-4 (35 mg, 50% yield). MS m / z: 233.25 [M+H] + .

[0746] Step 3: Synthesis of compound 61-5

[0747] The same protocol as in Example T47 was used to prepare 61-4. MS m / z: 203.25 [M+H] + .

[0748] Step 4: Synthesis of compound 61-6

[0749] The same protocol as in Example T16 was used to prepare 61-5. MS m / z: 541.25 [M+H] + .

[0750] Step 5 and Step 6: Synthesis of Compound 61-7

[0751] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 61-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 393 [M+H] + .

[0752] Step 7: Synthesis of compound T61

[0753] The same protocol as in Example T01 was used to prepare 61-7. MS m / z: 476 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.55 (d, J = 7.8Hz, 1H), 8.39 (t, J = 5.8Hz, 1H), 7.97 (d, J = 7.8Hz, 1H), 7.78-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.36-7.32(m, 1H), 5.95(s, 1H), 3.98-3.90(m, 1H), 3.19-3.15(m, 1H), 2 .90 (d, J=4.8Hz, 3H), 2.82 (s, 3H), 1.65-1.61 (m, 2H), 0.23-0.21 (m, 1H).

[0754] Example T62

[0755] Step 1: Synthesis of compound 62-3

[0756] The same protocol as in Example T38 was used to prepare 62-1. MS m / z: 298.15 [M+H] + .

[0757] Step 2: Synthesis of compound 62-4

[0758] The same protocol as in Example T38 was used to prepare 62-3. MS m / z: 218.25 [M+H] + .

[0759] Step 3: Synthesis of compound 62-5

[0760] The same protocol as in Example T47 was used to prepare 62-4. MS m / z: 188.30 [M+H] + .

[0761] Step 4: Synthesis of compound 62-6

[0762] The same protocol as in Example T16 was used to prepare 62-5. MS m / z: 526.30 [M+H] + .

[0763] Step 5 and Step 6: Synthesis of Compound 62-7

[0764] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 62-6 with LiOH and HCl / EtOAc, respectively. MS m / z: 378 [M+H] + .

[0765] Step 7: Synthesis of compound T62

[0766] The same protocol as in Example T01 was used to prepare 62-7. MS m / z: 461 [M+H] + .

[0767] Example T63

[0768] Step 1: Synthesis of compound 63-2

[0769] The same protocol as in Example T16 was used to prepare compound 63-1 (ie, 59-4). MS m / z: 330.25 [M+H] + .

[0770] Step 2: Synthesis of compound 63-3

[0771] The same protocol as in Example T47 was used to prepare 63-2. MS m / z: 300.25 [M+H] + .

[0772] Step 3: Synthesis of compound 63-4

[0773] The same protocol as in Example T16 was used to prepare 63-3. MS m / z: 638.30 [M+H] + .

[0774] Step 4 and Step 5: Synthesis of Compound 63-5

[0775] The same protocol as in Example T01 was used to remove the ethyl ester and PMB using 63-4 with LiOH and HCl / EtOAc, respectively. MS m / z: 390 [M+H] + .

[0776] Step 6: Synthesis of compound T63

[0777] The same protocol as in Example T01 was used to prepare 63-5. MS m / z: 473 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ9.22 (s, 1H), 8.58 (d, J = 7.8Hz, 1H), 8.40 (s, 1H), 8. 30 (s, 2H), 7.98 (d, J=7.8Hz, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.4 0 (m, 1H), 7.18-7.12 (m, 1), 5.90 (s, 1H), 3.92-3.86 (m, 1H), 2.86 (d, J=4.8Hz , 3H), 2.82 (s, 3H), 2.60-2.50 (m, 1H), 1.96-1.90 (m, 2H), 0.30-0.25 (m, 1H).

[0778] Example T64

[0779] Step 1: Synthesis of compound 64-3

[0780] Methylaminoacetaldehyde dimethyl acetal 64-1 (500 mg, 4.2 mmol) and N-Cbz glycine 64-2 (878 mg, 4.2 mmol) were dissolved in DMF (10 mL). 1-Hydroxybenzotriazole (62.5 mg, 0.46 mmol), EDCI (652 mg, 4.2 mmol), and N,N-diisopropylethylamine (81.4 mg, 0.63 mmol) were added, and the mixture was stirred at room temperature. TLC monitored the reaction completion. Water (10 mL) was added to the mixture, and the aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford 64-3 (the crude product was used directly in the next step). MS m / z: 311.20 [M+H] + .

[0781] Step 2: Synthesis of compound 64-4

[0782] Dissolve 64-3 (crude product) in methanol, add 10% Pd / C, and stir the reaction mixture under a hydrogen atmosphere at room temperature for 2 hours. TLC indicates the reaction is complete. The reaction mixture is filtered under reduced pressure and concentrated to obtain 64-4 (the crude product is directly used in the next step). MS m / z: 177.30 [M+H] + .

[0783] Step 3: Synthesis of compound 64-6

[0784] 2-Chloro-6-iodo-benzoic acid 64-5 (500 mg, 1.77 mmol) and HATU (808 mg, 2.12 mmol) were added to DMF (5 mL) and stirred at room temperature for half an hour. N,N-diisopropylethylamine (458 mg, 3.54 mmol) and 64-4 (312, 1.94 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was complete, water was added to the mixture, and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative TLC to give 64-6 (673 mg, 86.4%). MS m / z: 440.90 [M+H] + .

[0785] Step 4: Synthesis of compound 64-7

[0786] 64-6 (311 mg, 0.71 mmol) and p-toluenesulfonic acid monohydrate (31 mg, 0.16 mmol) were added to toluene (10 mL). The reaction solution was stirred at 80°C for 3 hours. The reaction was complete after monitoring by TLC. The reaction solution was cooled to room temperature and concentrated to obtain a crude product, which was purified by preparative TLC to obtain 64-7 (266 mg, 82%). MS m / z: 376.90 [M+H] + .

[0787] Step 5: Synthesis of compound 64-8

[0788] 64-7 (170 mg, 0.45 mmol), cesium carbonate (368 mg, 1.13 mmol), tricyclohexyl tetrafluoroborate PCy3HBF4 (133 mg, 0.36 mmol), sodium iodide (13.6 mg, 0.09 mmol), and palladium acetate (40.6 mg, 0.18 mmol) were added to toluene (5 mL) under nitrogen. The mixture was stirred at 110°C overnight. The reaction was monitored for completion by TLC. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated and the crude product was purified by preparative TLC (PE / EtOAc = 2 / 1) to yield 64-8 (99 mg, 88%). MS m / z: 249.15 [M+H] + .

[0789] Step 6: Synthesis of compound 64-9

[0790] 64-8 (99 mg, 0.4 mmol), cesium carbonate (260 mg, 0.8 mmol), tert-butyl carbamate (93.5 mg, 0.8 mmol), XPhos (59 mg, 0.08 mmol), and palladium acetate (9 mg, 0.04 mmol) were added to dioxane (5 mL) under nitrogen. The reaction solution was stirred at 100°C overnight. TLC monitored the reaction completion. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The crude product was purified by preparative TLC (PE / EtOAc = 1 / 1) to obtain 64-9 (103 mg, 78.6%). MS m / z: 330.35 [M+H] + .

[0791] Step 7: Synthesis of compound 64-10

[0792] The same protocol as in Example T16 was used to prepare 64-9. MS m / z: 230.35 [M+H] + .

[0793] Step 8: Synthesis of compound 64-11

[0794] The same protocol as in Example T56 was used to prepare 64-10. MS m / z: 623.55 [M+H] + .

[0795] Step 9: Synthesis of compound T64

[0796] The same protocol as in Example T56 was used to prepare 64-11. MS m / z: 503 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.80 (d, J = 7.8Hz, 1H), 8.27 (s, 1H), 7.89 ( d, J=7.8Hz, 1H), 7.83 (s, 1H), 7.61-7.57 (m, 1H), 7.42 (d, J=7.8Hz, 1H), 7.17 (s , 1H), 5.96 (s, 1H), 4.43 (s, 2H), 4.26-4.20 (m, 1H), 3.16 (s, 3H), 3.10 (s, 3H), 2 .88(d, J=4.8Hz, 3H), 1.98-1.94(m, 2H), 1.46-1.42(m, 1H), 0.83-0.80(m, 1H).

[0797] Example T65

[0798] Step 1: Synthesis of compound 65-3

[0799] The same protocol as in Example T42 was used to prepare 65-1. HRMS m / z: 320.9599, 322.9576 [M+H] + .

[0800] Step 2: Synthesis of compound 65-4

[0801] The same protocol as in Example T38 was used to prepare 65-3. MS m / z: 241.25 [M+H] + .

[0802] Step 3: Synthesis of compound 65-5

[0803] The same protocol as in Example T47 was used to prepare 65-4. MS m / z: 211.25 [M+H] + .

[0804] Step 4: Synthesis of compound 65-6

[0805] The same protocol as in Example T56 was used to prepare 65-5. MS m / z: 604.50 [M+H] + .

[0806] Step 5: Synthesis of compound T65

[0807] The same protocol as in Example T56 was used to prepare 65-6. MS m / z: 484 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 9.54 (s, 1H), 8.58 (d, J=7.8Hz, 1H), 8.15 (t, J=6.5Hz, 2H), 7.81 (s, 1H), 7.72-7.68 (m, 1H), 7.64-7. 60 (m, 1H), 6.02 (s, 1H), 4.08-4.00 (m, 1H), 2.91 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.88-2.83 (m, 1H), 1.78-1.74 (m, 2H), 0.52-0.50 (m, 1H).

[0808] Example T66

[0809] Step 1: Synthesis of compound 66-3

[0810] The same protocol as in Example T42 was used to prepare 66-1. MS m / z: 421 [M+H] + .

[0811] Step 2: Synthesis of compound 66-4

[0812] 66-3 (230 mg, 0.55 mmol) was dissolved in DMF (3 mL). Zinc cyanide (89 mg, 0.76 mmol) was added under nitrogen protection. The atmosphere was replaced with nitrogen three times, and Pd(PPh3)4 (95 mg, 0.1 mmol) was added. The mixture was heated to 75°C and stirred for 3 h. After completion, 10 mL of H2O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EtOAc = 2:1) to give 66-4 (130 mg, 74% yield). MS m / z: 320.20 [M+H] + .

[0813] Step 3: Synthesis of compound 66-5

[0814] The same protocol as in Example T53 was used to prepare 66-4. MS m / z: 240.05 [M+H] + .

[0815] Step 4: Synthesis of compound 66-6

[0816] The same protocol as in Example T47 was used to prepare 66-5. MS m / z: 210.15 [M+H] + .

[0817] Step 5: Synthesis of compound 66-7

[0818] The same protocol as in Example T56 was used to prepare 66-6. MS m / z: 603.55 [M+H] + .

[0819] Step 6: Synthesis of compound T66

[0820] The same protocol as in Example T56 was used to prepare 66-7. MS m / z: 483 [M+H] + .

[0821] Example T67

[0822] Step 1: Synthesis of compound 67-3

[0823] The same protocol as in Example T50 was used to prepare 67-1. MS m / z: 318.15 [M+H] + .

[0824] Step 2: Synthesis of compound 67-4

[0825] The same protocol as in Example T50 was used to prepare 67-3. MS m / z: 316 [M+H] + .

[0826] Step 3: Synthesis of compound 67-5

[0827] 67-4 (150 mg, 0.47 mmol) was dissolved in toluene (3 mL) in a reaction flask. Cesium carbonate (232 mg, 0.71 mmol), pivalic acid (14 mg, 0.14 mmol), and tricyclohexylphosphine (14 mg, 0.05 mmol) were added at room temperature. The atmosphere was purged with nitrogen three times. Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) was added and the atmosphere was purged with nitrogen three times. The mixture was heated to 80°C and stirred for 3 h. After complete consumption of the starting material as monitored by TLC, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. All organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered through celite, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative plate chromatography (PE / EtOAc = 1:1) to afford 67-5 (57 mg, 52% yield). MS m / z: 236.30 [M+H] + .

[0828] Step 4: Synthesis of compound 67-6

[0829] The same protocol as in Example T16 was used to prepare 67-5. MS m / z: 317 [M+H] + .

[0830] Step 5: Synthesis of compound 67-7

[0831] The same protocol as in Example T16 was used to prepare 67-6. MS m / z: 217.30 [M+H] + .

[0832] Step 6: Synthesis of compound 67-8

[0833] The same protocol as in Example T56 was used to prepare 67-7. MS m / z: 612 [M+H] + .

[0834] Step 7: Synthesis of compound T67

[0835] The same protocol as in Example T56 was used to prepare 67-8. MS m / z: 492 [M+H] + .

[0836] Example T68

[0837] Step 1: Synthesis of compound 68-3

[0838] The same protocol as in Example T52 was used to prepare 68-1. MS m / z: 334.15 [M+H] + .

[0839] Step 2: Synthesis of compound 68-4

[0840] The same protocol as in Example T22 was used to prepare 68-2. MS m / z: 318 [M+H] + .

[0841] Step 3: Synthesis of compound 68-5

[0842] The same protocol as in Example T26 was used to prepare 68-3. MS m / z: 282 [M+H] + .

[0843] Step 4: Synthesis of compound 68-6

[0844] Add dry, anhydrous THF to a Schlenk tube, cool to 0°C, add isopropylmagnesium chloride (0.07 mL, 0.14 mmol), stir for 2 minutes, and then add n-butyllithium (0.14 mL, 0.2 mmol). After stirring for 15 minutes, add 68-5 (75 mg, 0.27 mmol). The reaction system is allowed to warm to room temperature and stir for 1 hour. The reaction is quenched by adding heavy water (0.5 mL) and stirred for 15 minutes. Saturated aqueous ammonium chloride is then added to the reaction system, and the mixture is extracted with EtOAc (30 mL x 3). All organic phases are combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The resulting organic phase is filtered under reduced pressure and concentrated in vacuo. The crude product is purified by preparative plate chromatography (PE / EtOAc = 3:1) to afford 68-6 (45 mg, 81% yield). MS m / z: 205.30 [M+H] + .

[0845] Step 5: Synthesis of compound 68-7

[0846] The same protocol as in Example T16 was used to prepare 68-6. MS m / z: 286.35 [M+H] + .

[0847] Step 6: Synthesis of compound 68-8

[0848] The same protocol as in Example T16 was used to prepare 68-7. MS m / z: 186.35 [M+H] + .

[0849] Step 7: Synthesis of compound 68-9

[0850] The same protocol as in Example T56 was used to prepare 68-8. MS m / z: 579 [M+H] + .

[0851] Step 8: Synthesis of compound T68

[0852] The same protocol as in Example T56 was used to prepare 68-9. MS m / z: 459 [M+H] + .

[0853] Biological Example 1: Determination of the cell proliferation inhibitory activity of the compound using CTG (CELLTITER-GLO) luminescence method

[0854] Test principle: Using Promega's CellTiter-Glo TM Luciferase kit, this method uses luciferase as a detector. Luciferase requires ATP to participate in the luminescence process. ATP can be generated by the respiration and other life activities of metabolically active cells. Add an equal volume of CellTiter-Glo to the cell culture medium. TM Reagent, measures luminescence value, the light signal is proportional to the amount of ATP in the system, ATP is positively correlated with the number of living cells, and therefore is used to detect the inhibition of cell proliferation activity.

[0855] Experimental method: Complete medium (RPMI 1640 + 10% FBS + 1% P / S) was prepared to resuscitate Ba / F3-FL-TYK2-E957D cells (Hefei Puruisheng). After about two passages, cells in the logarithmic growth phase were collected by centrifugation and counted. The cells were resuspended to an appropriate concentration and the cell suspension was inoculated into a 96-well plate. 95 μL of cell suspension was added to each well of the plate. The plate density was 2000 cells / well. The test compound was prepared into a stock solution with DMSO and diluted stepwise 3-fold with DMSO with 1 mM as the highest concentration to obtain 10 concentration gradients. The test compound was diluted 50-fold with culture medium, and 5 μL was added to each 96-well cell plate containing 95 μL of cells. Culture medium without cells (containing 0.1% DMSO) was added to the Min control well, and 5 μL was added to the Max control well. Incubate the cells in a DMSO-cell culture medium mixture (final DMSO concentration 0.1%) at 37°C in a 5% CO2 incubator with a relative humidity of ≥90% for 72 h. Add 50 μL / well of CellTiter Glo to terminate the reaction, incubate at room temperature in the dark for 30 min, and gently shake before measuring on an Envision microscope. Read the fluorescence (RLU) of each well, and calculate the cell inhibition rate using the formula: % cell growth inhibition rate = (1-As / Ac) × 100. Where As is: RLU sample (cells + CTG + test compound) - RLU min (cell-free culture medium), and Ac is: RLU normal growth cell control (cells + CTG + DMSO) - RLU min (cell-free culture medium). Enter the inhibition rate (Inh% Y) corresponding to each concentration (X) in Excel, and calculate the half-maximal inhibitory concentration (IC50) of each compound using the built-in four-parameter fitting formula Y = Bottom + (Top - Bottom) / (1 + (IC50 / X) * Hill Slope) using Graphpad Prism 8 software.

[0856] Data for representative molecules of the invention tested using the assay described in Biological Example 1 are presented in Table 3 below.

[0857] Table 3 Cell proliferation inhibition test data

[0858] Biological Example 2 TYK2 JH2 in vitro enzyme binding assay

[0859] This experiment uses fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of compounds on the TYK2 JH2 pseudokinase. In this assay, the TYK2 JH2 pseudokinase binds simultaneously to the fluorescently labeled Tracer and the Tb antibody. The Tb antibody acts as a fluorescence donor, generating 495nm fluorescence under excitation light of a certain wavelength. Tracer, acting as a fluorescence acceptor, can only receive the 495nm fluorescence when in close proximity to the Tb antibody, generating 520nm fluorescence, representing the fluorescence resonance energy transfer signal. When a compound is added to compete with Tracer for binding to the JH2 region of the pseudokinase, the TR-FRET signal decreases due to reduced Tracer binding. The 520nm / 495nm signal ratio can be used to reflect the inhibitory activity of the compound against the pseudokinase.

[0860] B2.1 Experimental procedures are as follows:

[0861] B2.1.1 was dissolved in DMSO to a stock concentration of 10 mM.

[0862] B2.1.2 Prepare a dilution plate with a concentration gradient of 200 times the final concentration and transfer it to a 384-well plate.

[0863] B2.1.3 Use the Echo instrument to transfer 75 nL from the 384-well plate to the 384-well experimental plate. The positive control group and the negative control group are replaced with the same volume of DMSO.

[0864] B2.1.4 Add 5uL of TYK2 JH2 pseudokinase (3 times the final concentration (0.5nM)) to each well of a 384-well assay plate. Replace the negative control group with the same volume of 1X assay working solution. Centrifuge at 1000rpm for 30 seconds.

[0865] B2.1.5 Add 5 μL of Tb antibody at 3 times the final concentration (1x is the final concentration) to each well of a 384-well assay plate and centrifuge at 1000 rpm for 30 seconds.

[0866] B2.1.6 Add 5 μL of Tracer at 3 times the final concentration (1 nM) to each well of a 384-well assay plate and centrifuge at 1000 rpm for 30 seconds.

[0867] B2.1.7 Incubate at room temperature for 60 minutes and then at 4°C overnight.

[0868] B2.1.8 The 520 nm / 495 nm fluorescence signal ratio was read using Envision microplate reader (PerkinElmer).

[0869] B2.2 Data Analysis

[0870] Data processing and analysis were performed using XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment. First, the mean reaction signals for the positive and negative control groups were calculated. The inhibition rate for each well was then calculated using the formula: "Single-well inhibition rate % = ((positive control mean - single-well signal value) / (positive control mean - negative control mean)) × 100." The concentration and response data were then imported into XLfit, and the Dose Response One Site 205 model was used. A four-parameter inhibition model was employed to fit the inhibition rate-concentration curve and calculate the compound's IC50 value.

[0871] The data for representative molecules of the present invention tested using the test method described in Biological Example 2 are listed in Table 4 below. In Table 4, "A" represents IC 50 Value is less than 10 nM; "B" indicates IC 50 Value greater than or equal to 10 nM and less than 100 nM; "C" indicates IC 50 The value is greater than or equal to 100 nM and less than 1000 nM.

[0872] Table 4 TYK2 JH2 enzymatic test data

[0873] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, Indicates a single bond or a double bond; X 1 C or N; X 2 C or N; R 1 is H, C1-C6 alkyl, or C1-C6 alkyl substituted by one or more deuteriums; R 2 C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 2-1 Substituted C1-C6 alkyl, one or more R 2-2 Substituted C1-C6 alkoxy, one or more R 2-3 Substituted C3-C 12 Cycloalkyl or one or more R 2-4 substituted 3-12 membered heterocycloalkyl; R 2-1 and R 2-2 Each independently represents halogen, OH, C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl; Or, two adjacent R 2-1 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C4-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl; Alternatively, two R 2-1 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C5-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl; Or, two adjacent R 2-2 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C4-C 12 spirocyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl; Alternatively, two R 2-2 Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Cycloalkyl, C5-C 12 Bridged ring cycloalkyl, C4-C 12 spirocyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered cyclic heterocycloalkyl, 5-12 membered bridged heterocycloalkyl or 5-12 membered spirocyclic heterocycloalkyl; R 2-3 and R 2-4 Each is independently halogen, OH, C1-C6 alkyl or C1-C6 alkoxy; Or, two adjacent R 2-3 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group; Alternatively, two R 2-3 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group; Or, two adjacent R 2-4 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group; Alternatively, two R 2-5 Together with the carbon atoms to which they are attached, they form a C3-C7 cycloalkyl group or a 3-7 membered heterocycloalkyl group; Ring A, Ring B and Ring C are each independently a benzene ring, a 5-6 membered heteroaromatic ring, a C5-C6 cycloalkene or a 5-6 membered heterocycloalkene; Ring A and Ring B share a bond, which is a single bond or a double bond; Ring B and Ring C share a bond, which is a single bond or a double bond; R 3 is a substituent on Ring A, Ring B or Ring C; R 3 are independently halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-1 Substituted C1-C6 alkyl or one or more R 3-2 Substituted C1-C6 alkoxy; R 3-1 and R 3-2 are each independently halogen; n is 0, 1, 2, or 3; The "3-12 membered heterocycloalkyl" and " 2-4 In the "substituted 3-12 membered heterocycloalkyl", "5-6 membered heterocycloalkene", "3-8 membered heterocycloalkyl", "3-7 membered monocyclic heterocycloalkyl", "5-12 membered cyclic heterocycloalkyl", "5-12 membered bridged heterocycloalkyl", "5-12 membered spirocyclic heterocycloalkyl" and "3-7 membered heterocycloalkyl", the type of heteroatom or heteroatom group is independently selected from one or more of N, O, S, C(=O), S(=O)2, and the number of heteroatoms or heteroatom groups is independently one or more; In the "5-6 membered heteroaromatic ring", the types of heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently one or more.

2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) The "3-12 membered heterocycloalkyl" and "substituted by one or more R 2-4 In the "substituted 3-12 membered heterocycloalkyl", "5-6 membered heterocycloalkene", "3-8 membered heterocycloalkyl", "3-7 membered monocyclic heterocycloalkyl", "5-12 membered cyclic heterocycloalkyl", "5-12 membered bridged heterocycloalkyl", "5-12 membered spirocyclic heterocycloalkyl" and "3-7 membered heterocycloalkyl", the types of heteroatoms or heteroatomic groups are each independently selected from one, two or three of N, O, S, C(=O), S(=O)2, and the number of heteroatoms or heteroatomic groups is each independently one, two or three; (2) In the "5- to 6-membered heteroaromatic ring", the types of heteroatoms are each independently selected from one, two or three of N, O and S, and the number of heteroatoms is each independently one, two or three.

3. The compound of formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein: It meets one or more of the following conditions: (1) Each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)CH2CH3, -CH2CH2CH(CH3)2, -CH(C2H5)CH2CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, or -CH2C(CH3)3, for example, methyl, isopropyl, isobutyl, or -CH2C(CH3)3; (2) each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy; (3) Each "C3-C 12 "Cycloalkyl" are each independently C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl or spiro[2.3]hexyl, further such as (4) Each "3-12 membered heterocycloalkyl" is independently a 3-6 membered heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms, such as azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl or piperidinyl, and further such as (5) Each "halogen" is independently F, Cl, Br or I, for example, F; (6) Each "5- to 6-membered heteroaromatic ring" is a 5- to 6-membered heteroaromatic ring having one or more heteroatoms selected from N, O, and S, and having one or two heteroatoms, such as a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrazine ring, a pyridazine ring, or a pyrimidine ring; (7) Each "5-6 membered heterocyclic olefin" is For example 4. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) for in, X 3-1 is CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 3-2 、X 3-3 、X 3-4 、X 3-5 、X 3-6 、X 3-7 、X 3-8 and X 3- 9 are each independently CH or N; X 4-1 、X 4-2 、X 4-3 、X 4-4 、X 4-5 、X 4-6 、X 4-7 、X 4-8 、X 4-9 and X 4-10 are each independently CH or N; X 5-1 、X 5-2 、X 5-3 、X 5-4 、X 5-5 、X 5-6 、X 5-7 、X 5-8 、X 5-9 and X 5-10 are each independently CH or N; X 6-1 、X 6-7 and X 6-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 6-2 、X 6-3 、X 6-4 、X 6- 5 、X 6-6 and X 6-9 are each independently CH or N; X 7-1 and X 7-5 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 7-2 、X 7-3 、X 7-4 、X 7-6 、X 7- 7 、X 7-8 、X 7-9 and X7 -10 are each independently CH or N; X 8-1 、X 8-5 and X 8-7 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 8-2 、X 8-3 、X 8-4 、X 8- 6 、X 8-8 and X 8-9 are each independently CH or N; X 9-1 and X 9-3 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 9-2 、X 9-4 、X 9-5 、X 9-6 、X 9- 7 、X 9-8 、X 9-9 and X9 -10 are each independently CH or N; X 10-1 、X 10-2 、X 10-3 、X 10-4 、X 10-5 、X 10-6 、X 10-7 、X 10-8 、X 10-9 and X 10-10 are each independently CH or N; X 11-1 and X 11-7 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 11-2 、X 11-3 、X 11-4 、X 11- 5 、x 11-8 and X 11-9 are each independently CH or N; X 12-1 and X 12-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 12-2 、X 12-3 、X 12-4 、X 12- 5 、X 12-7 and X 12-9 are each independently CH or N; X 13-1 、X 13-5 and X 13-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 13-2 、X 13-3 、X 13- 4 、X 13-6 、X 13-7 and X 13-9 are each independently CH or N; X 14-1 、X 14-6 、X 14-7 and X 14-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 14-2 、X 14- 3 、X 14-4 and X 14-5 are each independently CH or N; X 15-1 、X 15-3 and X 15-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 15-2 、X 15-4 、X 15- 5 、X 15-6 、X 15-7 and X 15-9 are each independently CH or N; X 16-1 、X 16-2 and X 16-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 16-3 、X 16-4 、X 16- 5 、X 16-6 、X 16-7 and X 16-9 are each independently CH or N; (2)R 3 independently F, CN, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 alkyl substituted with one or more F; (3) n is 0, 1 or 2; (4)R 1 is a C1-C3 alkyl group; (5)R 2 is C1-C5 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 2-1 Substituted C1-C5 alkyl, one or more R 2-3 Substituted C3-C6 cycloalkyl, or one or more R 2-4 substituted 3-6 membered heterocycloalkyl; R 2-1 are independently OH or 3-6 membered heterocycloalkyl; R 2-3 are independently F, OH or OCH3; R 2-4 are independently OH or OCH3.

5. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) in, X 3-1 is CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 3-2 、X 3-3 、X 3-4 、X 3-6 、X 3-7 、X 3-8 and X 3-9 are each independently CH or N; X 4-1 、X 4-2 、X 4-3 、X 4-4 、X 4-5 、X 4-7 、X 4-8 、X 4-9 and X 4-10 are each independently CH or N; X 6-1 、X 6-7 and X 6-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 6-2 、X 6-3 、X 6-4 、X 6- 6 and X 6-9 are each independently CH or N; X 7-1 and X 7-5 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 7-2 、X 7-3 、X 7-6 、X 7-7 、X 7- 8 、X 7-9 and X 7-10 are each independently CH or N; X 8-1 、X 8-4 and X 8-7 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 8-2 、X 8-3 、X 8-6 、X 8- 8 and X 8-9 are each independently CH or N; X 9-1 and X 9-3 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 9-2 、X 9-4 、X 9-5 、X 9-6 、X 9- 7 、X 9-8 、X 9-9 and X 9-10 are each independently CH or N; X 10-1 、X 10-2 、X 10-3 、X 10-4 、X 10-5 、X 10-7 、X 10-8 、X 10-9 and X 10-10 are each independently CH or N; X 12-1 and X 12-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 12-2 、X 12-3 、X 12-4 、X 12- 7 and X 12-9 are each independently CH or N; X 14-1 、X 14-6 、X 14-7 and X 14-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 14-2 、X 14- 3 and X 14-4 are each independently CH or N; X 15-1 、X 15-3 and X 15-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 15-2 、X 15-4 、X 15- 5 、X 15-6 、X 15-7 and X 15-9 are each independently CH or N; X 16-1 、X 16-2 and X 16-8 are each independently CH2, NH, O, S, C(=O), S(=O) or S(=O)2, X 16-3 、X 16-4 、X 16- 5 、X 16-7 and X 16-9 are each independently CH or N; Preferably, Any of the following: Case 1: Case 2: (2)R 3 F, CN, CH3, CF3, OCH3 or (3)R 1 is methyl; (4)R 2 for 6. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: Any of the following: Case 1: Case 2:

7. The compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is a compound represented by formula (I-1), (I-2), (I-3) or (I-4): Among them, R 1 、R 2 、R 3 , n, Ring A, Ring B and Ring C are as defined in any one of claims 1-6.

8. The compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is any one of the following compounds:

9. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of the compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a TYK2 inhibitor, preferably, the TYK2 is TYK2-E957D.

11. Use of a compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a disease associated with TYK2; preferably, the disease associated with TYK2 is a disease associated with TYK2-E957D and / or TYK2 JH2; more preferably, the disease associated with TYK2 is an autoimmune disease, such as psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, or atopic dermatitis.

12. Use of a compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating an autoimmune disease, such as psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, or atopic dermatitis.