WO2025168035A1 - Heterocyclic compound, and pharmaceutical composition thereof and use thereof - Google Patents

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

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

The present invention relates to heterocyclic compounds, pharmaceutical compositions and applications thereof.

Background Art

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 signal transduction. TYK2 associates with the cytoplasmic domains of type I and II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines associated with 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 (STAT), which then enter the cell nucleus and participate in the production of specific proteins. This pathway involves 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.

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.

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

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, significantly inhibiting the proliferation of cells carrying the TYK2-E957D mutation.

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

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:

in,

represents a single bond or a double bond;

^X1 is C or N;

^X2 is C or N;

R ¹ is H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl substituted by one or more deuteriums;

R ² is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₁ -C ₆ alkyl substituted by one or more R ^2-1 , C ₁ -C ₆ alkoxy substituted by one or more R ^2-2 , C ₃ -C ₁₂ cycloalkyl substituted by one or more R ^2-3 , or 3-12 membered heterocycloalkyl substituted by one or more R ^2-4 ;

R ^2-1 and R ^2-2 are each independently halogen, OH, C ₃ -C ₁₂ cycloalkyl or 3-12 membered heterocycloalkyl;

Alternatively, two adjacent R ^{2-1 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloalkyl group, a C ₅ -C ₁₂ bridged cycloalkyl group, a C ₅ -C ₁₂ spirocycloalkyl group, a 3-7 membered monocyclic heterocycloalkyl group, a 5-12 membered cycloheterocycloalkyl group, a 5-12 membered bridged heterocycloalkyl group, or a 5-12 membered spiroheterocycloalkyl group;

Alternatively, two R ^2-1 on the same carbon atom together with the carbon atom to which they are attached form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloheterocycloalkyl, a C ₅ -C ₁₂ bridged cycloalkyl, a C ₅ -C ₁₂ spirocyclocycloalkyl, a 3-7 membered monocyclic heterocycloalkyl, a 5-12 membered cycloheterocycloalkyl, a 5-12 membered bridged heterocycloalkyl or a 5-12 membered spiro heterocycloalkyl;

Alternatively, two adjacent R ^{2-2 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloalkyl group, a C ₅ -C ₁₂ bridged cycloalkyl group, a C ₅ -C ₁₂ spirocycloalkyl group, a 3-7 membered monocyclic heterocycloalkyl group, a 5-12 membered cycloheterocycloalkyl group, a 5-12 membered bridged heterocycloalkyl group, or a 5-12 membered spiroheterocycloalkyl group;

Alternatively, two R ^2-2 on the same carbon atom together with the carbon atom to which they are attached form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloheterocycloalkyl, a C ₅ -C ₁₂ bridged cycloalkyl, a C ₅ -C ₁₂ spirocyclocycloalkyl, a 3-7 membered monocyclic heterocycloalkyl, a 5-12 membered cycloheterocycloalkyl, a 5-12 membered bridged heterocycloalkyl or a 5-12 membered spiro heterocycloalkyl;

R ^2-3 and R ^2-4 are each independently halogen, OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

Alternatively, two adjacent R ^{2-3 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ cycloalkyl group or a 3-7 membered heterocycloalkyl group;

Alternatively, two R ^2-3 on the same carbon atom and the carbon atom to which they are attached together form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl;

Alternatively, two adjacent R ^{2-4 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ cycloalkyl group or a 3-7 membered heterocycloalkyl group;

Alternatively, two R ^2-5 groups on the same carbon atom and the carbon atom to which they are attached together form a C ₃ -C ₇ 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 C ₅ -C ₆ 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 is independently halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₁ -C ₆ alkyl substituted by one or more R ^3-1 , or C ₁ -C ₆ alkoxy substituted by one or more R ^3-2 ;

R ^3-1 and R ^3-2 are each independently halogen;

n is 0, 1, 2, or 3;

In the “3-12 membered heterocycloalkyl”, “3-12 membered heterocycloalkyl substituted by one or more R ^2-4 ”, “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.

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").

In a certain embodiment of the present invention, in the “3-12 membered heterocycloalkyl”, “3-12 membered heterocycloalkyl substituted by one or more R ^2-4 ”, “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.

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.

In a certain embodiment of the invention, each “C ₁ -C ₆ alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -CH ₂ CH 2 CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -CH 2 CH(CH 3)CH ₂ CH _{3 ,} -CH 2 CH 2 CH(CH ₃ ) ₂ , -CH(C ₂ H ₅ )CH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , or -CH ₂ C(CH ₃ ) ₃ , for example, methyl, isopropyl, isobutyl or -CH ₂ C(CH ₃ ) ₃ .

In one embodiment of the present invention, each "C ₁ -C ₆ alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.

In one embodiment of the present invention, each "C ₃ -C ₁₂ cycloalkyl" is independently a C ₃ -C ₆ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.2]pentyl or spiro[2.3]hexyl, and further such as

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

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

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.

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

In one embodiment of the present invention, for

in,

X ^3-1 is CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , ^and 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;

^X4-1 , ^X4-2 , ^X4-3 , ^X4-4 , ^X4-5 , ^X4-6 , ^X4-7 , ^X4-8 , ^X4-9 and ^X4-10 are each independently CH or N;

^X5-1 , ^X5-2 , ^X5-3 , ^X5-4 , ^X5-5 , ^X5-6 , ^X5-7 , ^X5-8 , ^X5-9 and ^X5-10 are each independently CH or N;

X ^6-1 , X ^6-7 and X ^6-8 are each independently CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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;

^X8-1 , ^X8-5 and ^X8-7 are each independently _CH2 , NH, O, S, C(=O), S(=O) or S(=O) ₂ , and ^X8-2 , ^X8-3 , ^X8-4 , ^{X8-6 , X8-8 and X8-9} are each independently CH or N;

X ^9-1 and X ^9-3 are each independently CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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;

^X10-1 , ^X10-2 , ^X10-3 , ^X10-4 , ^X10-5 , ^X10-6 , ^X10-7 , ^X10-8 , ^X10-9 and ^X10-10 are each independently CH or N;

X ^11-1 and X ^11-7 are each independently CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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.

In one embodiment of the present invention, for

in,

X ^3-1 is CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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;

^X4-1 , ^X4-2 , ^X4-3 , ^X4-4 , ^X4-5 , ^X4-7 , ^X4-8 , ^X4-9 and ^X4-10 are each independently CH or N;

X ^6-1 , X ^6-7 and X ^6-8 are each independently CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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;

^X8-1 , ^X8-5 and ^X8-7 are each independently _CH2 , NH, O, S, C(=O), S(=O) or S(=O) ₂ , and ^X8-2 , ^X8-3 , ^{X8-6 , X8-8} and ^X8-9 are each independently CH or N;

X ^9-1 and X ^9-3 are each independently CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and X ^16-3 , X ^16-4 , X ^{16-5 , X 16-7 and} X ^16-9 are each independently CH or N.

In one embodiment of the present invention, Any of the following:

Case 1:

Case 2:

In one embodiment of the present invention, R ³ is independently F, CN, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl substituted with one or more F, such as F, CN, CH ₃ , CF ₃ , OCH ₃ or

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

In one embodiment of the present invention, Any of the following:

Case 1:

Case 2:

In one embodiment of the present invention, R ¹ is a C ₁ -C ₃ alkyl group, such as a methyl group.

In one embodiment of the present invention, R ² is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ^2-1 , C ₃ -C ₆ cycloalkyl substituted by one or more R ^2-3 , or 3-6 membered heterocycloalkyl substituted by one or more R ^2-4 ;

R ^2-1 is independently OH or a 3-6 membered heterocycloalkyl group;

R ^2-3 are independently F, OH or OCH ₃ ;

R ^2-4 are independently OH or OCH ₃ .

In one embodiment of the present invention, ^R2 is

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

R ¹ , R ² , R ³ , n, Ring A, Ring B and Ring C are as defined in any embodiment of the present invention.

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

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

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

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.

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.

The present invention also provides a compound as shown in formula (I) as described in 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 a disease associated with TYK2. Preferably, the disease associated with TYK2 is a disease associated with TYK2-E957D and/or TYK2 JH2.

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.

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.

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

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.

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.

When any variable (e.g., R ³ ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-3 R ^{3 s} , then the group may be optionally substituted with up to three R ^{3 s} , with each occurrence of R ³ being an independent choice. Furthermore, combinations of substituents and/or their variants are permissible only if such combinations result in stable compounds.

In the present invention, the "C ₁ -C ₆ alkyl" in each "C ₁ -C ₆ alkyl" refers not only to an independent C ₁ -C ₆ alkyl group, but also to a "C ₁ -C ₆ alkyl" in a substituted C ₁ -C ₆ 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".

The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group having the specified number of carbon atoms. For example, _C1 - _C6 alkyl 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).

The term "alkoxy" refers to a group _-ORX , wherein _RX is an alkyl group as defined above.

The term "cycloalkyl" refers to a saturated monocyclic, fused, bridged or spirocyclic group having the specified number of ring carbon atoms (eg, C ₃ -C ₁₂ ), the ring atoms consisting solely of carbon atoms.

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), and 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.

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

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.

The term "cycloalkene" refers to a cyclic, partially unsaturated ring having the specified number of carbon atoms (eg, _C5 - _C6 ), having one or more (eg, 1 or 2) carbon-carbon ^sp2 double bonds, which is not aromatic.

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), which has one or more (e.g., 1 or 2) carbon-carbon ^sp2 double bonds and is not aromatic.

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.

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 pharmaceutical preparations. For a complete list, see the Pharmacopoeia of the People's Republic of China (2020 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

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.

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.

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.

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.

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

The positive progressive effect of the present invention is 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

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.

Example T01

Step 1: Synthesis of Compounds 1-3

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] ⁺ .

Step 2: Synthesis of Compounds 1-4

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 slowly quenched by 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] ^⁺ .

Step 3: Synthesis of compound INT01

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) afforded the product INT01 (1.2 g, 83% yield). MS m/z: 375 [M+H] ^⁺ .

Step 4: Synthesis of Compounds 1-7

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 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 separate the product 1-7 (1 g, 60% yield). MS m/z: 522 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ )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).

Step 5: Synthesis of Compound 1-8

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 completion of the reaction, 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 the filter cake, transfer it to a single-necked flask with ethyl acetate, dry it, and concentrate it to obtain product 1-8 (542 mg, 94% yield), which was used directly in the next reaction. MS m/z: 494 [M+H] ⁺ .

Step 6: Synthesis of compound INT02

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 system was concentrated under reduced pressure to obtain crude product INT02 (411 mg, 100% yield), which was used directly in the next reaction. MS m/z: 374 [M+H] ⁺ .

Step 7: Synthesis of compound T01

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 then spin-dried to obtain the crude product. Preparative TLC (petroleum ether:ethyl acetate = 2:1) was used to separate 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).

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.

Table 1 Identification data of Examples T02-T14

Example T16

Step 1: Synthesis of compound 16-2

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] ⁺ .

Step 2: Synthesis of compound 16-3

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 the crude product, which was then purified by preparative TLC (PE:EtOAc = 10:1) to afford 16-3 (50 mg, 46% yield). MS m/z: 204 [M+H] ⁺ .

Step 3: Synthesis of compound 16-4

To a 25 mL Schlenk flask, 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) were added. 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 the crude product, which was purified by preparative TLC (PE:EtOAc = 6:1) to afford 16-4 (67 mg). MS m/z: 285 [M+H] ⁺ .

Step 4: Synthesis of compound 16-5

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] ⁺ .

Step 5: Synthesis of compound 16-6

To a 50 mL single-necked reaction vial 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 vial. 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 obtain 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] ⁺ .

Step 6 and Step 7: Synthesis of Compound 16-7

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] ⁺ .

Step 8: Synthesis of compound T16

The same protocol as in Example T01 was used to prepare 16-7. MS m/z: 432 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.47 (d, J=5.4 Hz, 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).

Example T17

Step 1: Synthesis of compound INT03

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

Step 2: Synthesis of compound 17-4

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

Step 3 and Step 4: Synthesis of Compound INT04

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] ⁺ .

Step 5: Synthesis of compound T17

The same protocol as in Example T01 was used to prepare INT04. MS m/z: 431 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.92 (dd, J = 7.7, 1.2 Hz, 1H), 7.85 (s, 1H), 7.70 (t, J = 7.4 Hz, 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).

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.

Table 2 Identification data of Examples T18-T19

Example T20

Step 1: Synthesis of compound 20-2

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] ⁺ .

Step 2 and Step 3: Synthesis of Compound 20-3

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] ⁺ .

Step 4: Synthesis of compound T20

The same protocol as in Example T01 was used to prepare 20-3. MS m/z: 432 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 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).

Example T21

Step 1: Synthesis of compound 21-2

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

Step 2 and Step 3: Synthesis of Compound 21-3

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] ⁺ .

Step 4: Synthesis of compound T21

The same protocol as in Example T01 was used to prepare 21-3. MS m/z: 473 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.52 (d, J = 9.4 Hz, 1H), 8.45 (s, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 6.2 Hz, 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).

Example T22

Step 1: Synthesis of compound 22-2

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 then purged with _nitrogen five times. Cesium carbonate (2.3 g, 7.04 mmol) and Pd(dppf) _Cl₂ (285.3 mg, 0.352 mmol) were then added under nitrogen. The mixture was purged with nitrogen 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 yield 22-2 (855 mg, 70% yield). MS m/z: 344 [M+H] ^⁺ .

Step 2: Synthesis of compound 22-3

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] ^⁺ .

Step 3: Synthesis of compound 22-4

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

Step 4: Synthesis of compound 22-5

Prepared using 22-4 using the same protocol as in Example T16. MS m/z: 285 [M+H] ⁺ .

Step 5: Synthesis of compound 22-6

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

Step 6: Synthesis of compound 22-7

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

Step 7 and Step 8: Synthesis of Compound 22-8

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] ⁺ .

Step 9: Synthesis of compound T22

The same protocol as in Example T01 was used to prepare 22-8. MS m/z: 458 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ9.33 (s, 1H), 8.68 (dd, J=4.8, 1.3 Hz, 1H), 8.58 (d, J=9.0 Hz, 1H), 8.23-8.16 (m, 2H), 8.06 (d, J=7.6 Hz, 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).

Example T23

Step 1: Synthesis of compound 23-3

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

Step 2: Synthesis of compound 23-4

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

Step 3: Synthesis of compound 23-5

Prepared similarly to the corresponding step of Example T16 using 23-4 in NMP at 110°C. MS m/z: 222 [M+H] ⁺ .

Step 4: Synthesis of compound 23-6

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

Step 5: Synthesis of compound 23-7

Prepared using the same protocol as in Example T16 using 23-6. MS m/z: 203 [M+H] ⁺ .

Step 6: Synthesis of compound 23-8

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

Step 7 and Step 8: Synthesis of Compound 23-9

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] ⁺ .

Step 9: Synthesis of compound T23

The same protocol as in Example T01 was used to prepare 23-9. MS m/z: 476 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ9.36 (s, 1H), 8.74 (dd, J=2.5, 1.3 Hz, 1H), 8.58 (d, J=9.0 Hz, 1H), 8.35 (dd, J=9.2, 2.5 Hz, 1H), 8.30-8.20 (bs, 1H), 8.03 (dd, J=7.8, 1.2 Hz, 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).

Example T24

Step 1: Synthesis of compound 24-3

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. Under nitrogen protection, palladium acetate (126.0 mg, 0.56 mmol) was added to the reaction flask. 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] ⁺ .

Step 2: Synthesis of compound 24-4

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

Step 3: Synthesis of compound 24-5

Prepared similarly to the corresponding step of Example T16 using 24-4 in DMF at 100°C. MS m/z: 205 [M+H] ⁺ .

Step 4: Synthesis of compound 24-6

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

Step 5: Synthesis of compound 24-7

Prepared using the same protocol as in Example T16 using 24-6. MS m/z: 186 [M+H] ⁺ .

Step 6: Synthesis of compound 24-8

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

Step 7 and Step 8: Synthesis of Compound 24-9

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] ⁺ .

Step 9: Synthesis of compound T24

The same protocol as in Example T01 was used to prepare 24-9. MS m/z: 459 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.81 (d, J = 2.8 Hz, 1H), 8.65 (d, J = 9.1 Hz, 1H), 8.56 (d, J = 2.7 Hz, 1H), 8.45-8.25 (bs, 1H), 8.08 (dd, J = 7.8, 1.2 Hz, 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).

Example T25

Step 1: Synthesis of compound 25-3

25-1 (500 mg, 1.91 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and K ₃ PO ₄ (815 mg, 3.82 mmol) and 25-2 (357 mg, 1.91 mmol) were added. The nitrogen atmosphere was purged three times, and then Pd(dppf)Cl ₂ (140 mg, 0.19 mmol) was added. The nitrogen atmosphere was purged 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 isolated and purified by preparative TLC (petroleum ether:ethyl acetate = 10:1) to obtain 25-3 (384 mg, 62% yield). MS m/z: 322 [M+H] ⁺ .

Step 2: Synthesis of compound 25-4

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

Step 3: Synthesis of compound 25-5

Prepared using 25-4 using the same protocol as in Example T24. MS m/z: 272 [M+H] ⁺ .

Step 4: Synthesis of compound 25-6

Prepared using 25-5, the same protocol as in Example T16. MS m/z: 353 [M+H] ⁺ .

Step 5: Synthesis of compound 25-7

Prepared using the same protocol as in Example T16 using 25-6. MS m/z: 253 [M+H] ⁺ .

Step 6: Synthesis of compound 25-8

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

Step 7 and Step 8: Synthesis of Compound 25-9

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] ⁺ .

Step 9: Synthesis of compound T25

The same protocol as in Example T01 was used to prepare 25-9. MS m/z: 526 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.09 (dd, J = 2.0, 0.9 Hz, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.328.20 (bs, 1H), 8.23 (s, 1H), 7.84 (dd, J = 7.8, 1.2 Hz, 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).

Example T26

Step 1: Synthesis of compound 26-2

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

Step 2: Synthesis of compound 26-3

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

Step 3: Synthesis of compound 26-4

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 85°C oil bath 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] ⁺ .

Step 4: Synthesis of compound 26-5

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

Step 5: Synthesis of compound 26-6

Prepared using 26-5, using the same protocol as in Example T16. MS m/z: 199 [M+H] ⁺ .

Step 6: Synthesis of compound 26-7

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

Step 7 and Step 8: Synthesis of Compound 26-8

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] ⁺ .

Step 9: Synthesis of compound T26

The same protocol as in Example T01 was used to prepare 26-8. MS m/z: 472 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.63-8.53 (m, 2H), 8.27-8.10 (bs, 1H), 8.05-7.97 (m, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J=7.7 Hz, 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).

Example T27

Step 1: Synthesis of compound 27-3

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

Step 2: Synthesis of compound 27-4

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

Step 3: Synthesis of compound 27-5

Prepared using the same procedure as in Example T24 using 27-4. MS m/z: 233 [M+H] ⁺ .

Step 4: Synthesis of compound 27-6

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

Step 5: Synthesis of compound 27-7

Prepared using 27-6 using the same protocol as in Example T16. MS m/z: 214 [M+H] ⁺ .

Step 6: Synthesis of compound 27-8

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

Step 7 and Step 8: Synthesis of Compound 27-9

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] ⁺ .

Step 9: Synthesis of compound T27

The same protocol as in Example T01 was used for the preparation of 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).

Example T28

Step 1: Synthesis of compound 28-2

Dissolve 1 (1.0 g, 10.41 mmol) in DMAP (100 mL), then add thionyl chloride (4 mL). 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] ⁺ .

Step 2: Synthesis of compound 28-3

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

Step 3: Synthesis of compound 28-4

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

Step 4: Synthesis of compound 28-5

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

Step 5: Synthesis of compound 28-6

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

Step 6: Synthesis of compound 28-7

Prepared using 28-6, the same protocol as in Example T16. MS m/z: 186 [M+H] ⁺ .

Step 7: Synthesis of compound 28-8

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

Steps 8 and 9: Synthesis of Compounds 28-9

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] ⁺ .

Step 10: Synthesis of compound T28

The same protocol as in Example T01 was used to prepare 28-9. MS m/z: 459 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.37 (d, J = 6.0 Hz, 1H), 8.78-8.70 (bs, 1H), 8.57 (d, J = 8.9 Hz, 1H), 8.26 (dd, J = 7.8, 1.2 Hz, 1H), 8.13 (d, J = 5.9 Hz, 1H), 7.92 (dd, J = 7.9, 1.2 Hz, 1H). 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).

Example T29

Step 1: Synthesis of compound 29-2

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] ⁺ .

Step 2: Synthesis of compound 29-3

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] ^⁺ .

Step 3: Synthesis of compound 29-4

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] ⁺ .

Step 4: Synthesis of compound 29-5

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

Step 5 and Step 6: Synthesis of Compound 29-6

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] ⁺ .

Step 7: Synthesis of compound T29

The corresponding step scheme is the same as that of Example T01, and 29-6 is used for preparation. 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).

Example T30

Step 1: Synthesis of compound 30-3

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

Step 2: Synthesis of compound 30-4

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

Step 3: Synthesis of compound 30-5

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

Step 4: Synthesis of compound 30-6

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

Step 5: Synthesis of compound 30-7

Prepared using 30-6, the same protocol as in Example T16. MS m/z: 213 [M+H] ⁺ .

Step 6: Synthesis of compound 30-8

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

Step 7 and Step 8: Synthesis of Compound 30-9

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] ⁺ .

Step 9: Synthesis of compound T30

The same protocol as in Example T01 was used to prepare 30-9. MS m/z: 486 [M+H] ⁺ . ¹ H N-MR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.58 (d, J = 9.1 Hz, 1H), 8.25 (bs, 1H), 7.97 (dd, J = 7.7, 1.1 Hz, 2H), 7.66 (d, J = 7.7 Hz, 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).

Example T31

Step 1: Synthesis of compound 31-3

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

Step 2: Synthesis of compound 31-4

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

Step 3: Synthesis of compound 31-5

Prepared using 31-4 using the same protocol as in Example T26. MS m/z: 219 [M+H] ⁺ .

Step 4: Synthesis of compound 31-6

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

Step 5: Synthesis of compound 31-7

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

Step 6: Synthesis of compound 31-8

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

Step 7 and Step 8: Synthesis of Compounds 31-9

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] ⁺ .

Step 9: Synthesis of compound T31

The same protocol as in Example T01 was used to prepare 31-9. MS m/z: 473 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.21 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.25 (bs, 1H), 8.09 (dd, J = 7.9, 1.2 Hz, 1H), 7.94 (dd, J = 7.8, 1.2 Hz, 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).

Example T32

Step 1: Synthesis of compound 32-2

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

Step 2: Synthesis of compound 32-3

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

Step 3: Synthesis of compound 32-4

Prepared using 32-3, the same protocol as in Example T26. MS m/z: 218 [M+H] ⁺ .

Step 4: Synthesis of compound 32-5

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

Step 5: Synthesis of compound 32-6

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

Step 6: Synthesis of compound 32-7

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

Step 7 and Step 8: Synthesis of Compound 32-8

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] ⁺ .

Step 9: Synthesis of compound T32

The same protocol as in Example T01 was used to prepare 32-8. MS m/z: 472 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 7.9 Hz, 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).

Example T33

Step 1: Synthesis of compound 33-2

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

Step 2: Synthesis of compound 33-3

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

Step 3: Synthesis of compound 33-4

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

Step 4: Synthesis of compound 33-5

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

Step 5: Synthesis of compound 33-6

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

Step 6: Synthesis of compound 33-7

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

Step 7 and Step 8: Synthesis of Compound 33-8

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] ⁺ .

Step 9: Synthesis of compound T33

The same protocol as in Example T01 was used to prepare 33-8. MS m/z: 472 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.25 (bs, 1H), 8.10-7.98 (m, 2H), 7.79 (s, 1H), 7.72 (dd, J = 7.7, 1.2 Hz, 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).

Example T35

Step 1: Synthesis of compound 35-2

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

Step 2: Synthesis of compound 35-3

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

Step 3: Synthesis of compound 35-4

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

Step 4: Synthesis of compound 35-5

Prepared using 35-4 using the same protocol as in Example T16. MS m/z: 353 [M+H] ⁺ .

Step 5: Synthesis of compound 35-6

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

Step 6: Synthesis of compound 35-7

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

Step 7 and Step 8: Synthesis of Compound 35-8

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] ⁺ .

Step 9: Synthesis of compound T35

The same protocol as in Example T01 was used to prepare 35-8. MS m/z: 526 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.31 (dd, J = 20.2, 8.8 Hz, 2H), 8.01 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 7.7 Hz, 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).

Example T36

Step 1: Synthesis of compound 36-2

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 then 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] ^⁺ .

Step 2: Synthesis of compound 36-3

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

Step 3: Synthesis of compound 36-4

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

Step 4: Synthesis of compound 36-5

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

Step 5: Synthesis of compound 36-6

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

Step 6: Synthesis of compound 36-7

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

Step 7 and Step 8: Synthesis of Compound 36-8

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] ⁺ .

Step 9: Synthesis of compound T36

The same protocol as in Example T01 was used to prepare 36-8. MS m/z: 499 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.92 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.37 (dd, J = 10.0, 6.1 Hz, 2H), 5.75 (s, 1H), 3.74 (q, J = 8.6 Hz , 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).

Example T37

Step 1: Synthesis of compound 37-2

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) _Cl₂ (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] ^⁺ .

Step 2: Synthesis of compound 37-3

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

Step 3: Synthesis of compound 37-4

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

Step 4: Synthesis of compound 37-5

Prepared using 37-4 using the same protocol as in Example T16. MS m/z: 299 [M+H] ⁺ .

Step 5: Synthesis of compound 37-6

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

Step 6: Synthesis of compound 37-7

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

Step 7 and Step 8: Synthesis of Compound 37-8

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] ⁺ .

Step 9: Synthesis of compound T37

The same protocol as in Example T01 was used to prepare 37-8. MS m/z: 472 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.73-8.56 (m, 1H), 8.34 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.9 Hz, 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).

Example T38

Step 1: Synthesis of compound 38-2

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 confirms the reaction is complete. The reaction mixture is cooled to 0°C and the pH is adjusted to 7-8 with concentrated hydrochloric acid. Extraction is performed with a 10:1 dichloromethane:methanol mixture, and the organic phase is concentrated under reduced pressure to yield 38-2 (382.3 mg, 81.1% yield). MS m/z: 99 [M+H] ⁺ .

Step 2: Synthesis of compound 38-3

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] ⁺ .

Step 3: Synthesis of compound 38-4

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 atmosphere was purged _with nitrogen three times. Palladium acetate (4.9 mg, 0.022 mmol) was then added under nitrogen, and the mixture was purged with nitrogen six times. Stir in an oil bath at 135°C for 3 h. LCMS confirmed the reaction was complete. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in DCM. The crude product was purified by silica gel column chromatography (dichloromethane) to yield 38-4 (51.0 mg, 70% yield). MS m/z: 218 [M+H] ⁺ .

Step 4: Synthesis of compound 38-5

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] ⁺ .

Step 5: Synthesis of compound 38-6

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

Step 6 and Step 7: Synthesis of Compound 38-7

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] ⁺ .

Step 8: Synthesis of compound T38

The same protocol as in Example T01 was used to prepare compound 38-7. MS m/z: 461 [M+H] ⁺ . ¹ H 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).

Example T39

Step 1: Synthesis of compound 39-3

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 afford 39-3 (21.5 mg, 13.6% yield). MS m/z: 205 [M+H] ⁺ .

Step 2: Synthesis of compound 39-4

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

Step 3: Synthesis of compound 39-5

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

Step 4: Synthesis of compound 39-6

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

Step 5 and Step 6: Synthesis of Compound 39-7

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] ⁺ .

Step 7: Synthesis of compound T39

The same protocol as in Example T01 was used to prepare 39-7. MS m/z: 459 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.49 (d, J = 8.0 Hz, 1H), 9.15 (s, 1H), 8.81 (d, J = 8.9 Hz, 1H), 8.68 (d, J = 6.7 Hz, 1H), 8.32 (s, 2H), 8.21 (d, J = 7.4 Hz, 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).

Example T40

Step 1: Synthesis of compound 40-2

40-1 (200 mg, 1.07 mmol) was dissolved in toluene, and 3-bromo-4-iodopyridine (364 mg, 1.28 mmol), Cs ₂ CO ₃ (1.05 g, 3.21 mmol), and 1,10-phenanthroline (77 mg, 0.43 mmol) were added. The atmosphere was purged with nitrogen three times. CuI (68 mg, 0.21 mmol) was then added, and the atmosphere was purged with nitrogen 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] ⁺ .

Step 2: Synthesis of compound 40-3

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

Step 3: Synthesis of compound 40-4

Prepared using the same protocol as in Example T16 using 40-3. MS m/z: 199 [M+H] ⁺ .

Step 4: Synthesis of compound 40-5

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

Step 5 and Step 6: Synthesis of Compound 40-6

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] ⁺ .

Step 7: Synthesis of compound T40

The same protocol as in Example T01 was used to prepare 40-6. MS m/z: 472 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ9.62 (s, 1H), 9.29 (bs, 1H), 9.28 (s, 1H), 8.94 (s, 1H), 8.67 (d, J=4.4 Hz, 1H), 8.49 (dd, J=22.2, 8.7 Hz, 2H), 8.18 (d, J=8.6 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=5.1 Hz, 1H), 7.52 (d, J=8.6 Hz, 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).

Example T41

Step 1: Synthesis of compound 41-2

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. The reaction was quenched by the addition of 2 mL of methanol, and the reaction solution was concentrated under reduced pressure to afford compound 41-2 (440 mg, 95% yield). MS m/z: 173 [M+H] ⁺ .

Step 2: Synthesis of compound 41-4

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 x 3), washed with 2N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 41-4 (1.3 g, 31% yield). MS m/z: 163 [M+H] ⁺ .

Step 3: Synthesis of compound 41-5

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] ⁺ .

Step 4: Synthesis of compound 41-6

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

Step 5: Synthesis of compound 41-7

Prepared using the same protocol as in Example T16 using 41-6. MS m/z: 316 [M+H] ⁺ .

Step 6: Synthesis of compound 41-8

Prepared using the same protocol as in Example T16 using 41-7. MS m/z: 216 [M+H] ⁺ .

Step 7: Synthesis of compound 41-9

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

Steps 8 and 9: Synthesis of compounds 41-10

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] ⁺ .

Step 10: Synthesis of compound T41

The same protocol as in Example T01 was used to prepare 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).

Example T42

Step 1: Synthesis of compound 42-3

42-1 (460 mg, 4.21 mmol) was dissolved in acetonitrile (5 mL), and K ₃ CO ₃ (582 mg, 8.42 mmol) and 42-2 (1000 mg, 4.21 mmol) were added. The atmosphere was purged with nitrogen 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] ⁺ .

Step 2: Synthesis of compound 42-4

Prepared using the same protocol as in Example T38 using 42-3. MS m/z: 230 [M+H] ⁺ .

Step 3: Synthesis of compound 42-5

Prepared using the same protocol as in Example T38 using 42-4. MS m/z: 200 [M+H] ⁺ .

Step 4: Synthesis of compound 42-6

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

Step 5 and Step 6: Synthesis of Compound 42-7

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] ⁺ .

Step 7: Synthesis of compound T42

The same protocol as in Example T01 was used to prepare 42-7. MS m/z: 473 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.28 (s, 1H), 8.94 (s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.49 (dd, J = 22.2, 8.7 Hz, 2H), 8.18 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 8.6 Hz, 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).

Example T43

Step 1: Synthesis of compound 43-2

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] ⁺ .

Step 2: Synthesis of compound 43-3

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 purged with nitrogen three times, and the mixture was stirred in an oil bath at 75°C overnight. The reaction mixture was concentrated and the crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to afford 43-3 (0.16 g, 30% yield). MS m/z: 329 [M+H] ⁺ .

Step 3: Synthesis of compound 43-4

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 in chloroform (5 mL), diisopropylethylamine (0.2 mL) was added, nitrogen was replaced three times and the mixture was 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 and reacted for half an hour. After the reaction solution was concentrated, 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] ⁺ .

Step 4: Synthesis of compound 43-5

Prepared using the same protocol as in Example T16 using 43-4. MS m/z: 199 [M+H] ⁺ .

Step 5: Synthesis of compound 43-6

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

Step 6: Synthesis of compound 43-7

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

Step 7: Synthesis of compound T43

(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 solution of AlMe ₃ in toluene was added. The reaction system was stirred at room temperature for 1 h. 43-7 (20 mg, 0.048 mmol) was added to the above reaction solution and reacted at room temperature for 3 h. 2 mL of water was added dropwise to quench the reaction, and then extracted 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] ⁺ . ¹ HNMR (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).

Example T44

Step 1: Synthesis of compound 44-2

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

Step 2: Synthesis of compound 44-3

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

Step 3: Synthesis of compound 44-4

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

Step 4: Synthesis of compound 44-5

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 mixture was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by silica gel column chromatography to afford 44-5 (70 mg, 20% yield). HRMS m/z: 201.0657 [M+H] ⁺ .

Step 5: Synthesis of compound 44-6

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

Step 6: Synthesis of compound 44-7

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

Step 7: Synthesis of compound T44

The same protocol as in Example T43 was used to prepare 44-7. MS m/z: 474 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 9.2 Hz, 1H), 8.55 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 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).

Example T45

Step 1: Synthesis of compound 45-2

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

Step 2: Synthesis of compound 45-3

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

Step 3: Synthesis of compound 45-4

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

Step 4: Synthesis of compound 45-5

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

Step 5: Synthesis of compound 45-6

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

Step 6 and Step 7: Synthesis of Compound 45-7

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

Step 8: Synthesis of compound T45

The same protocol as in Example T01 was used to prepare compound 45-7. MS m/z: 475 [M+H] ⁺ . ¹ H 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).

Example T46

Step 1: Synthesis of compound T46

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 afford T46 (7 mg, 72% yield). HRMS m/z: 475.1811 [M+H] ⁺ .

Example T47

Step 1: Synthesis of compound 47-2

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

Step 2: Synthesis of compound 47-3

47-2 (200 mg, 0.615 mmol) was dissolved in HBr (33 wt% in AcOH) and allowed to stand at 50°C overnight. The reaction was quenched with water, the pH adjusted to 7 with sodium bicarbonate, and the aqueous phase 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] ⁺ .

Step 3: Synthesis of compound 47-4

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 a 1 atm hydrogen atmosphere 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] ⁺ .

Step 4: Synthesis of compound 47-5

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

Step 5: Synthesis of compound 47-6

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

Step 6 and Step 7: Synthesis of Compound 47-7

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] ⁺ .

Step 8: Synthesis of compound T47

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

Example T48

Step 1: Synthesis of compound T48

T21 (5 mg, 10.6 μmol) was suspended in dichloromethane (1 mL). mCPBA (5.5 mg, 31.7 μmol) was added at room temperature, and 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] ⁺ .

Example T49

Step 1: Synthesis of compound 49-2

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

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] ⁺ .

Step 4: Synthesis of compound T49

The same protocol as in Example T01 was used to prepare 49-3. MS m/z: 469 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 59.33 (s, 1H), 8.75 (d, J=7.8 Hz, 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=7.8 Hz, 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).

Example T50

Step 1: Synthesis of compound 50-3

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. The mixture was stirred for 0.5 h. At this temperature, 50-2 (350 mg, 2.25 mmol) was added, and the mixture was allowed to warm to room temperature. After completion, saturated aqueous ammonium chloride was added to quench the reaction. After slowly warming to room temperature, the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were 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] ⁺ .

Step 2: Synthesis of compound 50-4

50-3 (450 mg, 1.18 mmol) was dissolved in DCM (3 mL) and cooled to 0°C under nitrogen. Dess-Martin periodinane (1 g, 2.3 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 0.5 h. After completion, the reaction was quenched by addition of saturated aqueous sodium sulfite. The mixture was extracted with EtOAc (30 mL x 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 afford 50-4 (380 mg, 86% yield). MS m/z: 379.00 [M+H] ⁺ .

Step 3: Synthesis of compound 50-5

Compound 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, 10 mL of _H₂O was added to quench the reaction. The mixture was extracted with DCM (30 mL x 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 = 3:1) to afford compound 50-5 (300 mg, 79% yield). MS m/z: 479.05 [M+H] ^⁺ .

Step 4: Synthesis of compound 50-6

Compound 50-5 (200 mg, 0.43 mmol) was dissolved in DMF (3 mL). Potassium acetate (68 mg, 0.68 mmol) was added under nitrogen, and the atmosphere was replaced with nitrogen three times. Palladium acetate (15 mg, 0.06 mmol) was added, and the mixture was heated to 85°C and stirred for 3 h. After completion, the reaction was quenched by the addition of 20 mL of _H₂O . The mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were 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 compound 50-6 (90 mg, 54% yield). MS m/z: 397.15 [M+H] ^⁺ .

Step 5: Synthesis of compound 50-7

Prepared using 50-6, the same protocol as in Example T16. MS m/z: 197.15 [M+H] ⁺ .

Step 6: Synthesis of compound 50-8

Prepared using 50-7, the same protocol as in Example T16. MS m/z: 535.10 [M+H] ⁺ .

Step 7 and Step 8: Synthesis of Compound 50-9

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] ⁺ .

Step 9: Synthesis of compound T50

Prepared using 50-9 using the same protocol as in Example T01. MS m/z: 470 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (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=4.8 Hz, 3H), 2.64-2.60 (m, 1H), 1.88-1.84 (m, 2H), 0.77-0.74 (m, 1H).

Example T51

Step 1: Synthesis of compound 51-2

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 mixture 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 the reaction was complete, and the reaction mixture was filtered and concentrated under reduced pressure to yield 51-2 (the crude product was directly used in the next step). MS m/z: 263.20 [M+H] ⁺ .

Step 2: Synthesis of compound 51-3

51-2 (1.4 g, 5.3 mmol) was weighed into a 250 mL three-necked flask with toluene (60 mL) as the solvent. Trifluoromethanesulfonic acid (1.6 g, 10.7 mmol) was added under nitrogen. The reaction mixture was stirred at 90°C for 10 h. TLC indicated the reaction was complete. The reaction mixture 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] ⁺ .

Step 3: Synthesis of compound 51-4

Prepared using 51-4 using the same protocol as in Example T44. MS m/z: 215.25 [M+H] ⁺ .

Step 4: Synthesis of compound 51-5

51-4 (65 mg, 0.3 mmol), INT03 (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 yield 51-5 (18 mg, 11%). MS m/z: 553.20 [M+H] ⁺ .

Step 5 and Step 6: Synthesis of Compound 51-6

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] ⁺ .

Step 7: Synthesis of compound T51

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

Example T52

Step 1: Synthesis of compound 52-3

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 replaced 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 x 3). The combined organic phases were 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 = 5:1) to afford 52-3 (200 mg, 52% yield). MS m/z: 272.00 [M+H] ⁺ .

Step 2: Synthesis of compound 52-4

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

Step 3: Synthesis of compound 52-5

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

Step 4: Synthesis of compound 52-6

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

Step 5: Synthesis of compound 52-7

Prepared using 52-6, the same protocol as in Example T16. MS m/z: 203.20 [M+H] ⁺ .

Step 6: Synthesis of compound 52-8

Prepared using 52-7 using the same protocol as in Example T16. MS m/z: 541.15 [M+H] ⁺ .

Step 7 and Step 8: Synthesis of Compound 52-9

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] ⁺ .

Step 9: Synthesis of compound T52

The same protocol as in Example T01 was used to prepare 52-9. MS m/z: 476 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Example T53

Step 1: Synthesis of compound 53-3

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

Step 2: Synthesis of compound 53-4

53-3 (200 mg, 0.65 mmol) was dissolved in DMF (3 mL). Potassium carbonate (90 mg, 0.65 mmol) was added under nitrogen, and the atmosphere was replaced with nitrogen three times. Pd(OAc) _₂ (23 mg, 0.1 mmol) was added, and the mixture was heated to 75°C and stirred for 3 h. After completion, the reaction was quenched by the addition of 10 mL of _H₂O . The mixture was extracted with DCM (30 mL × 3). The combined organic phases were 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 plate chromatography (PE/EtOAc = 2:1) to afford 53-4 (34 mg, 23% yield). MS m/z: 229.15 [M+H] ^⁺ .

Step 3: Synthesis of compound 53-5

Prepared using 53-4 using the same protocol as in Example T47. MS m/z: 199.40 [M+H] ⁺ .

Step 4: Synthesis of compound 53-6

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

Step 5 and Step 6: Synthesis of Compound 53-7

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] ⁺ .

Step 7: Synthesis of compound T53

The same protocol as in Example T01 was used for the preparation using 53-7. MS m/z: 472[M+H] ⁺ . ¹ H NMR (600MHz, DMSO-d ₆ )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=1 6.9, 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).

Example T54

Step 1: Synthesis of compound 54-3

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

Step 2: Synthesis of compound 54-4

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

Step 3: Synthesis of compound 54-5

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

Step 4: Synthesis of compound 54-6

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

Step 5: Synthesis of compound 54-7

Prepared using 54-6 using the same protocol as in Example T16. MS m/z: 199.15 [M+H] ⁺ .

Step 6: Synthesis of compound 54-8

Prepared using 54-7 using the same protocol as in Example T16. MS m/z: 537.40 [M+H] ⁺ .

Step 7 and Step 8: Synthesis of Compound 54-9

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] ⁺ .

Step 9: Synthesis of compound T54

The same protocol as in Example T01 was used to prepare 54-9. MS m/z: 472 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.64 (d, J=7.8 Hz, 1H), 8.49 (s, 1H), 8.28 (s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J=7.8 Hz, 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).

Example T55

Step 1: Synthesis of compound 55-3

Prepared using 55-1, the same protocol as in Example T50. MS m/z: 393 [M+H] ⁺ .

Step 2: Synthesis of compound 55-4

Prepared using 55-3 using the same protocol as in Example T50. MS m/z: 391 [M+H] ⁺ .

Step 3: Synthesis of compound 55-5

Prepared using 55-4 using the same protocol as in Example T50. MS m/z: 491 [M+H] ⁺ .

Step 4: Synthesis of compound 55-6

Prepared using 55-5 using the same protocol as in Example T50. MS m/z: 411.10 [M+H] ⁺ .

Step 5: Synthesis of compound 55-7

Prepared using 55-6, the same protocol as in Example T16. MS m/z: 211.15 [M+H] ⁺ .

Step 6: Synthesis of compound 55-8

Prepared using 55-7 using the same protocol as in Example T16. MS m/z: 549.15 [M+H] ⁺ .

Step 7 and Step 8: Synthesis of Compound 55-9

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] ⁺ .

Step 9: Synthesis of compound T55

The same protocol as in Example T01 was used to prepare compound 55-9. MS m/z: 484 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Example T56

Step 1: Synthesis of compound INT05

INT03 (200 mg, 0.53 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (2 mL). Lithium hydroxide (51 mg, 2.14 mmol) in _H₂O (2 mL) was added, and the mixture was stirred at room temperature. TLC confirmed the reaction was complete. The reaction solution was concentrated to remove methanol and tetrahydrofuran. The remaining phase was adjusted to pH 4-5 with 1N hydrochloric acid. 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 yield INT05 (the crude product was used directly in the next step). MS m/z: 347.20 [M+H] ⁺ .

Step 2: Synthesis of compound INT06

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-methoxycyclobutanamine hydrochloride (40 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature. TLC monitored the reaction for completion. The reaction solution was concentrated, and the crude product was purified by preparative TLC to yield INT06 (196 mg, 79%). MS m/z: 430.25 [M+H] ⁺ .

Step 3: Synthesis of compound 56-3

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

Step 4: Synthesis of compound 56-4

Prepared using 56-3, the same protocol as in Example T38. MS m/z: 240.15 [M+H] ⁺ .

Step 5: Synthesis of compound 56-5

Prepared using 56-4 using the same protocol as in Example T47. MS m/z: 210.25 [M+H] ⁺ .

Step 6: Synthesis of compound 56-6

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. The atmosphere was purged with nitrogen three times, and Brettphos G3 Pd (10 mg, 0.01 mmol) was added. The mixture was heated to 75°C and stirred for 3 h. After completion, the reaction was quenched by the addition of 10 mL of _H2O . The mixture was extracted with EtOAc (30 mL x 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 (D/M = 20:1) to afford 56-6 (55 mg, 48% yield). MS m/z: 603.25 [M+H] ⁺ .

Step 7: Synthesis of compound T56

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 mixture was then dried. 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-d ₆ ) δ9.43 (s, 1H), 9.30 (d, J = 4.4Hz, 1H), 8.97 (d, J = 4.4Hz, 1H), 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).

Example T57

Step 1: Synthesis of compound 57-3

Prepared using 57-1 in the same manner as in Example T42. MS m/z: 314.90 [M+H] ⁺ .

Step 2: Synthesis of compound 57-4

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

Step 3: Synthesis of compound 57-5

Prepared using 57-4 using the same protocol as in Example T47. MS m/z: 203 [M+H] ⁺ .

Step 4: Synthesis of compound 57-6

Prepared using 57-5 using the same protocol as in Example T16. MS m/z: 541.25 [M+H] ⁺ .

Step 5 and Step 6: Synthesis of Compound 57-7

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] ⁺ .

Step 7: Synthesis of compound T57

The same protocol as in Example T01 was used to prepare 57-7. MS m/z: 476 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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, 1 H), 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).

Example T58

Step 1: Synthesis of compound 58-2

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 completion, 10 mL of aqueous ammonia was added to quench the reaction. The mixture was washed with water (10 mL x 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 afford 58-2 (190 mg, 96% yield). MS m/z: 208 [M+H] ^⁺ .

Step 2: Synthesis of compound 58-3

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 completion of the reaction, 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 58-3 (160 mg, 80% yield). MS m/z: 222 [M+H] ^⁺ .

Step 3: Synthesis of compound 58-5

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 replaced 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 x 3). The combined organic phases were 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 = 1:1) to afford 58-5 (100 mg, 40% yield). MS m/z: 285.95 [M+H] ⁺ .

Step 4: Synthesis of compound 58-6

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

Step 5: Synthesis of compound 58-7

Prepared using 58-6, the same protocol as in Example T26. MS m/z: 234 [M+H] ⁺ .

Step 6: Synthesis of compound 58-8

Prepared using 58-7, the same protocol as in Example T16. MS m/z: 315.10 [M+H] ⁺ .

Step 7: Synthesis of compound 58-9

Prepared using 58-8 using the same protocol as in Example T16. MS m/z: 215 [M+H] ⁺ .

Step 8: Synthesis of compound 58-10

Prepared using 58-9 using the same protocol as in Example T56. MS m/z: 608.15 [M+H] ⁺ .

Step 9: Synthesis of compound T58

The same protocol as in Example T56 was used to prepare compound 58-10. MS m/z: 488 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.12(s, 1H), 8.78(s, 1H), 8.71(d, J=7.8Hz, 1H), 7.77(s, 1H), 7.67(d , J=7.8Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.34 (d, J=7.8Hz, 1H), 6.40 (s , 1H), 5.90 (s, 1H), 4.06-4.00 (m, 1H), 3.54 (s, 3H), 2.91 (d, J=4.8Hz, 3H ), 2.87(s, 3H), 1.79-1.75(m, 2H), 1.31-1.27(m, 1H), 0.68-0.46(m, 1H).

Example T59

Step 1: Synthesis of compound 59-3

Prepared using 59-1 in the same manner as in Example T42. MS m/z: 328.90, 330.90 [M+H] ⁺ .

Step 2: Synthesis of compound 59-4

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

Step 3: Synthesis of compound 59-5

Prepared using 59-4 using the same protocol as in Example T47. MS m/z: 219 [M+H] ⁺ .

Step 4: Synthesis of compound 59-6

Prepared using 59-5 using the same protocol as in Example T16. MS m/z: 557.10 [M+H] ⁺ .

Step 5 and Step 6: Synthesis of Compound 59-7

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] ⁺ .

Step 7: Synthesis of compound T59

The same protocol as in Example T01 was used to prepare compound 59-7. MS m/z: 492 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ )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), 7.3 5-7.31 (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).

Example T60

Step 1: Synthesis of compound 60-3

Prepared using 60-1, the same protocol as in Example T42. MS m/z: 321.90 [M+H] ⁺ .

Step 2: Synthesis of compound 60-4

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

Step 3: Synthesis of compound 60-5

Prepared using 60-4 using the same protocol as in Example T47. MS m/z: 210.15 [M+H] ⁺ .

Step 4: Synthesis of compound 60-6

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

Step 5: Synthesis of compound T60

The same protocol as in Example T56 was used to prepare 60-6. MS m/z: 483 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Example T61

Step 1: Synthesis of compound 61-3

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). 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 afford 61-3 (90 mg, 55% yield). MS m/z: 313.10, 315.10 [M+H] ^⁺ .

Step 2: Synthesis of compound 61-4

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, and the atmosphere was replaced with nitrogen three times. Pd(OAc) _₂ (23 mg, 0.1 mmol) was added, and the mixture was heated to 75°C and stirred for 3 h. After completion, the reaction was quenched by the addition of 10 mL of _H₂O . The mixture was extracted with DCM (30 mL x 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 afford 61-4 (35 mg, 50% yield). MS m/z: 233.25 [M+H] ^⁺ .

Step 3: Synthesis of compound 61-5

Prepared using the same protocol as in Example T47 using 61-4. MS m/z: 203.25 [M+H] ⁺ .

Step 4: Synthesis of compound 61-6

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

Step 5 and Step 6: Synthesis of Compound 61-7

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] ⁺ .

Step 7: Synthesis of compound T61

The same protocol as in Example T01 was used to prepare compound 61-7. MS m/z: 476 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Example T62

Step 1: Synthesis of compound 62-3

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

Step 2: Synthesis of compound 62-4

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

Step 3: Synthesis of compound 62-5

Prepared using the same protocol as in Example T47 using 62-4. MS m/z: 188.30 [M+H] ⁺ .

Step 4: Synthesis of compound 62-6

Prepared using 62-5, the same protocol as in Example T16. MS m/z: 526.30 [M+H] ⁺ .

Step 5 and Step 6: Synthesis of Compound 62-7

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] ⁺ .

Step 7: Synthesis of compound T62

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

Example T63

Step 1: Synthesis of compound 63-2

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

Step 2: Synthesis of compound 63-3

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

Step 3: Synthesis of compound 63-4

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

Step 4 and Step 5: Synthesis of Compound 63-5

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] ⁺ .

Step 6: Synthesis of compound T63

The same protocol as in Example T01 was used to prepare compound 63-5. MS m/z: 473 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ )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), 7.40 (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).

Example T64

Step 1: Synthesis of compound 64-3

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 confirmed 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] ⁺ .

Step 2: Synthesis of compound 64-4

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 yield 64-4 (the crude product is used directly in the next step). MS m/z: 177.30 [M+H] ⁺ .

Step 3: Synthesis of compound 64-6

2-Chloro-6-iodobenzoic 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 then added. The mixture was stirred at room temperature overnight. Upon completion of the reaction, water was added to the mixture, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative TLC to yield 64-6 (673 mg, 86.4%). MS m/z: 440.90 [M+H] ⁺ .

Step 4: Synthesis of compound 64-7

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 was stirred at 80°C for 3 hours. TLC monitored the reaction to completion. The reaction solution was cooled to room temperature and concentrated to obtain a crude product, which was purified by preparative TLC to yield 64-7 (266 mg, 82%). MS m/z: 376.90 [M+H] ⁺ .

Step 5: Synthesis of compound 64-8

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] ⁺ .

Step 6: Synthesis of compound 64-9

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 mixture was stirred at 100°C overnight. TLC monitored the reaction completion. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated, and the crude product was purified by preparative TLC (PE/EtOAc = 1/1) to yield 64-9 (103 mg, 78.6%). MS m/z: 330.35 [M+H] ⁺ .

Step 7: Synthesis of compound 64-10

Prepared using the same protocol as in Example T16 using 64-9. MS m/z: 230.35 [M+H] ⁺ .

Step 8: Synthesis of compound 64-11

Prepared using the same protocol as in Example T56 using 64-10. MS m/z: 623.55 [M+H] ⁺ .

Step 9: Synthesis of compound T64

The same protocol as in Example T56 was used to prepare compound 64-11. MS m/z: 503 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Example T65

Step 1: Synthesis of compound 65-3

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

Step 2: Synthesis of compound 65-4

Prepared using 65-3, the same protocol as in Example T38. MS m/z: 241.25 [M+H] ⁺ .

Step 3: Synthesis of compound 65-5

Prepared using the same protocol as in Example T47 using 65-4. MS m/z: 211.25 [M+H] ⁺ .

Step 4: Synthesis of compound 65-6

Prepared using 65-5 using the same protocol as in Example T56. MS m/z: 604.50 [M+H] ⁺ .

Step 5: Synthesis of compound T65

The same protocol as in Example T56 was used to prepare 65-6. MS m/z: 484[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )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).

Example T66

Step 1: Synthesis of compound 66-3

Prepared using the same protocol as in Example T42 using 66-1. MS m/z: 421 [M+H] ⁺ .

Step 2: Synthesis of compound 66-4

66-3 (230 mg, 0.55 mmol) was dissolved in DMF (3 mL). Zinc cyanide (89 mg, 0.76 mmol) was added under nitrogen. The atmosphere was replaced with nitrogen three times, and Pd(PPh ₃ ) 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 H ₂ O was added to quench the reaction. The mixture was extracted with EtOAc (30 mL x 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 afford 66-4 (130 mg, 74% yield). MS m/z: 320.20 [M+H] ⁺ .

Step 3: Synthesis of compound 66-5

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

Step 4: Synthesis of compound 66-6

Prepared using the same protocol as in Example T47 using 66-5. MS m/z: 210.15 [M+H] ⁺ .

Step 5: Synthesis of compound 66-7

Prepared using the same protocol as in Example T56 using 66-6. MS m/z: 603.55 [M+H] ⁺ .

Step 6: Synthesis of compound T66

Prepared using the same protocol as in Example T56 using 66-7. MS m/z: 483 [M+H] ⁺ .

Example T67

Step 1: Synthesis of compound 67-3

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

Step 2: Synthesis of compound 67-4

Prepared using the same protocol as in Example T50 using 67-3. MS m/z: 316 [M+H] ⁺ .

Step 3: Synthesis of compound 67-5

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(PPh ₃ ) ₂ Cl ₂ (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] ⁺ .

Step 4: Synthesis of compound 67-6

Prepared using the same protocol as in Example T16 using 67-5. MS m/z: 317 [M+H] ⁺ .

Step 5: Synthesis of compound 67-7

Prepared using the same protocol as in Example T16 using 67-6. MS m/z: 217.30 [M+H] ⁺ .

Step 6: Synthesis of compound 67-8

Prepared using the same protocol as in Example T56 using 67-7. MS m/z: 612 [M+H] ⁺ .

Step 7: Synthesis of compound T67

Prepared using the same protocol as in Example T56 using 67-8. MS m/z: 492 [M+H] ⁺ .

Example T68

Step 1: Synthesis of compound 68-3

Prepared using the same protocol as in Example T52 using 68-1. MS m/z: 334.15 [M+H] ⁺ .

Step 2: Synthesis of compound 68-4

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

Step 3: Synthesis of compound 68-5

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

Step 4: Synthesis of compound 68-6

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, 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 was naturally warmed to room temperature and stirred for 1 hour. The reaction was quenched by adding heavy water (0.5 mL) and stirred for 15 minutes. Saturated aqueous ammonium chloride was then added to the reaction system, and the mixture was extracted with EtOAc (30 mL x 3). All organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The resulting organic phase was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by preparative plate chromatography (PE/EtOAc = 3:1) to afford 68-6 (45 mg, 81% yield). MS m/z: 205.30 [M+H] ⁺ .

Step 5: Synthesis of compound 68-7

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

Step 6: Synthesis of compound 68-8

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

Step 7: Synthesis of Compound 68-9

Prepared using the same protocol as in Example T56 using 68-8. MS m/z: 579 [M+H] ⁺ .

Step 8: Synthesis of compound T68

Prepared using compound 68-9, using the same protocol as in Example T56. MS m/z: 459 [M+H] ⁺ .

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

Test Principle: Utilizing Promega's CellTiter-Glo ^™ Luciferase Assay Kit, this method uses luciferase as the assay. Luminescence requires the presence of ATP, which is produced by respiration and other life processes in metabolically active cells. An equal volume of CellTiter-Glo ^™ reagent is added to the cell culture medium, and the luminescence value is measured. The light signal is proportional to the amount of ATP in the system, and ATP is positively correlated with the number of viable cells. Therefore, this assay is used to detect inhibition of cell proliferation.

Experimental method: Prepare complete medium (RPMI 1640 + 10% FBS + 1% P/S) to resuscitate Ba/F3-FL-TYK2-E957D cells (Hefei Puruisheng). After about two generations, centrifuge and collect cells in the logarithmic growth phase and count them. Resuspend the cells to an appropriate concentration and inoculate the cell suspension into a 96-well plate. Add 95 μL of cell suspension to each well. The plate density is 2000 cells/well. The test compound is prepared into a storage solution with DMSO, and 1 mM is the highest concentration. The concentration was diluted 3-fold with DMSO to create 10 concentration gradients. The test compound was diluted 50-fold with culture medium, and 5 μL of each was added to 95 μL of cells in a 96-well plate. Cell-free culture medium (containing 0.1% DMSO) was added to the Min control well, and 5 μL of a DMSO-cell culture medium mixture (final DMSO concentration of 0.1%) was added to the Max control well. The cells were incubated for 72 hours at 37°C in a 5% CO2 incubator with a relative humidity of ≥90%. The reaction was terminated by adding 50 μL/well CellTiter Glo. The cells were incubated at room temperature in the dark for 30 minutes, gently shaken, and then analyzed using Envision. The fluorescence (RLU) value of each well was measured, and the cell growth inhibition rate was calculated according to the formula: Cell growth inhibition rate (%) = (1-As/Ac) × 100. Where As is RLU sample (cells + CTG + test compound) minus RLU min (cell-free culture medium), and Ac is RLU normal growth cell control (cells + CTG + DMSO) minus RLU min (cell-free culture medium). Enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, and use GraphpadPrism 8 software according to the built-in four-parameter fitting formula Y = Bottom + (Top-Bottom) / (1 + (IC50/X) * HillSlope) to calculate the half-maximal inhibitory concentration IC50 value of each compound.

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

Table 3 Cell proliferation inhibition test data

Biological Example 2 TYK2 JH2 in vitro enzyme binding assay

This experiment uses fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of compounds on the TYK2 JH2 pseudokinase. In this experiment, the TYK2 JH2 pseudokinase is simultaneously bound to the fluorescently labeled Tracer and the Tb antibody. The Tb antibody acts as a fluorescence donor, generating 495nm fluorescence under the influence of excitation light of a certain wavelength. The Tracer, acting as a fluorescence acceptor, can only receive the 495nm fluorescence when it is sufficiently close to the Tb antibody, thereby generating 520nm fluorescence, i.e., the fluorescence resonance energy transfer signal. When a compound is added to compete with the 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 reflect the inhibitory activity of the compound binding to the pseudokinase.

B2.1 Experimental procedures are as follows:

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

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.

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.

B2.1.4 Add 5uL of TYK2 JH2 pseudokinase (3 times the final concentration (0.5nM)) into each 384-well experimental plate. Replace the negative control group with the same volume of 1X experimental working solution and centrifuge at 1000rpm for 30 seconds.

B2.1.5 Add 5uL of Tb antibody 3 times the final concentration (1x is the final concentration) into each 384-well experimental plate and centrifuge at 1000rpm for 30 seconds.

B2.1.6 Add 5uL of Tracer which is 3 times the final concentration (1nM is the final concentration) into each well of the 384-well assay plate and centrifuge at 1000rpm for 30 seconds.

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

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

B2.2 Data Analysis

The test data was processed and analyzed using XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment. First, the average reaction signals of the positive control group and the negative control group were calculated separately, and then the reaction inhibition rate of each well was calculated according to the formula "single-well inhibition rate % = ((positive control group average value - single-well signal value) / (positive control group average value - negative control group average value)) × 100". The concentration and pair data were then imported into the XLfit software, and the Dose Response One Site 205 model was used. The four-parameter inhibition model was adopted, and the four-parameter inhibition rate-concentration curve was fitted to calculate the IC50 value of the compound.

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" indicates an _IC50 value of less than 10 nM; "B" indicates an _IC50 value greater than or equal to 10 nM and less than 100 nM; and "C" indicates an _IC50 value greater than or equal to 100 nM and less than 1000 nM.

Table 4 TYK2 JH2 enzymatic test data

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 (12)

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; ^X1 is C or N; ^X2 is C or N; R ¹ is H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl substituted by one or more deuteriums; R ² is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₁ -C ₆ alkyl substituted by one or more R ^2-1 , C ₁ -C ₆ alkoxy substituted by one or more R ^2-2 , C ₃ -C ₁₂ cycloalkyl substituted by one or more R ^2-3 , or 3-12 membered heterocycloalkyl substituted by one or more R ^2-4 ; R ^2-1 and R ^2-2 are each independently halogen, OH, C ₃ -C ₁₂ cycloalkyl or 3-12 membered heterocycloalkyl; Alternatively, two adjacent R ^{2-1 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ monocyclic cycloalkyl group, a C ₅ -C ₁₂ cycloalkyl group, a C ₅ -C ₁₂ bridged cycloalkyl group, a C ₄ -C ₁₂ spirocycloalkyl group, a 3-7 membered monocyclic heterocycloalkyl group, a 5-12 membered cycloheterocycloalkyl group, a 5-12 membered bridged heterocycloalkyl group, or a 5-12 membered spiroheterocycloalkyl group; Alternatively, two R ^2-1 on the same carbon atom together with the carbon atom to which they are attached form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloheterocycloalkyl, a C ₅ -C ₁₂ bridged cycloalkyl, a C ₅ -C ₁₂ spirocyclocycloalkyl, a 3-7 membered monocyclic heterocycloalkyl, a 5-12 membered cycloheterocycloalkyl, a 5-12 membered bridged heterocycloalkyl or a 5-12 membered spiro heterocycloalkyl; Alternatively, two adjacent R ^{2-2 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloalkyl group, a C ₅ -C ₁₂ bridged cycloalkyl group, a C ₄ -C ₁₂ spirocycloalkyl group, a 3-7 membered monocyclic heterocycloalkyl group, a 5-12 membered cycloheterocycloalkyl group, a 5-12 membered bridged heterocycloalkyl group, or a 5-12 membered spiroheterocycloalkyl group; Alternatively, two R ^2-2 on the same carbon atom together with the carbon atom to which they are attached form a C ₃ -C ₇ monocyclic cycloalkyl, a C ₅ -C ₁₂ cycloalkyl group, a C ₅ -C ₁₂ bridged cycloalkyl group, a C ₄ -C ₁₂ spirocycloalkyl group, a 3-7 membered monocyclic heterocycloalkyl group, a 5-12 membered cycloheterocycloalkyl group, a 5-12 membered bridged heterocycloalkyl group or a 5-12 membered spiro heterocycloalkyl group; R ^2-3 and R ^2-4 are each independently halogen, OH, C ₁ -C ₆ alkyl group or C ₁ -C ₆ alkoxy group; Alternatively, two adjacent R ^{2-3 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ cycloalkyl group or a 3-7 membered heterocycloalkyl group; Alternatively, two R ^2-3 on the same carbon atom and the carbon atom to which they are attached together form a C ₃ -C ₇ cycloalkyl or a 3-7 membered heterocycloalkyl; Alternatively, two adjacent R ^{2-4 groups} and the carbon atom to which they are attached together form a C ₃ -C ₇ cycloalkyl group or a 3-7 membered heterocycloalkyl group; Alternatively, two R ^2-5 groups on the same carbon atom and the carbon atom to which they are attached together form a C ₃ -C ₇ 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 C ₅ -C ₆ 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 is independently halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocycloalkyl, C ₁ -C ₆ alkyl substituted by one or more R ^3-1 , or C ₁ -C ₆ alkoxy substituted by one or more R ^3-2 ; R ^3-1 and R ^3-2 are each independently halogen; n is 0, 1, 2, or 3; In the “3-12 membered heterocycloalkyl”, “3-12 membered heterocycloalkyl substituted by one or more R ^2-4 ”, “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. 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 satisfies one or more of the following conditions: (1) In the “3-12 membered heterocycloalkyl”, “3-12 membered heterocycloalkyl substituted by one or more R ^2-4 ”, “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 independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently one, two or three. 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, characterized in that it satisfies one or more of the following conditions: (1) Each “C ₁ -C ₆ alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -CH 2 CH(CH 3 )CH ₂ CH 3 , -CH ₂ CH 2 CH(CH ₃ ) ₂ , -CH(C ₂ H ₅ )CH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , or -CH ₂ C(CH ₃ ) ₃ , for example, methyl, isopropyl, isobutyl, or -CH ₂ C(CH ₃ ) ₃ ; (2) Each "C ₁ -C ₆ alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy; (3) Each "C ₃ -C ₁₂ cycloalkyl" is independently a C ₃ -C ₆ 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, 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 alkene” is For example 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 satisfies one or more of the following conditions: (1) for in, X ^3-1 is CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , ^and 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; ^X4-1 , ^X4-2 , ^X4-3 , ^X4-4 , ^X4-5 , ^X4-6 , ^X4-7 , ^X4-8 , ^X4-9 and ^X4-10 are each independently CH or N; ^X5-1 , ^X5-2 , ^X5-3 , ^X5-4 , ^X5-5 , ^X5-6 , ^X5-7 , ^X5-8 , ^X5-9 and ^X5-10 are each independently CH or N; X ^6-1 , X ^6-7 and X ^6-8 are each independently CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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; ^X7-1 and ^X7-5 are each independently _CH2 , NH, O, S, C(=O), S(=O) or S(=O) ₂ , and ^X7-2 , ^X7-3 , ^X7-4 , ^X7-6 , ^X7-7 , ^{X7-8 , X7-9} and ^X7-10 are each independently CH or N; ^X8-1 , ^X8-5 and ^X8-7 are each independently _CH2 , NH, O, S, C(=O), S(=O) or S(=O) ₂ , and ^X8-2 , ^X8-3 , ^X8-4 , ^{X8-6 , X8-8 and X8-9} are each independently CH or N; ^X9-1 and ^X9-3 are each independently _CH2 , NH, O, S, C(=O), S(=O) or S(=O) ₂ , and ^X9-2 , ^X9-4 , ^X9-5 , ^X9-6 , ^X9-7 , ^{X9-8 , X9-9} and ^X9-10 are each independently CH or N; ^X10-1 , ^X10-2 , ^X10-3 , ^X10-4 , ^X10-5 , ^X10-6 , ^X10-7 , ^X10-8 , ^X10-9 and ^X10-10 are each independently CH or N; X ^11-1 and X ^11-7 are each independently CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 is independently F, CN, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, or C ₁ -C ₃ alkyl substituted with one or more Fs; (3) n is 0, 1 or 2; (4) ^R1 is a _C1 - _C3 alkyl group; (5) R ² is C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ^2-1 , C ₃ -C ₆ cycloalkyl substituted by one or more R ^2-3 , or 3-6 membered heterocycloalkyl substituted by one or more R ^2-4 ; R ^2-1 is independently OH or a 3-6 membered heterocycloalkyl group; R ^2-3 are independently F, OH or OCH ₃ ; R ^2-4 are independently OH or OCH ₃ . 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 satisfies one or more of the following conditions: (1) in, X ^3-1 is CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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; ^X4-1 , ^X4-2 , ^X4-3 , ^X4-4 , ^X4-5 , ^X4-7 , ^X4-8 , ^X4-9 and ^X4-10 are each independently CH or N; X ^6-1 , X ^6-7 and X ^6-8 are each independently CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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; ^X8-1 , ^X8-4 and ^X8-7 are each independently _CH2 , NH, O, S, C(=O), S(=O) or S(=O) ₂ , and ^X8-2 , ^X8-3 , ^{X8-6 , X8-8} and ^X8-9 are each independently CH or N; X ^9-1 and X ^9-3 are each independently CH ₂ , NH, O, S, C(═O), S ⁽ ═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 CH ₂ , NH, O, S, C(═O), S(═O) or S(═O) ₂ , and 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 is F, CN, CH ₃ , CF ₃ , OCH ₃ or (3) ^R1 is methyl; (4) R ² is 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: 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):
wherein R ¹ , R ² , R ³ , n, ring A, ring B and ring C are as defined in any one of claims 1-6. 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:



A pharmaceutical composition comprising 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, and a pharmaceutically acceptable excipient. A 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 TYK2 inhibitor, preferably, the TYK2 is TYK2-E957D. A use of a compound of formula (I) as described in 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 as described in 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. A 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.