WO2025011533A1 - Carboxylic acid compound, and preparation method therefor and use thereof - Google Patents

Abstract

Provided are a carboxylic acid compound, and a preparation method therefor and the use thereof. The present invention relates to a carboxylic acid compound as represented by formula (I) for treating cancers, an isotope marker, an enantiomer, a diastereoisomer, a solvate or a pharmaceutically acceptable salt thereof. The carboxylic acid compound is as represented by formula (I), has a good inhibitory activity on eIF4E, and has good application prospects.

Description

A kind of carboxylic acid compound and its preparation method and application

This application claims the priority of Chinese Patent Application No. 2023108318007 filed on July 7, 2023, Chinese Patent Application No. 2023114105313 filed on October 27, 2023, Chinese Patent Application No. 2023116154102 filed on November 29, 2023, Chinese Patent Application No. 2024102810810 filed on March 12, 2024, and Chinese Patent Application No. 2024108556175 filed on June 27, 2024. This application cites the full text of the above Chinese patent applications.

Technical Field

The present invention relates to an eIF4E inhibitor and a preparation method and application thereof, and in particular to a class of carboxylic acid compounds, a composition thereof and their use in treating and preventing cancer.

Background Art

Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in the initiation of protein synthesis in eukaryotic cells. As the rate-limiting step for the initiation of cap-dependent translation, the binding of eIF4E to the m7GTP cap structure at the 5' end of mRNA leads to the formation of the eIF4F complex composed of eIF4E, DEAD-box RNA helicase eIF4A and scaffold protein eIF4G (Volpon L et al., Biochemical and Structural Insights into the Eukaryotic Translation Initiation Factor eIF4E. Curr Protein Pept Sci. 2019, 20(6): 525-535). The interaction between eIF4E and eIF4G promotes the loading of the 40S ribosomal small subunit onto the mRNA molecule, thereby triggering the scanning of the start codon. eIF4E binding protein (4E-BP) inhibits cap-dependent translation by competing with eIF4G for binding to eIF4E, and thus becomes an important regulator of this process. The binding of 4E-BP to eIF4E is regulated by its phosphorylation state. After being phosphorylated by mTORC1, 4E-BP releases eIF4E to bind to eIF4G and form an eIF4F complex (Bordeleau ME et al., Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008, 118(7): 2651-60).

Lazaris-Karatzas A et al. first discovered in 1990 that overexpression of eIF4E in NIH3T3 and rat fibroblasts can cause their tumorigenic transformation (Lazaris-Karatzas A et al., Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5'cap. Nature. 1990, 345(6275): 544-7). In 2004, Ruggero D et al. reported that eIF4E overexpression in mice can promote tumorigenesis in animals (Ruggero D et al., The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med. 2004, 10(5): 484-6), which revealed the important role of eIF4E in cancer occurrence. Overexpression of eIF4E has been found to be widely present in various types of cancers such as breast cancer, colon cancer, ovarian cancer, lung cancer, basal cell carcinoma, head and neck cancer, renal cell carcinoma, gallbladder cancer, melanoma, and non-Hodgkin's lymphoma, and is associated with tumor grade, metastasis and poor prognosis (Lu C et al., Targeting translation: eIF4E as an emerging anticancer drug target. Expert Rev Mol Med. 2016, 18: e2). Importantly, high expression of eIF4E in tumor cells can lead to increased translation efficiency of certain oncogenic mRNA populations. Such mRNAs have a more complex 5' untranslated region (5'-UTR), which usually encodes proteins involved in cell proliferation, survival, invasion and metastasis, such as cyclin D1, c-Myc, survivin, Pim-1, and VEGF (De Benedetti A et al., eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004, 23 (18): 3189-99), which means that cancer The cells were more sensitive to inhibition of eIF4E than normal cells. Since then, more reports have found that gene knockout or knockdown, as well as targeted inhibition of eIF4E expression by small molecule inhibitors, can significantly control the growth of tumor cells and mouse models, and enhance the sensitivity of cells to chemotherapy and immunotherapy (Li S et al., Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma. Mol Cancer Ther. 2016, 15(4): 711-9; Cao J et al., Inhibition of eIF4E cooperates with chemotherapy and immunotherapy in renal cell carcinoma. Clin Transl Oncol. 2018, 20(6): 761-767; Gong C et al., Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer. Oncogene. 2020, 39(15): 3206-3217; Matsumoto M et al., Control of the MYC-eIF4E axis plus mTOR inhibitor treatment in small cell lung cancer). cancer.BMC Cancer.2015,15:241; Pettersson F et al., Genetic and pharmacologic inhibition of eIF4Ereduces breast cancer cell migration, invasion, and metastasis.Cancer Res.2015,75(6):1102-12).

Although the above studies have shown that eIF4E is a very promising target for cancer treatment, the development of eIF4E inhibitors has been slow so far. Although eIF4E antisense oligonucleotide LY-2275796 and nucleoside (m7G) analog Ribavirin have been tested in preliminary clinical trials, they have not achieved ideal results in terms of efficacy and safety (Hong DS, Kurzrock R, et al., A phase 1 dose escalation, pharmacokinetic, and pharmacokinetic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with adverse reactions). nced cancer. Clin Cancer Res. 2011, 17(20): 6582-91; Assouline S et al., A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E. Haematologica. 2015, 100(1): e7-9). Therefore, there is an urgent need to develop eIF4E inhibitors with higher activity and selectivity. Since the binding of eIF4E to eIF4G is a key event in the process of cap-dependent translation initiation, small molecule inhibitors targeting the eIF4E/eIF4G interaction are likely to be a new strategy for safe and effective cancer treatment.

Summary of the invention

In order to overcome the defects in the prior art, the present invention provides a class of compounds and a preparation method and application thereof. The compounds of the present invention have good inhibitory activity on eIF4E.

The present invention also provides a compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the following structures:

in,

^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ;

^R3 , ^R4 , ^R5 and ^R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted with one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted with one or more substituents selected from Group A, C6-C10 aromatic which is unsubstituted or substituted with one or more substituents selected from Group A, substituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, unsubstituted or substituted by one or more substituents selected from Group A;

for

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, ^cyano , ^-NR7R8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group C, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group C, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group C; ^R7 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R ⁸ is selected from hydrogen, C1-C6 alkyl; C group substituents include: oxo, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, ^-NRx1Ry1 , C3-C6 ^cycloalkyl , 3-8 membered heterocyclyl, -C(O) ^ORz ; ^Rx1 and ^Ry1 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; ^Rz is hydrogen or C1-C6 alkyl;

^R2 is selected from C1-C8 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkenyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, _C2 -C6 alkenyl, C2- _C6 alkynyl, carboxyl, _thiol , _-SF5 ^, _{-S - CH3} , _-CONH2 , - ₍ CH2)iSO2R9, -( ^CH2 ) _iSO2NH2 , - ₍ CH2)iSO2NR13R11, _- ( _CH2 )iP(O ⁾ _R9R10 , -( ^CH2 _{) iC} (O) ^-OR11 , _- ( _CH2 ) _iOC (O) ^{R11 ,} -CONR13R11 ^{, -NR13CO} _- ^{R11 ,} -NR13R11 ^{, -O} ( _CH2 ) _iR12 , -( _CH2 ) ^{iR12 ;}

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 ^alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 alkoxy, C3-C6 ^{cycloalkyloxy} , -NRxRy, -CONRxRy, -NRxCO ^{- Ry} , -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered ^heterocyclyl , 5-10 membered heteroaryl; ^{Rx and Ry are} each independently H, deuterium _, C1-C6 alkyl, Halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S;

The compound of formula (I) is not any of the following compounds:

As a preferred technical solution, the compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, the compound of formula (I) is selected from the following structures:

in,

^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

for

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, or C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, _carboxyl , cyano ^{, -CONR7R8} , -NR8CO- ^{R7 , -NR7R8} , ^-SO2R7 , _-SO2NR7R8 , C2- ^{C6 alkenyl} , C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^R R ⁷ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C6-C10 aryl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R ⁸ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl;

^R2 is selected from C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2- _C6 alkynyl, carboxyl, _thiol , _-SF5 , _{-S - CH3} , _-CONH2 , -(CH2)iSO2R9 ^, - ₍ ^{CH2 )} _iSO2NH2 , -(CH2) ^{iSO2NR13R11 ,} -(CH2) _iP (O) ^R9R10 , -( _CH2 ) _iC (O) ^-OR11 _{, -CONR13R11 , -NR13CO -} ^{R11 , -NR13R11 ,} _-O ( _CH2 ) _iR12 ^, -( ^CH2 ) _iR12 ^;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 ^alkyl , halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, ^halogenated C1-C6 alkoxy, C3-C6 ^{cycloalkyloxy} , -NRxRy, -CONRxRy, -NRxCO ^{- Ry} , -SO2Rx, _-SO2NRxRy , C6- _C10 ^aryl , C3-C6 ^cycloalkyl , ^3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^Rx and ^Ry are each independently H, ^deuterium , C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, the present invention provides a compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the following structures:

in,

^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

for

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, ^cyano , ^-NR7R8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group C, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group C, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group C; ^R7 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; ^R8 is selected from hydrogen, C1-C6 alkyl; the substituents in Group C include: oxo, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 ^{cycloalkyloxy} , ^-NRx1Ry1 , C3-C6 cycloalkyl; ^Rx1 and R ^y1 is each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

^R2 is selected from C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, _C2 -C6 alkenyl, C2- _C6 alkynyl, carboxyl, _thiol , _-SF5 , _{-S - CH3} , _-CONH2 , -(CH2)iSO2R9 ^, - ₍ ^{CH2 )} _iSO2NH2 , -(CH2) ^{iSO2NR13R11 ,} -(CH2) _iP (O) ^R9R10 , -( _CH2 ) _iC (O)-OR11 _{, -CONR13R11} ^, _{-NR13CO -} ^{R11 , -NR13R11 ,} _-O ( _CH2 ) _iR12 ^, -( ^CH2 ) _iR12 ^;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, the present invention also provides a compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the following structures:

in,

^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

for

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, ^cyano , ^-NR7R8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group C, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group C, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group C; ^R7 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R ⁸ is selected from hydrogen, C1-C6 alkyl; C group substituents include: oxo, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, ^-NRx1Ry1 , C3-C6 ^cycloalkyl , 3-8 membered heterocyclyl, -C(O) ^ORz ; ^Rx1 and ^Ry1 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; ^Rz is hydrogen or C1-C6 alkyl;

^R2 is selected from C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, _-SF5 , -S _{- CH3} ^, _-CONH2 , -( _CH2 )iSO2R9, -(CH2)iP( ^O _{) R9R10} , -(CH2) _iC (O ^{) -OR11} , -( _CH2 ) _iOC ⁽ O) ^{R11 ,} _{-CONR13R11 ,} ^-NR13CO -R11 _, ^{-NR13R11 ,} -O( _CH2 ) ^iR12 , ^- ( _CH2 ) _iR12 ^;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3- ^C6 cycloalkoxy, -NRxRy, ^-CONRxRy , ^{-NRxCO - Ry} , _-SO2Rx , _-SO2NRxRy ^{, C6-} C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R ^x and R ^y are each independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, ^X1 is N or ^CR3 , ^X2 is ^CR4 , ^X3 is ^CR5 , and ^X4 is N or ^CR6 ; the definitions of other substituents are the same as described above.

As a preferred technical solution, the compound of formula (I) is selected from the following structures:

Wherein, R ⁰ , R ¹ , R ² and R ⁵ are as defined above;

Preferably, when formula (I) is formula (I-1) or (I-4), ^R2 is selected from unsubstituted C1-C8 alkyl, ^R1 is selected from C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl, and the definitions of ^R0 and ^R5 are the same as described above.

As a preferred technical solution, in ^R0 , ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 , ^R12 , ^R13 , Rz, ^Rx , ^Ry , the substituents in Group C, the substituents in Group B and the substituents in Group A, the C1-C6 alkyl group, the C1-C6 alkyl group in ^{the unsubstituted} or substituted C1-C6 alkyl group, the C1-C6 alkyl group in the unsubstituted or substituted C1-C6 alkyl group, the C1-C6 alkyl group in the halogenated C1-C6 alkyl group, and the C1-C6 alkyl group in the C3-C6 cycloalkyl group which is unsubstituted or substituted with C1-C6 alkyl group are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

As a preferred technical solution, in ^R2 , the C1-C8 alkyl group in the C1-C8 alkyl group which is unsubstituted or substituted by one or more substituents selected from Group A is a C1-C6 alkyl group or a C6-C8 alkyl group. The C1-C6 alkyl group is independently a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group.

As a preferred technical solution, among ^R3 , ^R4 , ^R5 , ^R6 , the substituents in the substituted C1-C6 alkyl, the substituents in group B and the substituents in group C, the C1-C6 alkoxy group, the C1-C6 alkoxy group in the halogenated C1-C6 alkoxy group and the C1-C6 alkoxy group in the C1-C6 alkoxy group which is unsubstituted or substituted with one or more substituents selected from group A are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

As a preferred technical solution, among ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R11 , ^R12 and the substituents in group B, the C6-C10 aryl group, the C6-C10 aryl group in the C6-C10 aryl group which is unsubstituted or substituted with one or more substituents selected from group A, the C6-C10 aryl group in the C6-C10 aryl group which is unsubstituted or substituted with one or more substituents selected from group C, and the C6-C10 aryl group in the unsubstituted or substituted C6-C10 aryl group are independently phenyl or naphthyl.

As a preferred technical solution, ^R2 , ^R3 , ^R4 , R5, ^R6 , ^R11 , ^R12 , the substituents in the substituted C1- ^C6 alkyl and the substituents in Group B, the 5-10 membered heteroaryl, the 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group A, The 5-10 membered heteroaryl in the aryl group, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group C, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group A, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted, and the 5-10 membered heteroaryl in the benzo 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group A are independently 5-6 membered monocyclic heteroaryl groups, the heteroatoms are N and/or S, the number of which is 1, 2 or 3, and are preferably pyridyl, pyridazinyl, 1H-pyrazolyl or thienyl.

As a preferred technical solution, among ^R1 , ^R11 , ^R12 , the substituents in the substituted C1-C6 alkyl, the substituents in Group B and the substituents in Group C, the C3-C6 cycloalkyl, the C3-C6 cycloalkyl in the C3-C6 cycloalkyl that is unsubstituted or substituted with C1-C6 alkyl and the C3-C6 cycloalkyl in the C3-C6 cycloalkyl that is unsubstituted or substituted with one or more substituents selected from Group C are independently C3-C6 monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As a preferred technical solution, in ^R2 , the unsubstituted or substituted C3-C12 cycloalkyl group selected from Group A is a C3-C8 monocyclic alkyl group, a 6-8-membered bicyclic spirocyclic group or a bridged cycloalkyl group, preferably a cyclopropyl group, a cyclohexyl group, a cycloheptyl group, a spiro[2.5]octyl group, a bicyclo[3.2.1]octyl group or a bicyclo[1.1.1]pentyl group.

As a preferred technical solution, in ^R2 , the 3-8-membered heterocyclic group in the 3-8-membered heterocyclic group which is unsubstituted or substituted by one or more substituents selected from Group A is independently a 3-6-membered monocyclic heterocyclic group or a 6-8-membered bicyclic bridged heterocyclic group, the heteroatoms are N and/or O, the number of which is 1, 2 or 3, and is preferably piperidinyl, 8-azabicyclo[3.2.1]octanyl or -8-oxabicyclo[3.2.1]octanyl.

As a preferred technical solution, in formula (I), formula (I-1) to formula (I-6),

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; more preferably, R ⁰ is selected from hydrogen, halogen, methyl, ethyl; more preferably, R ⁰ is hydrogen.

As a preferred technical solution, in formula (I) and (I-1) to (I-6),

^R1 is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in ^R1 refers to a substituent selected from the following: deuterium, halogen, amino, hydroxyl, cyano, C6-C10 aryl unsubstituted or substituted with one or more substituents selected from Group C, C3-C6 cycloalkyl, 3-8 membered heterocyclyl unsubstituted or substituted with -C(O)O C1-C6 alkyl, and 5-10 membered heteroaryl.

More preferably, ^R1 is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in ^R1 refers to a substituent selected from the following substituents: deuterium, halogen, amino, hydroxyl, cyano, phenyl, halophenyl, pyridine, halopyridyl, cyclopropyl, cyclohexyl and piperidinyl substituted by -C(O)O C1-C6 alkyl.

More preferably, ^R1 is selected from methyl, ethyl, n-propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl,

Most preferably, R ¹ is -CH ₂ CH(CH ₃ ) ₂ .

As a preferred technical solution, in formula (I) and (I-1) to (I-6), ^R4 and ^R6 are each independently selected from hydrogen, hydroxyl, carboxyl, cyano or The amino group is preferably hydrogen.

As a preferred technical solution, in formula (I) and (I-1) to (I-6), R ⁵ is selected from 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents in Group A are selected from halogen and -(CH ₂ ) _i R ¹² ; R ¹² is C1-C6 alkyl;

Preferably, ^R5 is

Most preferably, R ⁵ is

As a preferred technical solution, in formula (I) and (I-1) to (I-6),

^R2 is selected from C1-C6 alkyl or halogenated C1-C6 alkyl, For example, ^R2 is selected from More preferably, ^R2 is selected from

in,

n is 0, 1, 2, 3 or 4; preferably, n is 0, 1, 2 or 3; more preferably, n is 0, 1 or 2;

each ^Ra is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2- _C6 alkenyl, C2- ^C6 alkynyl, _carboxyl , _thiol , -SF5, -S- _CH3 , _-CONH2 , - _{( CH2} )iSO2R9, ^- (CH2)iSO2NH2, -(CH2)iSO2NR13R11, -(CH2 _{) iP (} ^{O )} _{R9R10 , -} ( ^CH2 ) _iC (O) ^{-OR11 ,} -( _CH2 ⁾ _iOC (O ^{) R11} , _{-CONR13R11 ,} ^{-NR13CO - R11} _{, -NR13R11} , ^-O ( _CH2 ) ^iR12 , -( _CH2 ) _iR12 ;

i is 0, 1, 2 or 3; preferably, i is 0, 1 or 2;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Substituents in Group B include: oxo (=O), deuterium, halogen, hydroxyl, cyano, C1-C6 ^alkyl , halogenated C1-C6 alkyl, C1-C6 ^alkoxy , halogenated C1- ^C6 alkoxy, C3-C6 ^{cycloalkyloxy} , ^-NRxRy , -CONRxRy, -NRxCO ^{- Ry} , -SO2Rx, _-SO2NRxRy , C6-C10 ^aryl , C3-C6 cycloalkyl, ^3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^Rx and ^Ry are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S;

R ^d is selected from hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl.

Preferably, R ² is selected from any of the following structures:

As a preferred technical solution, in formula (I),

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; more preferably, R ⁰ is selected from hydrogen, halogen, methyl, ethyl; more preferably, R ⁰ is hydrogen;

R ¹ is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in R ¹ refers to substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, phenyl, C3-C6 cycloalkyl; more preferably, R ¹ is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in R ¹ refers to substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, phenyl, C3-C6 cycloalkyl; more preferably, R ¹ is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in R ¹ refers to substituted by one or more selected from halogen, phenyl, C3-C6 cycloalkyl; more preferably, R ¹ is selected from the group consisting of methyl, ethyl, propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl, Preferably, R ¹ is selected from methyl, ethyl, propyl, butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl; most preferably, R ¹ is -CH ₂ CH(CH ₃ ) ₂ ;

R ⁵ is a 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more substituents selected from Group A; the definition of the substituents in Group A is the same as described above; more preferably, R ⁵ is Most preferably, R ⁵ is

As a preferred technical solution, the substituents in Group A of the present invention include: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF ₅ , -S-CH ₃ , -CONH ₂ , -(CH ₂ ) _i SO ₂ R ⁹ , -(CH ₂ ) _i P(O)R ⁹ R ¹⁰ , -(CH ₂ ) _i C(O)-OR ¹¹ , -CONR ¹³ R ¹¹ , -NR ¹³ CO-R ¹¹ , -NR ¹³ R ¹¹ , -O(CH ₂ ) _i R ¹² , -(CH ₂ ) _i R ¹² ;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, the compound of formula (I) is selected from the following structures:

n is 0, 1, 2, 3 or 4; preferably, n is 0, 1, 2 or 3; more preferably, n is 0, 1 or 2;

m is 0, 1, 2 or 3; preferably, m is 0 or 1; more preferably, m is 0;

p is 0, 1, 2 or 3; preferably, p is 0, 1 or 2; more preferably, p is 1 or 2;

r is 0, 1, 2 or 3; preferably, r is 0, 1 or 2; more preferably, r is 0 or 1;

q is 0, 1, 2 or 3; preferably, q is 0, 1 or 2; more preferably, q is 1 or 2;

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl;

each ^Ra and ^Rb are independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, _carboxyl , _thiol , ^-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) ^iSO2R9 , _- ( _CH2 ) _iSO2NH2 , -(CH2)iSO2NR13R11 _, -( _CH2 ) ^iP (O) ^R9R10 _, - ⁽ _CH2 ) _iC (O) ^-OR11 _, - ⁽ _CH2 ) _iOC ( ^{O )R11 , -CONR13R11} _{, -NR13CO -} R11 _, ^-NR13R11 , _-O ( _CH2 ) ^iR12 , -( _CH2 ) ^{iR 12} ;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

Alternatively, ^Ra is as defined above as the substituent group in Group A for ^R5 , and ^Rb is as defined above as the substituent group in Group A for ^R2 .

As a preferred technical solution, in formula (II), formula ( ^{III), formula (IV) and formula (V), at least one Ra is -O(CH2)iR12 ,} _{and i} is 0.

As a preferred technical solution, in formula (II), formula (III), formula (IV) and formula (V),

n is 0, 1 or 2;

m is 0 or 1;

p is 1 or 2;

r is 0 or 1;

q is 1 or 2;

R ⁰ is hydrogen;

R ^b is methyl, ethyl or halogen;

each ^Ra is independently selected from the group consisting of oxo, deuterium, halogen, cyano ^, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O)R9R10 ^, -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^{-CONR13R11 , -NR13CO} - ^{R11 ,} _-NR13R11 , _-O ( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;}

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, in formula (II), formula (III), formula (IV) and formula (V),

n is 0 or 1;

m is 0 or 1;

p is 1 or 2;

r is 0 or 1;

q is 1 or 2;

R ⁰ is hydrogen;

R ^e is hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl or -OC(O)C(CH ₃ ) ₃ ;

R ^b is methyl, ethyl or halogen;

each ^Ra is independently selected from the group consisting of oxo, deuterium, halogen, cyano ^, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O)R9R10 ^, -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^{-CONR13R11 , -NR13CO} - ^{R11 ,} _-NR13R11 , _-O ( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;}

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; the substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1- C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy.

As a preferred technical solution, the compound of formula (I) is selected from the following structures:

s is 0, 1, 2, or 3;

t is 0, 1, 2, or 3;

p1 is 0, 1, or 2;

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl;

R ^e is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OC(O)C(CH ₃ ) ₃ ;

R ^a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

Each ^Ra1 and ^Rb1 are independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, _carboxyl , thiol, _-SF5 ^, -S- _CH3 , _-CONH2 , -( _CH2 ) ^iSO2R9 , _- ( _CH2 ) _iSO2NH2 , -(CH2)iSO2NR13R11 _, -( _CH2 ) ^iP (O) ^R9R10 _, - ⁽ _CH2 ) _iC (O) ^-OR11 _, - ⁽ _CH2 ) _iOC (O ^{) RxRy , -CONR13R11} _{, -NR13CO} - ^R11 _, ^-NR13R11 , _-O (CH2) _iR12 , ^- (CH2 ₎ ⁱ ) _i R ¹² ;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3- ^C6 cycloalkoxy, -NRxRy, ^-CONRxRy , ^{-NRxCO - Ry} , _-SO2Rx , _-SO2NRxRy ^{, C6-} C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R ^x and R ^y are each independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

Or R ^b1 is as defined above for the substituent group A in R ⁵ , and ^Ra1 , ^Ra1 and ^Re are independently as defined above for the substituent group A in R ² .

As a preferred technical solution, in formula (VI), formula (VII), formula (VIII), formula (VIIII) and formula (X),

s is 0, 1, or 2;

t is 0 or 1;

p1 is 1 or 2;

R ⁰ is hydrogen;

R ^e is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or -OC(O)C(CH ₃ ) ₃ ;

R ^b1 is methyl, ethyl or halogen;

R ^a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , ^- ( _CH2 ) _iSO2R9 , -( _CH2 ) _{iP (} O) ^{R9R10 ,} -( _CH2 ) ^iC (O ^{) -OR11} , -(CH2) _{iOC ( O} ) ^{RxRy , -CONR13R11} _, ^-NR13CO -R11 ^{, -NR13R11} , -O( _CH2 ) _iR12 , -( _CH2 ) ^{iR12 ;}

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, in formula (VI), formula (VII), formula (VIII), formula (VIIII) and formula (X),

s is 0 or 1;

t is 0 or 1;

p1 is 1;

R ⁰ is hydrogen;

R ^e is hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl or -OC(O)C(CH ₃ ) ₃ ;

R ^b1 is methyl, ethyl or halogen;

R ^a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl;

Each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl ^, _thiol , _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 ) _{iP (} O) ^R9R10 , ^{- (} CH2 _{) iC} (O) ^-OR11 , -( _CH2 )iOC(O ^{) RxRy} , ^-CONR13R11 , - NR ¹³ CO-R ¹¹ , -NR ¹³ R ¹¹ , -O(CH ₂ ) _i R ¹² , -(CH ₂ ) _i R ¹² ;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; the substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy.

As a preferred technical solution, in formula (VI) and formula (VII), at least one ^Ra1 is -O( _CH2 ) _iR12 , ^and i is 0. As a preferred technical solution, the compound of formula (I) is selected from the following structures:

s is 0, 1, 2, or 3;

t is 0, 1, 2, or 3;

R ⁰ is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl;

each ^Ra1 and ^Rb1 are independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, _carboxyl , thiol, _-SF5 ^, -S- _CH3 , _-CONH2 , -( _CH2 ) ^iSO2R9 , _- ( _CH2 ) _iSO2NH2 , -(CH2)iSO2NR13R11 _, -( _CH2 ) ^{iP (} O)R9R10 _, - ⁽ _CH2 ) _iC (O) ^-OR11 _, - ⁽ _CH2 ) _iOC (O ^{)R11 , -CONR13R11} _{, -NR13CO} -R11 _, ^-NR13R11 , _-O ( _CH2 ) ^iR12 , ^- ( _CH2 ) ⁱ _i R ¹² ;

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

Or R ^b1 is as defined above for the substituent group A in R ⁵ , and ^Ra1 , ^Ra1 and ^Re are independently as defined above for the substituent group A in R ² .

As a preferred technical solution, in formula (XI) and formula (XII),

s is 0, 1, or 2;

t is 0, 1, or 2;

R ⁰ is hydrogen;

R ^b1 is methyl, ethyl or halogen;

R ^a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O) ^{R9R10 ,} -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^-CONR13R11 _, ^{-NR13CO - R11 ,} _-NR13R11 , -O( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;}

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B;

Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S.

As a preferred technical solution, in formula (XI) and formula (XII),

s is 0, 1, or 2;

t is 0, 1, or 2;

p1 is 1;

R ⁰ is hydrogen;

R ^b1 is methyl, ethyl or halogen;

R ^a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl;

each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O) ^{R9R10 ,} -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^-CONR13R11 _, ^{-NR13CO - R11 ,} _-NR13R11 , -O( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;}

i is 0, 1, 2, or 3;

^R9 and ^R10 are independently hydrogen or C1-C6 alkyl;

R ¹³ is hydrogen or C1-C6 alkyl;

R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; the substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy.

As a preferred technical solution, in formula ( ^XI ) and formula (XII), at least one ^Ra1 is -O( _CH2 ) _iR12 , and i is 0.

As a preferred technical solution, the compound represented by formula (I) is selected from the following compounds:

The present invention also provides a method for preparing the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, including the following methods:

Method 1:

Step 1: Compound a-1 undergoes nucleophilic substitution or Mitsunobu reaction with compound R ¹ -Z ² to obtain compound a-2; wherein R ¹ is as defined above; Z ¹ is selected from Cl, Br, I; Z ² is selected from Cl, Br, I, OTf, OH;

Step 2: Compound a-2 and compound a-3 undergo Suzuki coupling reaction to obtain compound a-4; wherein R ² is as defined above;

Step 3: Compound a-4 undergoes electrophilic halogenation reaction with a halogenating agent to obtain compound a-5; wherein Z ³ is selected from Cl, Br, and I;

Step 4: Compound a-5 is subjected to metal-catalyzed hydrogenation conditions or metal organic reagents to remove a halogen molecule to obtain compound a- 6; the metal may be Pd; the metal organic reagent may be ethylmagnesium bromide;

Step 5: Compound a-6 and compound a-7 undergo metal-catalyzed coupling reaction to obtain compound a-8; X ¹ , X ² , X ³ , and X ⁴ are as defined above; Z ⁴ is a C1-C6 alkyl group; the metal reagent may be a reagent containing Pd or Cu, such as a palladium reagent;

Step 6: Compound a-8 is subjected to alkaline or acidic conditions to obtain compound a; the alkaline conditions may be carried out in the presence of an inorganic base (such as LiOH, NaOH); the acidic conditions may be carried out in the presence of trifluoroacetic acid or hydrochloric acid.

Method 2:

Step 1: Compound b-1 undergoes nucleophilic substitution or Mitsunobu reaction with compound R ¹ -Z ² to obtain compound b-2; R ¹ is as defined above; Z ¹ is selected from Cl, Br, I; Z ² is selected from Cl, Br, I, OTf, OH;

Step 2: Compound b-2 and compound b-3 undergo Suzuki coupling reaction to obtain compound b-4; wherein R ² is as defined above;

Step 3: Compound b-4 undergoes nitro reduction to obtain aminoimidazole compound b-5;

Step 4: Compound b-5 and compound b-6 undergo metal-catalyzed coupling reaction or direct nucleophilic substitution to obtain compound b-7; X ¹ , X ² , X ³ , and X ⁴ are as defined above; Z ⁵ is selected from Cl, Br, I, and OTf; Z ⁴ is a C1-C6 alkyl group; the metal may be a metal reagent, and the reagent may be a reagent containing Pd or Cu, such as a palladium reagent;

Step 5: Compound b-7 is subjected to alkaline or acidic conditions to obtain compound b; the alkaline conditions may be carried out in the presence of an inorganic base (such as LiOH, NaOH); the acidic conditions may be carried out in the presence of trifluoroacetic acid or hydrochloric acid.

Method 3:

Step 1: Compound c-1 undergoes Chan-Lam reaction with compound R ² (OH) ₂ to obtain compound c-2, or c-1 undergoes nucleophilic substitution or Mitsunobu reaction with compound R ² Z ² to obtain compound c-2; R ⁰ and R ² are as defined above; Z ¹ is selected from Cl, Br, I; Z ² is selected from Cl, Br, I, OTf, OTs, OH;

Step 2: Compound c-2 and compound c-3 undergo a metal-catalyzed coupling reaction to obtain compound c-4; R ^c and R ^c' are each independently selected from H and C1-C4 alkyl;

Step 3: Compound c-4 is subjected to reduction of carbon-carbon double bonds under hydrogenation conditions to obtain compound c-5; R ¹ is CH ₂ CH(R ^c )R ^c' ; the hydrogenation conditions may be carried out in the presence of PtO ₂ /H ₂ ;

Step 4: Compound c-5 and compound c-6 undergo metal-catalyzed coupling reaction to obtain compound c-7; X ¹ , X ² , X ³ , and X ⁴ are as defined above; Z ⁴ is a C1-C6 alkyl group; the metal may be a metal reagent or a reagent containing Pd or Cu, such as a palladium reagent;

Step 5: Compound c-7 is subjected to alkaline or acidic conditions to obtain compound c; the alkaline conditions may be carried out in the presence of an inorganic base (such as LiOH, NaOH); the acidic conditions may be carried out in the presence of trifluoroacetic acid or hydrochloric acid.

The present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof and pharmaceutical excipients.

In the composition, the amount of the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof can be an effective therapeutic amount.

The present invention also provides a use of the above-mentioned compound as shown in formula (I), its isotope-labeled product, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of eIF4E inhibitors (such as in vivo or in vitro) or drugs; the drug is a drug for treating and/or preventing diseases by inhibiting eIF4E.

The present invention also provides the use of the above-mentioned compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and/or preventing cancer.

The cancer is preferably breast cancer.

The present invention also provides a method for treating and/or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the compound of formula (I), its isotope label, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof.

The cancer is preferably breast cancer.

The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

The term "solvate" refers to a substance formed by the combination of a compound and a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

The term "pharmaceutically acceptable salt solvate" refers to a substance formed by combining a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of the solvent may be stoichiometric or non-stoichiometric. Quantitative.

A "-" at the end of a group means that the group is attached to the rest of the molecule through that site. For example, CH3 _- C(=O)- refers to an acetyl group.

When the group valence bond has a wavy line When, for example, The wavy line indicates the point of attachment of the group to the rest of the molecule.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, replacing a methylene group with a carbonyl group.

The term "alkyl" refers to a linear or branched, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₁ -C ₆ ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "alkoxy" refers to the group R ^X -O-, where R ^X is defined as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C ₂ -C ₆ ) and having one or more (e.g., one, two, or three) carbon-carbon sp ² double bonds. Alkenyl groups include, but are not limited to, vinyl, wait.

The term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having a specified number of carbon atoms (e.g., C3-C12, C3-C8, C3-C6), including monocyclic and bicyclic structures such as fused rings, bridged rings, and spiro rings. Cycloalkyl groups include, but are not limited to: wait.

The term "cycloalkenyl" refers to an alicyclic hydrocarbon group having a specified number of carbon atoms (e.g., C3-C12, C3-C8, C3-C6) and containing 1, 2 or 3 double bonds. Cycloalkyl groups include, but are not limited to: wait.

The term "cycloalkoxy" refers to the group R ^Y -O-, where R ^Y is defined as the term "cycloalkyl". Cycloalkoxy includes, but is not limited to, cyclopropyloxy and the like.

The term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of carbon atoms (e.g., C ₆ -C ₁₀ ), which is a single ring or multiple rings (e.g., 2 or 3). When it is a multiple ring, the single rings share two atoms and one bond, and each ring has aromaticity. Aryl includes, but is not limited to, phenyl, naphthyl, etc.

In the present invention, the term "heterocyclic group" refers to a non-aromatic cyclic group containing at least one carbon atom and at least one (e.g., 1-3) ring heteroatom selected from N, O, and S, wherein the sulfur atom may be optionally oxidized or aminated. Examples of "heterocyclic groups" include cycloalkyl groups as defined in the present invention in which one or more ring carbon atoms are selected from -O-, -N=, -NR-, -S-, -S(=O)- and -S(=O) _2- , wherein R is hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). "Heterocyclic group" includes monocyclic and bicyclic structures such as fused rings, bridged rings, spiro rings, etc. and may be partially or completely saturated, such as 4-10 membered Saturated or unsaturated heterocyclic group, 4-6-membered saturated or unsaturated heterocyclic group, 3-8-membered heterocyclic group, 3-6-membered heterocyclic group, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, oxhexyl, azetidinyl, oxirane, aziridine, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxetanyl, etc. For example, the heterocyclic group of the present invention can be preferably selected from the following groups:

In the present invention, the term "heteroaryl" refers to a monocyclic or bicyclic or condensed polycyclic aromatic hydrocarbon group having a specified number of ring atoms (e.g., 5-10 members), which contains at least one (e.g., 1-3) ring heteroatom independently selected from N, O and S (e.g., N) in the ring, and the remaining ring atoms are carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolyl, isoquinolyl, etc.

The term "isotope label" refers to an isotope-labeled compound in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally occurring in nature, compared to a nitrogen-containing compound as shown in formula (I). Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or prodrugs thereof are within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example compounds incorporating radioactive isotopes (such as ³ H and ¹⁴ C), can be used for drug and/or substrate tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (ie, ² H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. The compounds of the invention as claimed in the claims may be specifically defined as being substituted with deuterium or tritium. Furthermore, the presence of hydrogen in a substituent without the term deuterium or tritium being separately listed does not exclude deuterium or tritium, but may also include deuterium or tritium.

The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the "Pharmacopoeia of the People's Republic of China (2020 Edition)" and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

The term "treating" refers to removing the cause or alleviating the symptoms.

The term "prevention" refers to reducing the risk of developing a disease.

The term "patient" refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

The term "PG" represents a protecting group, such as a Boc protecting group and the like.

On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

The positive improvement effect of the present invention is that the compounds of the present invention have better inhibitory activity on eIF4E.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the immunoblotting results of the m7GTP pull-down experiment in ZR-75-1 cells.

Figure 2 shows the results of immunoblotting experiments on ZR-75-1 cells.

FIG3 is a tumor growth curve of the ZR-75-1 human breast cancer orthotopic xenograft model.

FIG. 4 shows the relative body weight changes of mice in the ZR-75-1 human breast cancer orthotopic xenograft model.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

In each example, ¹ HNMR was recorded by BRUKER AVANCE NEO 400 MHz, JNM-ECZ400s NMR, and chemical shifts were expressed in δ (ppm); LCMS was recorded by Shimadzu LC-20AD, Agilent 1260 and Agilent 1200 mass spectrometers; preparative HPLC separation was performed using WATERS Autop, Shimadzu LC20AR liquid chromatograph.

In the following experimental descriptions, the following abbreviations may be used:

Preparation of intermediate INT-1

Step 1: 2-amino-5-(thiophen-2-yl)nicotinate methyl ester

Under nitrogen protection, thiophene-2-boronic acid pinacol ester INT-1-1 (9.09 g, 43.3 mmol) and 2-amino-5-bromonicotinoic acid methyl ester INT-1-2 (5.00 g, 21.6 mmol) were dissolved in 1,4-dioxane (50 mL) and water (30 mL), tetrakistriphenylphosphine palladium (2.50 g, 2.16 mmol) and sodium carbonate (6.88 g, 64.9 mmol) were added, and the system was reacted at 90 ° C for 16 hours. The reaction solution was cooled, water (500 mL) was added, and it was extracted with ethyl acetate (300 mL × 2). The organic phase was washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (PE: EA = 1: 1) to obtain the product 2-amino-5-(thiophen-2-yl) nicotinate methyl ester INT-1 (3.80 g, yield 74.9%, yellow solid). LC-MS calc.for C ₁₁ H ₁₁ N ₂ O ₂ S[M+1] ⁺ :m/z=235.1; Found: 235.1.

Preparation of intermediate INT-2

Step 1: 2-Chloro-5-(thiophen-2-yl)nicotinate methyl ester

Under nitrogen protection, thiophene-2-boronic acid pinacol ester INT-1-1 (419 mg, 2.00 mmol) and 2-chloro-5-bromonicotinoic acid methyl ester INT-2-2 (500 mg, 2.00 mmol) were dissolved in tetrahydrofuran (5 mL) and water (3 mL), tetrakistriphenylphosphine palladium (231 mg, 200 μmol) and sodium carbonate (635 mg, 5.99 mmol) were added, and the system was reacted at 50 ° C for 6 hours. The reaction solution was cooled, water (10 mL) was added, and ethyl acetate was extracted (10 mL×2), the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, concentrated, and purified by column chromatography (PE:EA＝3:1) to obtain the product 2-Chloro-5-(thiophen-2-yl)nicotinate methyl ester INT-2 (230 mg, yield 45.3%, yellow solid). LC-MS calc.for Ｃ ₁₁ H ₉ ClNO ₂ S[M+1] ⁺ :m/z＝254.0；Found:254.0.

Example 1: 2-(2-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-1)

Step 1: 1-isobutyl-2-bromoimidazole

Under nitrogen protection, 2-bromo-1H-imidazole 1-1 (5.00 g, 34.0 mmol), 1-iodo-2-methylpropane (18.8 g, 102 mmol) and tetrahydrofuran (50 mL) were added to the reaction flask, and then sodium hydrogen (4.08 g, 102 mmol, 60%) was added in batches. After stirring at 50°C for 6 hours, the reaction mixture was poured into water and extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EA＝10:1) to obtain 1-isobutyl-2-bromoimidazole 1-2 (3.20 g, yield 46.3%, yellow liquid). LC-MS calc.for C ₇ H ₁₂ BrN ₂ [M+1] ⁺ :m/z＝203.0/205.0；Found:203.0/205.0.

Step 2: 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutylimidazole

Under nitrogen protection, tetrakis(triphenylphosphine)palladium (1.82g, 1.58mmol) and sodium carbonate (3.34g, 31.5mmol) were added to a mixed solution of 1-isobutyl-2-bromoimidazole 1-2 (3.19g, 15.7mmol) and [3-chloro-4-(2-methoxyethoxy)phenyl]boronic acid 1-3 (4.36g, 18.9mmol) in toluene (30mL), methanol (15mL) and water (15mL) under nitrogen protection, and the system was stirred at 100°C for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EA=10:1) to obtain 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutylimidazole 1-4 (4.45 g, yield 91.7%, yellow solid). LC-MS calc.for C ₁₆ H ₂₂ ClN ₂ O ₂ [M+1] ⁺ :m/z=309.1;Found:309.2.

Step 3: 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4,5-diiodo-1-isobutylimidazole

2-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutylimidazole 1-4 (4.02 g, 13.0 mmol), DMF (40 mL) and N-iodosuccinimide (14.6 g, 65.1 mmol) were added to the reaction flask in sequence, and the system was stirred at 90 ° C for 18 h. The reaction solution was cooled, water was added, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE: EA = 10: 1) to obtain 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4,5-diiodo-1-isobutylimidazole 1-5 (2.60 g, yield 35.6%, yellow solid). LC-MS calc.for C ₁₆ H ₂₀ ClI ₂ N ₂ O ₂ [M+1] ⁺ :m/z=560.9; Found: 561.0.

Step 4: 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4-iodo-1-isobutylimidazole

Under nitrogen protection, 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4,5-diiodo-1-isobutylimidazole 1-5 (2.41 g, 4.30mmol) and tetrahydrofuran (25mL), the system was stirred at -15℃ for 10min, then ethylmagnesium bromide tetrahydrofuran solution (6.40mL, 6.40mmol, 1mol/mL) was added dropwise, and stirring was continued for 1 hour after the addition was completed. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (40mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (PE:EA＝10:1) to obtain 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4-iodo-1-isobutylimidazole 1-6 (880mg, yield 47.0%, white solid). LC-MS calc.for C ₁₆ H ₂₁ ClIN ₂ O ₂ [M+1] ⁺ :m/z＝435.0；Found:435.1.

Step 5: 2-(2-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4-iodo-1-isobutylimidazole 1-6 (50.0 mg, 115 μmol), 2-amino-5-(thiophen-2-yl)pyridine-3-carboxylic acid methyl ester INT-1 (27.0 mg, 115 μmol), 8-hydroxyquinoline (8.34 mg, 57.5 μmol), cuprous iodide (11.0 mg, 57.5 μmol), cesium carbonate (75.0 mg, 230 μmol) and DMF (0.5 mL) were added sequentially into a microwave tube. After sealing, the tube was stirred at 100 °C for 1 hour under microwave irradiation, and the reaction mixture was added 6 times in parallel. The reaction mixture was combined, adjusted to pH = 2-3 with 1N dilute hydrochloric acid, extracted with ethyl acetate (10 mL × 3), and the organic phase was dried over sodium sulfate, concentrated, and purified by preparative column to obtain 2-(2-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid Cpd-1 (5.00 mg, yield 8.25%, yellow solid). LC-MS calc.for C ₂₆ H ₂₈ ClN ₄ O ₄ S[M+H] ⁺ :m/z＝527.1；Found:527.2； ¹ H NMR(400MHz,DMSO-d ₆ )δ11.00(s,1H),8.73(s,1H),8.36(s,1H),7.67(d,J＝4Hz,1H),7.56-7.48(m,4H),7.26(d,J＝8Hz,1H),7.15-7.13(m ,1H),4.27-4.24(m,2H),3.88(d,J＝8Hz,2H),3.74-3.71(m,2H),3.32(s,3H),2.02-1.92(m,1H),0.77(d,J＝8Hz,6H).

Example 2: 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-2)

Step 1: 3,5-dibromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]pyrazole

Pyridine (2.15 mL, 26.6 mmol) and copper acetate (2.42 g, 13.3 mmol) were added to a toluene (30 mL) solution of compound 2-1 (2.00 g, 8.85 mmol) and compound 1-3 (2.04 g, 8.85 mmol), and the mixture was stirred at 90°C for 16 hours. After filtration, the filtrate was concentrated and purified by column chromatography (PE:EA=3:17) to obtain 3,5-dibromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]pyrazole 2-2 (3.17 g, yield 87.4%, white solid). LC-MS calc.for C ₁₂ H ₁₂ Br ₂ ClN ₂ O ₂ [M+H] ⁺ :m/z＝408.9/410.9/412.9；Found:408.9/410.9/412.9.

Step 2: 3-Bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-(2-methylprop-1-en-1-yl)pyrazole

Under nitrogen protection, compound 2-3 (814 mg, 4.47 mmol), Pd(dppf)Cl ₂ (811 mg, 1.12 mmol) and potassium phosphate (2.37 g, 11.2 mmol) were added to a solution of compound 2-2 (2.29 g, 5.59 mmol) in tetrahydrofuran (10 mL) and water (2 mL). The system was heated at 70 °C. Stir for 16 hours. Cool, add water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and purify by column chromatography (PE:EA＝1:9) to obtain 3-bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-(2-methylprop-1-enyl)pyrazole 2-4 (1.58 g, yield 91.6%, white solid). LC-MS calc.for C ₁₆ H ₁₉ BrClN ₂ O ₂ [M+H] ⁺ :m/z＝385.0/387.0；Found:385.0/387.0.

Step 3: 3-Bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazole

Platinum dioxide (94.2 mg, 415 μmol) was added to a solution of compound 2-4 (795 mg, 2.07 mmol) in methanol (3 mL) at 0°C, and the mixture was stirred for half an hour in a hydrogen atmosphere. After filtration, the filtrate was concentrated and purified by column chromatography (PE:EA=1:9) to obtain 3-bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazole 2-5 (672 mg, yield 83.7%, colorless oil). LC-MS calc.for C ₁₆ H ₂₁ BrClN ₂ O ₂ [M+H] ⁺ :m/z＝387.0/389.0；Found:387.0/389.0.

Step 4: 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, Xantphos (119 mg, 206 μmol), tris(dibenzylideneacetone)dipalladium (94.5 mg, 103 μmol) and cesium carbonate (420 mg, 1.29 mmol) were added to a toluene (10 mL) solution of compound 2-5 (200 mg, 516 μmol) and compound INT-1 (145 mg, 619 μmol), and the mixture was stirred at 100 ° C for 10 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (PE: EA = 1: 3) to obtain 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate methyl ester 2-6 (190 mg, yield 68.1%, yellow solid). LC-MS calc.for C ₂₇ H ₃₀ ClN ₄ O ₄ S[M+H] ⁺ :m/z=541.2; Found: 541.2.

Step 5: 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Lithium hydroxide (45.2 mg, 1.89 mmol) was added to a mixed solution of compound 2-6 (170 mg, 314 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and the mixture was stirred at 75°C for 1 hour. The mixture was concentrated, and hydrochloric acid (1.5 N) was added to adjust the pH to 5-6, and dichloromethane/methanol = 10/1 (10 mL × 3) was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparation to obtain 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid Cpd-2 (95.2 mg, yield 57.5%, yellow solid). LC-MS calc.for C ₂₆ H ₂₈ ClN ₄ O ₄ S[M+H] ⁺ :m/z＝527.1; Found: 527.4; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.94(s,1H),10.69(s,1H),8.81(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7. 60-7.52(m,3H),7.42(dd,J＝8.8,2.6Hz,1H),7.28(d,J＝8.9Hz,1H),7.16(dd,J ＝4.9,3.8Hz,1H),6.90(s,1H),4.27-4.25(m,2H),3.74-3.72(m,2H),3.36(s,3 H), 2.56 (d, J = 7.0Hz, 2H), 1.79 (dp, J = 13.6, 6.8Hz, 1H), 0.85 (d, J = 6.6Hz, 6H).

Example 3: 2-((2-(3-ethoxyphenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-3)

Step 1: 1-isobutyl-2-bromo-4-nitroimidazole

Under nitrogen protection, compound 3-1 (2.00 g, 10.4 mmol), isobutyl bromide (2.88 g, 15.6 mmol), potassium carbonate (4.32 g, 31.3 mmol) and acetonitrile (20 mL) were added to the reaction bottle in sequence, and the system was stirred at 90 ° C for 12 hours. After cooling to room temperature, the reaction solution was filtered, concentrated, and saturated aqueous ammonium chloride solution (20 mL) was added, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 3: 1) to obtain compound 1-isobutyl-2-bromo-4-nitroimidazole 3-2 (2.10 g, yield 81.4%, yellow solid). LC-MS calc.for C ₇ H ₁₁ BrN ₃ O ₂ [M+H] ⁺ :m/z＝248.0/250.0; Found: 248.0/250.0.

Step 2: 1-isobutyl-2-(3-ethoxyphenyl)-4-nitroimidazole

Under nitrogen protection, compound 3-2 (1.98 g, 8.00 mmol), compound 3-3 (1.34 g, 8.00 mmol), tetrakis(triphenylphosphine)palladium (1.86 g, 1.61 mmol) and cesium carbonate (6.57 g, 20.2 mmol) were dissolved in a mixed solvent of dioxane and water (35 mL, 6:1), and then stirred at 100 ° C for 20 hours. After cooling to room temperature, the reaction solution was filtered and concentrated, and the residue was added with saturated aqueous ammonium chloride solution (30 mL), and then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed twice with saturated sodium chloride water, and then dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 3: 1) to obtain compound 3-4 (2.00 g, yield 86.5%, white solid). LC-MS calc.for C ₁₅ H ₂₀ N ₃ O ₃ [M+H] ⁺ :m/z=290.1; Found: 290.2.

Step 3: 1-isobutyl-2-(3-ethoxyphenyl)-4-aminoimidazole

Compound 3-4 (1.50 g, 5.18 mmol), palladium hydroxide (873 mg, 6.22 mmol) and methanol (10 mL) were added to the reaction flask, and the air was replaced with hydrogen three times. The reaction was stirred at 35 ° C for 1 hour. After cooling to room temperature, a methanol solution of hydrochloric acid (5 mL, 4N) was added and stirred for 10 minutes. The reaction solution was filtered and concentrated to obtain a crude product 3-5 (1.20 g, yield 89.3%, yellow liquid), which was directly used for the next step. LC-MS calc.for C ₁₅ H ₂₂ N ₃ O[M+H] ⁺ :m/z＝260.2；Found:260.3.

Step 4: 2-((2-(3-ethoxyphenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 3-5 (1.00 g, 3.86 mmol), Xantphos Pd G2 (1.03 g, 1.16 mmol), cesium carbonate (3.77 g, 11.6 mmol) and compound INT-2 (978 mg, 3.86 mmol) were dissolved in toluene (15 mL), and the system was stirred at 100 ° C for 10 hours. Cool to room temperature, add saturated aqueous ammonium chloride solution (30 mL), extract with ethyl acetate (30 mL × 3), the combined organic phase is washed twice with saturated aqueous sodium chloride solution, and then dried with anhydrous sodium sulfate. The crude product obtained after filtration and concentration is subjected to column chromatography (PE: EA = 3: 1) to obtain compound 3-6 (700 mg, yield 38.0%, yellow solid). LC-MS calc. for C ₂₆ H ₂₉ N ₄ O ₃ S [M + H] ⁺ : m / z = 477.2; Found: 477.3.

Step 5: 2-((2-(3-ethoxyphenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 3-6 (650 mg, 1.36 mmol) and lithium hydroxide (163 mg, 6.82 mmol) were dissolved in a mixed solution of methanol (3 mL), tetrahydrofuran (3 mL) and water (3 mL). The system was stirred at 70°C for 1 hour. The reaction solution was adjusted to pH 5 with 1N hydrochloric acid. Solid precipitation was observed. The solid was collected by filtration and then dissolved. Compound Cpd-3 (250 mg, yield 39.7%, yellow solid) was prepared and purified directly by reverse phase. LC-MS calc.for C ₂₅ H ₂₇ N ₄ O ₃ S[M+H] ⁺ :m/z＝463.2；Found:463.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ10.64(s,1H),8.83(d,J＝2.5Hz,1H),8.43(t,J＝2.3Hz,1H),7.83(s,1H),7.58(d,J＝6.2Hz,2H),7.49(t,J＝8.0Hz,1H),7.26(d,J＝8.6H z,2H),7.20-7.10(m,2H),4.12(q,J＝7.4Hz,2H),4.01(d,J＝7.3Hz,2H),2.05-1.97(m,1H),1.36(t,J＝6.9Hz,3H),0.79(d,J＝6.5Hz,6H).

Example 4: 2-[[1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-4)

Step 1: 3,5-dibromo-1-[3-(2,2-difluoroethoxy)phenyl]pyrazole

Compound 2-1 (2.40 g, 10.6 mmol) and 4-1 (2.36 g, 11.7 mmol) were dissolved in toluene (30 mL), pyridine (2.57 mL, 31.9 mmol) and copper acetate (2.89 g, 15.9 mmol) were added at room temperature, and the system was stirred at 90 ° C for 12 hours in an oxygen atmosphere. TLC showed that the reaction was complete. Filter and concentrate under reduced pressure to obtain a crude compound, which was purified by column chromatography (PE: EA = 5: 1) to obtain compound 4-2 (2.90 g, yield 71.6%, colorless liquid). LCMS calc. for C ₁₁ H ₉ Br ₂ F ₂ N ₂ O [M + H] ⁺ : m / z = 380.9/382.9/384.9; Found: 380.9/383.0/384.9.

Step 2: 3-Bromo-1-[3-(2,2-difluoroethoxy)phenyl]-5-(22-methylprop-1-en-1-yl)pyrazole

Compound 4-2 (2.90 g, 7.59 mmol) and 2-3 (1.66 g, 9.11 mmol) were dissolved in tetrahydrofuran (8 mL) and water (2 mL), and Pd(dppf)Cl ₂ (555 mg, 759 μmol) and potassium phosphate (3.22 g, 15.2 mmol) were added at room temperature. The nitrogen atmosphere was replaced three times, and the system was stirred at 70°C for 2 hours. The reaction solution was extracted with ethyl acetate (20 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (PE:EA＝20:1) to obtain compound 4-3 (2.50 g, yield 92.5%, colorless liquid). LCMS calc.for C ₁₅ H ₁₆ BrF ₂ N ₂ O[M+H] ⁺ :m/z＝357.0/359.0；Found:357.0/359.1.

Step 3: 3-Bromo-1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutylpyrazole

Compound 4-3 (1.00 g, 2.80 mmol) was dissolved in methanol (20 mL), and platinum dioxide (127 mg, 560 μmol) was added. The air was replaced by hydrogen three times, and then the system was stirred at 0°C for 0.5 hours. Filter, wash the solid with methanol (10 mL), and concentrate the filtrate under reduced pressure to obtain a crude product, which was subjected to column chromatography (PE:EA＝4:1) to obtain compound 4-4 (750 mg, yield 74.8%, colorless liquid). LCMS calc.for C ₁₅ H ₁₈ BrF ₂ N ₂ O[M+H] ⁺ :m/z＝359.1/361.1；Found:359.0/361.1.

Step 4: 2-[[1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 4-4 (180 mg, 501 μmol) and INT-1 (129 mg, 551 μmol) were dissolved in toluene (3 mL), t-BuBrettphos Pd G3 (42.8 mg, 50.1 μmol) and cesium carbonate (407 mg, 1.25 mmol) were added at room temperature, and the system was stirred for 2 hours at 120 ° C under nitrogen atmosphere. Filter and concentrate under reduced pressure to obtain a crude product, which was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 4-5 (250 mg, yield 97.4%, yellow solid). LCMS calc. for C ₂₆ H ₂₇ F ₂ N ₄ O ₃ S [M + H] ⁺ : m / z = 513.2; Found: 513.3.

Step 5: 2-[[1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 4-5 (270 mg, 527 μmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide (100 mg, 4.21 mmol) was added at room temperature, and the system was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with 2N hydrochloric acid, and extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was purified by reverse phase preparation to obtain compound Cpd-4 (112 mg, yield 42.6%, yellow solid). LCMS calc.for C ₂₅ H ₂₅ F ₂ N ₄ O ₃ S[M+H] ⁺ :m/z＝499.2; Found: 499.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.95 (s, 1H), 8.77 (d, J＝2.6Hz, 1H), 8.38 (d, J＝ 2.6Hz,1H),7.56-7.36(m,3H),7.17-7.04(m,4H),6.92(s,1H),6.55-6.26(m,1H), 4.57-4.30(m,2H),2.62(d,J＝7.1Hz,2H),1.94-1.71(m,1H),0.84(d,J＝6.6Hz,6H).

Example 5: 2-((5-isobutyl-1-(3-methylphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-5)

Step 1: 3,5-dibromo-1-(3-methylphenyl)-1H-pyrazole

3,5-Dibromo-1H-pyrazole 2-1 (500 mg, 2.21 mmol) and 3-methylphenylboronic acid 5-1 (331 mg, 2.44 mmol) were dissolved in toluene (10 mL), pyridine (0.535 mL, 6.64 mmol) and copper acetate (603 mg, 3.32 mmol) were added, and the system was stirred at 90 ° C for 16 hours under an oxygen atmosphere. After the reaction was completed, it was cooled to room temperature, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude compound, which was purified by column chromatography (PE: EA = 10: 1) to obtain compound 5-2 (583 mg, yield 83.6%, yellow liquid). LCMS calc. for C ₁₀ H ₉ Br ₂ N ₂ [M+H] ⁺ : m/z = 314.9/316.9/318.9; Found: 315.2/317.2/319.2.

Step 2: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(3-methylphenyl)-1H-pyrazole

Compound 5-2 (1.00 g, 3.16 mmol) and 2-3 (576 mg, 3.16 mmol) were dissolved in tetrahydrofuran (10 mL) and water (2 mL), potassium phosphate (1.34 g, 6.33 mmol) and Pd(dppf)Cl ₂ (459 mg, 633 μmol) were added, and the system was stirred at 70°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was cooled, water (25 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and purified by column chromatography (PE:EA=19:1) to obtain compound 5-3 (552 mg, yield 60.2%, colorless liquid). LCMS calc.for C ₁₄ H ₁₆ BrN ₂ [M+H] ⁺ :m/z=291.0/293.0;Found:291.3/293.3.

Step 3: 3-Bromo-5-isobutyl-1-(3-methylphenyl)-1H-pyrazole

Compound 5-3 (650 mg, 2.23 mmol) was dissolved in methanol (10 mL), and platinum dioxide (101 mg, 446 μmol) was added. The system was stirred at 0°C for 30 minutes under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated, and purified by column chromatography (PE:EA=9:1) to obtain compound 5-4 (600 mg, yield 92.1%, colorless liquid). LCMS calc.for C ₁₄ H ₁₈ BrN ₂ [M+H] ⁺ :m/z＝293.1/295.1；Found:293.3/295.3.

Step 4: 2-(5-isobutyl-1-(3-methylphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Compound 5-4 (420 mg, 1.43 mmol) and INT-1 (403 mg, 1.72 mmol) were dissolved in toluene (2 mL), t-BuBrettphos Pd G3 (122 mg, 143 μmol) and cesium carbonate (933 mg, 2.86 mmol) were added, and the system was stirred at 120 ° C for 16 hours under nitrogen protection. After the reaction was completed, the residue was filtered and concentrated, and the residue was dissolved in dichloromethane (10 mL) and purified by column chromatography (PE: EA = 3: 1) to obtain compound 5-5 (100 mg, yield 15.6%, yellow solid). LCMS calc. for C ₂₅ H ₂₇ N ₄ O ₂ S [M + H] ⁺ : m / z = 447.2; Found: 447.4.

Step 5: 2-((5-isobutyl-1-(3-methylphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 5-5 (100 mg, 224 μmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide (32.2 mg, 1.34mmol), the system was stirred at 50℃ for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 4, extracted with dichloromethane (10mL), and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by preparative column to obtain compound Cpd-5 (70.0mg, yield 72.3%, yellow solid). LCMS calc.for C ₂₄ H ₂₅ N ₄ O ₂ S[M+H] ⁺ :m/z＝433.2；Found:433.4； ¹ H NMR (400MHz, DMSO-d ₆ )δ13.92(s,1H),10.66(s,1H),8.81(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.54(t,J＝4.3Hz,2H),7.39(t,J＝7.7Hz,1H),7.31-7.30(m ,1H),7.28-7.21(m,2H),7.17-7.13(m,1H),6.91(s,1H),2.59(d,J＝7.2Hz,2H),2.39(s,3H),1.83-1.77(m,1H),0.85(d,J＝6.6Hz,6H).

Example 6: 2-((5-isobutyl-1-(3-ethoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-6)

Step 1: 3,5-dibromo-1-(3-ethoxyphenyl)-1H-pyrazole

Under oxygen atmosphere, compound 2-1 (5.00 g, 22.1 mmol), compound 6-1 (3.67 g, 22.1 mmol), copper acetate (6.03 g, 33.2 mmol) and pyridine (5.37 mL, 66.4 mmol) were dissolved in toluene (50 mL), and the system was stirred at 90 ° C for 16 hours. Cool to room temperature, filter the reaction solution, and filter and concentrate the crude product to obtain compound 6-2 (5.01 g, yield 65.3%, colorless liquid). LCMS calc.for C ₁₁ H ₁₁ Br ₂ N ₂ O[M+H] ⁺ :m/z＝344.9/346.9/348.9；Found:345.2/347.2/349.2.

Step 2: 3-Bromo-1-(3-ethoxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 6-2 (4.00 g, 11.6 mmol), compound 2-3 (2.32 g, 12.7 mmol), Pd(dppf)Cl ₂ (1.68 g, 2.31 mmol), potassium phosphate (4.91 g, 23.1 mmol) and a mixed solvent of tetrahydrofuran/water (35 mL, 6:1) were added to the reaction flask, and the system was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with a saturated sodium chloride aqueous solution (50 mL×2) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝10:1) to obtain compound 6-3 (2.20 g, yield 59.2%, white solid). LCMS calc.for C ₁₅ H ₁₈ BrN ₂ O[M+H] ⁺ :m/z＝321.1/323.1; Found: 321.1/323.1.

Step 3: 3-Bromo-1-(3-ethoxyphenyl)-5-isobutyl-1H-pyrazole

Under nitrogen protection, compound 6-3 (2.00 g, 6.23 mmol), platinum dioxide (282 mg, 1.25 mmol) and methanol (20.0 mL) were added to the reaction flask. The nitrogen was replaced with hydrogen three times, and the system was stirred at 0°C for 0.5 hours. After filtration, the crude product obtained after the filtrate was concentrated was subjected to column chromatography (PE:EA＝10:1) to obtain compound 6-4 (1.50 g, yield 74.7%, colorless liquid). LCMS calc.for C ₁₅ H ₂₀ BrN ₂ O[M+H] ⁺ :m/z＝323.1/325.1；Found:323.3/325.3.

Step 4: 2-((1-(3-ethoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 6-4 (1.00 g, 3.09 mmol), INT-1 (1.09 g, 4.64 mmol), t- BuBrettphos Pd G3 (1.59 g, 1.86 mmol), cesium carbonate (2.52 g, 7.73 mmol) and toluene (10 mL), the system was stirred at 120 ° C for 1 hour. Cooled to room temperature, extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product for column chromatography (PE: EA = 5: 1) to obtain compound 6-5 (300 mg, yield 20.4%, yellow solid). LCMS calc. for C ₂₆ H ₂₉ N ₄ O ₃ S [M + H] ⁺ : m / z = 477.2; Found: 477.3.

Step 5: 2-((1-(3-ethoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 6-5 (300 mg, 629 μmol) and lithium hydroxide (75.4 mg, 3.15 mmol) were dissolved in a mixed solution of methanol (2 mL), water (2 mL) and tetrahydrofuran (2 mL). The system was stirred at 70 ° C for 0.5 hours, cooled to room temperature, and the reaction solution was extracted with ethyl acetate (10 mL × 3), and then the pH of the aqueous phase was adjusted to 5 with 1N hydrochloric acid, and then extracted with dichloromethane (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by preparative purification to obtain compound Cpd-6 (125 mg, yield 42.9%, yellow solid). LCMS calc.for C ₂₅ H ₂₇ N ₄ O ₃ S[M+H] ⁺ :m/z＝463.2；Found:463.2； ¹ H NMR (400MHz,DMSO-d ₆ )δ13.90(s,1H),10.66(s,1H),8.38(d,J＝2.5Hz,1H),7.54(t,J＝4.6Hz,2H),7.40(t,J＝8.0Hz,1H),7.18-7.11(m,1H),7.05-6.95(m ,3H),6.91(s,1H),4.13-4.03(m,2H),2.60(d,J＝7.2Hz,2H),1.81(dq,J＝13.5,7.0Hz,1H),1.34(t,J＝7.0Hz,3H),0.89-0.82(m,6H).

Example 7: 2-((5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-7)

Step 1: 3,5-dibromo-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazole

Under oxygen atmosphere, compound 2-1 (3.00 g, 13.3 mmol), compound 7-1 (2.60 g, 13.3 mmol), copper acetate (3.62 g, 19.9 mmol), pyridine (3.22 mL, 39.9 mmol) and toluene (30 mL) were added to the reaction bottle, and the system was stirred at 90°C for 16 hours. Cooled to room temperature, filtered, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 7-2 (3.40 g, yield 67.9%, white solid). LCMS calc. for C ₁₂ H ₁₃ Br ₂ N ₂ O ₂ [M+H] ⁺ : m/z = 374.9/376.9/378.9; Found: 375.2/377.2/379.2.

Step 2: 3-Bromo-1-(3-(2-methoxyethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 7-2 (1.00 g, 2.66 mmol), compound 2-3 (611 mg, 3.35 mmol), Pd(dppf)Cl ₂ (390 mg, 0.530 mmol), cesium carbonate (1.73 g, 5.32 mmol) and a mixed solvent of dioxane and water (20 mL, 5:1) were added to the reaction bottle, and the system was stirred at 120°C for 2 hours. Cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (30 mL×3), the combined organic phase was washed with saturated sodium chloride aqueous solution (30 mL×2), dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝5:1) to obtain compound 7-3 (680 mg, yield 73.0%, white solid). LCMS calc.for C ₁₆ H ₂₀ BrN ₂ O ₂ [M+H] ⁺ :m/z＝351.1/353.1; Found: 351.1/353.1.

Step 3: 3-Bromo-5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazole

Compound 7-3 (520 mg, 1.48 mmol) was dissolved in methanol (10 mL), and platinum dioxide (200 mg, 0.890 mmol) was added at 0°C. The system was stirred for 4 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝5:1) to obtain compound 7-4 (360 mg, yield 69.1%, colorless liquid). LCMS calc.for C ₁₆ H ₂₂ BrN ₂ O[M+H] ⁺ :m/z＝353.1/355.1；Found:353.1/355.1.

Step 4: 2-((5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 7-4 (360 mg, 1.02 mmol), INT-1 (291 mg, 1.22 mmol), t-BuBrettphos Pd G3 (260 mg, 0.31 mmol), cesium carbonate (662 mg, 2.04 mmol) and toluene (2 mL) were added to the reaction bottle, and the system was stirred at 100 ° C for 1.5 hours. Cool to room temperature, filter, extract the filtrate with ethyl acetate (10 mL × 3), wash the combined organic phase with saturated sodium chloride aqueous solution (10 mL × 2), and then dry with anhydrous sodium sulfate. The crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 7-5 (250 mg, yield 48.4%, white solid). LCMS calc. for C ₂₇ H ₃₁ N ₄ O ₄ S [M + H] ⁺ : m / z = 507.6; Found: 507.5.

Step 5: 2-((5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 7-5 (240 mg, 0.474 mmol) and lithium hydroxide (56.7 mg, 2.37 mmol) were dissolved in a mixed solvent of tetrahydrofuran/methanol/water (2 mL, 2:1:1). The system was stirred at 70°C for 10 minutes. After the reaction solution was concentrated, 1N hydrochloric acid was added to adjust the pH value to 5, and then extracted with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, and the crude product obtained after concentration was prepared and purified to obtain Cpd-7 (113 mg, yield 48.4%, yellow solid). LCMS calc.for C ₂₆ H ₂₉ N ₄ O ₄ S[M+H] ⁺ :m/z＝493.2；Found:493.2； ¹ H NMR(400MHz,DMSO-d ₆ )δ13.93(s,1H),10.69(s,1H),8.81(d,J＝2.6Hz,1H),8.39(d,J＝2.6Hz,1H), 7.57-7.53(m,2H),7.41(t,J＝7.9Hz,1H),7.16(dd,J＝5.0,3.7Hz,1H),7.07- 6.98(m,3H),6.92(s,1H),4.21-4.10(m,2H),3.72-3.64(m,2H),3.32(s,3H) ,2.61(d,J＝7.1Hz,2H),1.81(dp,J＝13.4,6.7Hz,1H),0.85(d,J＝6.6Hz,6H).

Example 8: 2-((5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-8)

Step 1: 3,5-dibromo-1-(3-isopropoxyphenyl)-1H-pyrazole

Under oxygen atmosphere, compound 2-1 (6.27 g, 27.8 mmol), 8-1 (5.00 g, 27.8 mmol), pyridine (6.74 mL, 83.3 mmol), copper acetate (7.57 g, 41.7 mmol) and toluene (60 mL) were added to the reaction bottle, and the system was stirred at 90°C for 16 hours. Cooled to room temperature, filtered, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 10: 1) to obtain compound 8-2 (8.01 g, yield 79.9%, yellow liquid). LCMS calc. for C ₁₂ H ₁₃ Br ₂ N ₂ O [M + H] ⁺ : m / z = 358.9/360.9/362.9; Found: 359.1/361.1/363.1.

Step 2: 3-Bromo-1-(3-isopropoxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 8-2 (2.00 g, 5.55 mmol), compound 2-3 (1.21 g, 6.67 mmol), Pd(dppf)Cl ₂ (813 mg, 1.11 mmol), potassium phosphate (2.59 g, 12.2 mmol) and a mixed solvent of dioxane/water (24 mL, 5:1), the system was stirred at 80°C for 2 hours. Cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (40 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝10:1) to obtain compound 8-3 (1.01 g, yield 54.4%, colorless liquid). LCMS calc.for C ₁₆ H ₂₀ BrN ₂ O[M+H] ⁺ :m/z＝335.1/337.2；Found:335.2/337.2.

Step 3: 3-Bromo-5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazole

Under nitrogen protection, compound 8-3 (700 mg, 2.09 mmol), platinum dioxide (94.8 mg, 418 μmol) and methanol (10 mL) were added to the reaction flask. The nitrogen was replaced with hydrogen three times, and the system was stirred at 0°C for 1 hour. Filtered, the filtrate was concentrated and purified by column chromatography (PE:EA＝10:1) to obtain compound 8-4 (600 mg, yield 85.4%, colorless liquid). LCMS calc.for C ₁₆ H ₂₂ BrN ₂ O[M+H] ⁺ :m/z＝337.1/339.1；Found:337.2/339.2.

Step 4: 2-((5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 8-4 (330 mg, 978 μmol), INT-1 (229 mg, 978 μmol), t-BuBrettphos Pd G3 (167 mg, 196 μmol), cesium carbonate (797 mg, 2.45 mmol) and toluene (5 mL) were added to the reaction bottle. The system was stirred at 120 ° C for 2 hours. Cooled to room temperature, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 8-5 (320 mg, yield 66.7%, yellow solid). LCMS calc. for C ₂₇ H ₃₁ N ₄ O ₃ S [M + H] ⁺ : m / z = 491.2; Found: 491.2.

Step 5: 2-((5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 8-5 (350 mg, 713 μmol) and lithium hydroxide (103 mg, 4.28 mmol) were dissolved in a mixed solution of methanol (3 mL), water (3 mL) and tetrahydrofuran (3 mL). The system was stirred at 70°C for 1 hour and cooled to room temperature. The reaction solution was extracted with ethyl acetate (10 mL×3), and then the pH was adjusted to 5 with 1N hydrochloric acid, and then extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative purification to obtain compound Cpd-8 (140 mg, yield 41.2%, yellow solid). LCMS calc.for: C ₂₆ H ₂₉ N ₄ O ₃ S[M+H] ⁺ :m/z＝477.2；Found:477.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ13.87(s,1H),10.65(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H ),7.54(t,J＝4.4Hz,2H),7.39(t,J＝8.0Hz,1H),7.15(dd,J＝5.0,3.7Hz,1H) ,7.02-6.94(m,3H),6.91(s,1H),4.74-4.64(m,1H),2.60(d,J＝7.2Hz,2H), 1.79(dq,J＝13.6,6.8Hz,1H), 1.28(d,J＝6.0Hz,7H), 0.84(d,J＝6.6Hz,7H).

Example 9: 2-((5-isobutyl-1-(3-cyclopropyloxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-9)

Step 1: 3,5-dibromo-1-(3-cyclopropyloxyphenyl)-1H-pyrazole

In an oxygen atmosphere, compound 2-1 (2.54 g, 11.2 mmol), compound 9-1 (2.00 g, 11.2 mmol), acetic acid Copper (3.06 g, 16.9 mmol), pyridine (2.72 mL, 33.7 mmol) and toluene (30 mL), the system was stirred at 90 ° C for 3 hours. Cooled to room temperature, the reaction solution was filtered, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 9-2 (2.60 g, yield 64.8%, white solid). LCMS calc. for C ₁₂ H ₁₁ Br ₂ N ₂ O [M + H] ⁺ : m / z = 356.9/358.9/360.9; Found: 357.1/359.1/361.1.

Step 2: 3-Bromo-1-(3-cyclopropyloxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 9-2 (1.00 g, 2.79 mmol), compound 2-3 (610 mg, 3.35 mmol), Pd(dppf)Cl ₂ (410 mg, 560 μmol), potassium phosphate (1.30 g, 6.14 mmol) and a mixed solvent of dioxane/water (20 mL, 5:1) were added to the reaction flask, and the system was stirred at 80°C for 2 hours. Cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (30 mL×3), the combined organic phase was washed with a saturated sodium chloride aqueous solution (30 mL×2), and then dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝5:1) to obtain compound 9-3 (820 mg, yield 88.5%, colorless liquid). LCMS calc.for C ₁₆ H ₁₈ BrN ₂ O[M+H] ⁺ :m/z＝333.1/335.1; Found: 333.1/335.1.

Step 3: 3-Bromo-1-(3-cyclopropyloxyphenyl)-5-isobutyl-1H-pyrazole

Compound 9-3 (680 mg, 2.04 mmol) was dissolved in methanol (2 mL), and platinum dioxide (140 mg, 610 μmol) was added at 0°C. The system was stirred and reacted for 0.5 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝6:1) to obtain compound 9-4 (551 mg, yield 80.8%, colorless liquid). LCMS calc.for C ₁₆ H ₂₀ BrN ₂ O[M+H] ⁺ :m/z＝335.1/337.1；Found:335.2/337.2.

Step 4: 2-((1-(3-cyclopropyloxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 9-4 (180 mg, 0.539 mmol), INT-1 (141 mg, 0.602 mmol), t-BuBrettphos Pd G3 (91.1 mg, 0.110 mmol), cesium carbonate (441 mg, 1.34 mmol) and toluene (2 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, filter, extract the filtrate with ethyl acetate (10 mL × 3), wash the combined organic phase with saturated sodium chloride aqueous solution (10 mL × 2), dry with anhydrous sodium sulfate, filter and concentrate, and the residue was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 9-5 (161 mg, yield 61.1%, yellow liquid). LCMS calc. for C ₂₇ H ₂₉ N ₄ O ₃ S [M + H] ⁺ : m / z = 489.2; Found: 489.2.

Step 5: 2-((1-(3-cyclopropyloxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 9-5 (150 mg, 310 μmol) and lithium hydroxide (73.5 mg, 3.07 mmol) were dissolved in a mixed solvent of tetrahydrofuran/methanol/water (2 mL; 2:1:1), and the system was stirred at 50°C for 0.5 hours. The reaction solution was concentrated, and 1N dilute hydrochloric acid was added to adjust the pH value to 5, then extracted with dichloromethane (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The crude product obtained after concentration was prepared and purified to obtain Cpd-9 (38.4 mg, yield 26.1%, yellow solid). LCMS calc.for C ₂₆ H ₂₇ N ₄ O ₃ S[M+H] ⁺ :m/z＝475.2; Found: 475.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.89(s,1H),10.66(s,1H),8.81(s,1H),8.39(s,1H),7.59-7.35(m,3H),7.20-7.04(m,4H),6.92(s ,1H),3.93(s,1H),2.62(d,J＝6.8Hz,2H),1.89-1.77(m,1H),0.84(dd,J＝21.3,5.9Hz,8H),0.70(s,2H).

Example 10: 2-((5-isobutyl-1-(3-(cyclopropylmethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-10)

Step 1: 3,5-dibromo-1-(3-(cyclopropylmethoxy)phenyl)-1H-pyrazole

Pyridine (2.15 mL, 26.6 mmol) and copper acetate (2.41 g, 13.3 mmol) were added to a toluene (20 mL) solution of compound 2-1 (2.00 g, 8.85 mmol) and compound 10-1 (1.70 g, 8.85 mmol), and the system was stirred at 90 ° C for 3 hours under an oxygen atmosphere. After cooling and filtration, the filtrate was concentrated and purified by column chromatography (PE: EA = 9: 1) to obtain compound 10-2 (1.97 g, yield 59.8%, yellow liquid). LCMS calc. for C ₁₃ H ₁₃ Br ₂ N ₂ O [M + H] ⁺ : m / z = 370.9/372.9/374.9; Found: 371.0/373.0/375.0.

Step 2: 3-Bromo-1-(3-(cyclopropylmethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Compound 2-3 (587 mg, 3.23 mmol), potassium phosphate (1.26 g, 5.91 mmol) and Pd(dppf)Cl ₂ (393 mg, 538 μmol) were added to a mixed solution of compound 10-2 (1.00 g, 2.69 mmol) in 1,4-dioxane (10 mL) and water (2 mL), and the system was stirred at 80°C for 1.5 hours under a nitrogen atmosphere. After cooling, ethyl acetate (15 mL) was added to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA=19:1) to obtain compound 10-3 (787 mg, yield 84.5%, yellow liquid). LCMS calc.for C ₁₇ H ₂₀ BrN ₂ O[M+H] ⁺ :m/z＝347.1/349.1; Found: 347.1/349.1.

Step 3: 3-Bromo-1-(3-(cyclopropylmethoxy)phenyl)-5-isobutyl-1H-pyrazole

Platinum dioxide (151 mg, 665 μmol) was added to a solution of compound 10-3 (770 mg, 2.22 mmol) in methanol (2 mL), and the system was stirred and reacted for 1 hour at 0°C in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=9:1) to obtain compound 10-4 (580 mg, yield 75.1%, yellow liquid). LCMS calc.for C ₁₇ H ₂₂ BrN ₂ O[M+H] ⁺ :m/z＝349.1/351.1；Found:349.1/351.1.

Step 4: 2-((1-(3-(cyclopropylmethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

To a toluene (5 mL) solution of compound 10-4 (200 mg, 573 μmol) and INT-1 (134 mg, 572 μmol) were added t-BuBrettphos Pd G3 (147 mg, 172 μmol) and cesium carbonate (466 mg, 1.43 mmol), and the system was stirred at 120°C under nitrogen protection for 1 hour. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=9:1) to obtain 10-5 (210 mg, yield 73.0%, yellow solid). LCMS calc.for C ₂₈ H ₃₁ N ₄ O ₃ S[M+H] ⁺ :m/z＝503.2；Found:503.2.

Step 5: 2-((1-(3-(cyclopropylmethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

At room temperature, lithium hydroxide (45.7 mg, 1.91 mmol) was added to a mixed solution of compound 10-5 (160 mg, 318 μmol) in tetrahydrofuran (10 mL) and water (2 mL), and the system was stirred at 50°C for 1 hour. 1.5 N hydrochloric acid was added to the reaction solution to adjust the pH to 5, and ethyl acetate (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified to obtain Cpd-10 (70.2 mg, yield 45.2%, yellow solid). LCMS calc.for C ₂₇ H ₂₉ N ₄ O ₃ S[M+H] ⁺ :m/z＝489.2; Found: 489.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.95(s,1H),10.65(s,1H),8.81(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.56-7.52(m,2H),7.39 (t,J＝8.1Hz,1H),7.15(dd,J＝5.1,3.6Hz,1H),7.04-7.01(m,1H),7.00-6.96(m,2H),6.91(s,1H),3.87(d,J＝7.0Hz,2H),2.60(d,J＝7.1Hz ,2H),1.81(dt,J＝13.4,6.5Hz,1H),1.23(dddd,J＝12.8,8.0,4.0,2.4Hz,1H),0.85(d,J＝6.6Hz,6H),0.60-0.55(m,2H),0.36-0.31(m,2H).

Example 11: 2-[[5-isobutyl-1-[3-(1,1,2,2,2-pentadeuterioethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-11)

Step 1: 1-Bromo-3-(1,1,2,2,2-pentadeuteroethoxy)benzene

Compound 11-1 (2.50 g, 14.5 mmol) and deuterated bromoethane (1.98 g, 17.3 mmol) were dissolved in acetonitrile (20 mL), potassium carbonate (3.99 g, 28.9 mmol) was added at room temperature, the air was replaced by nitrogen three times, and the system was stirred at 65 ° C for 12 hours. Filter and concentrate under reduced pressure to obtain a crude product, add water (50 mL), extract with dichloromethane (40 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate to obtain compound 11-2 (2.98 g, crude product, colorless liquid). ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.27-7.16 (m, 1H), 7.10-7.01 (m, 2H), 6.95-6.81 (m, 1H).

Step 2: 3-(1,1,2,2,2-pentadeuterioethoxy)phenylboronic acid

Compound 11-2 (1.60 g, 7.76 mmol) was dissolved in tetrahydrofuran (15 mL), and the air was replaced by nitrogen three times. At -78 ° C, n-butyl lithium (7.28 mL, 11.6 mmol, 1.6 M n-hexane solution) was added dropwise, and stirred for 0.5 hours. Trimethyl borate (2.42 g, 23.3 mmol) was added dropwise, and stirred for 12 hours. The system was slowly warmed to room temperature, and pH was adjusted to 4 with 2N hydrochloric acid. Ethyl acetate (10 mL × 3) was added for extraction. The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was slurried (PE: EA = 10: 1) to obtain compound 11-3 (532 mg, yield 40.1%, white solid). LCMS calc. for C ₈ H ₇ D ₅ BO ₃ [M+H] ⁺ : m/z = 172.1; Found: 172.2.

Step 3: 3,5-dibromo-1-[3-(1,1,2,2,2-pentadeuteroethoxy)phenyl]pyrazole

Compound 2-1 (490 mg, 2.17 mmol) and 11-3 (408 mg, 2.39 mmol) were dissolved in toluene (10 mL), pyridine (0.524 mL, 6.51 mmol) and copper acetate (591 mg, 3.25 mmol) were added, and the air was replaced by oxygen three times. The system was stirred at 90°C for 12 hours. Filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA＝20:1) to obtain compound 11-4 (446 mg, yield 58.5%, light yellow liquid). LCMS calc.for C ₁₁ H ₆ D ₅ Br ₂ N ₂ O[M+H] ⁺ :m/z＝350.0/352.0/354.0；Found:350.0/352.1/354.1.

Step 4: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-[3-(1,1,2,2,2-pentadeuteroethoxy)phenyl]pyrazole

Compound 11-4 (470 mg, 1.34 mmol) and 2-3 (256 mg, 1.41 mmol) were dissolved in tetrahydrofuran (12 mL) and water (3 mL), and Pd(dppf)Cl ₂ (98.0 mg, 134 μmol) and potassium phosphate (568 mg, 2.68 mmol) were added at room temperature. The air was replaced by nitrogen three times, and the system was stirred at 70°C for 2 hours. After cooling, the reaction solution was extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝10:1) to obtain compound 11-5 (320 mg, yield 73.4%, colorless liquid). LCMS calc.for C ₁₅ H ₁₃ D ₅ BrN ₂ O[M+H] ⁺ :m/z＝326.1/328.1；Found:326.1/328.1.

Step 5: 3-Bromo-5-isobutyl-1-[3-(1,1,2,2,2-pentadeuteroethoxy)phenyl]pyrazole

Compound 11-5 (400 mg, 1.23 mmol) was dissolved in methanol (6 mL), and platinum dioxide (55.7 mg, 245 μmol) was added at 0°C. The air was replaced by hydrogen three times, and the system was stirred at 0°C for 1 hour. After filtration, the solid was washed with methanol (10 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA = 25: 1) to obtain compound 11-6 (216 mg, yield 53.7%, colorless liquid). LCMS calc.for C ₁₅ H ₁₅ D ₅ BrN ₂ O[M+H] ⁺ :m/z＝328.1/330.1; Found: 328.1/330.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.39(t,J＝8.0Hz,1H),7.07-6.93(m,3H),6.42(s,1H),2.51-2.48(m,2H),1.76-1.70(m,1H),0.77(d,J＝6.6Hz,6H).

Step 6: 2-[[5-isobutyl-1-[3-(1,1,2,2,2-pentadeuterioethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 11-6 (200 mg, 609 μmol) and INT-1 (157 mg, 670 μmol) were dissolved in DMF (4 mL), t-BuBrettphos Pd G3 (52.1 mg, 60.9 μmol) and cesium carbonate (495 mg, 1.52 mmol) were added at room temperature, and the system was stirred at 125 ° C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with 2N hydrochloric acid, and extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain compound Cpd-11 (82.7 mg, yield 29.1%, yellow solid). LCMS calc.for C ₂₅ H ₂₂ D ₅ N ₄ O ₃ S[M+H] ⁺ :m/z＝468.2; Found: 468.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.67(s,1H),8.82(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.57-7.53(m,2H),7.40(t,J＝8.0Hz,1H),7.17- 7.13(m,1H),7.05-6.95(m,3H),6.91(s,1H),2.61(d,J＝7.2Hz,2H),1.84-1.77(m,1H),0.85(d,J＝6.6Hz,6H).

Example 12: 2-[[5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-12)

Step 1: 3,5-dibromo-1-[3-(methoxymethyl)phenyl]pyrazole

Compound 2-1 (1.30 g, 5.76 mmol) and 12-1 (1.00 g, 6.04 mmol) were dissolved in toluene (10 mL), pyridine (1.39 mL, 17.3 mmol) and copper acetate (1.57 g, 8.63 mmol) were added at room temperature, and the air was replaced by oxygen three times. The system was stirred at 90°C for 12 hours. Filter and concentrate, and the residue was subjected to column chromatography (PE:EA＝10:1) to obtain compound 12-2 (701 mg, yield 35.1%, yellow liquid). LCMS calc.for C ₁₁ H ₁₁ Br ₂ N ₂ O[M+H] ⁺ :m/z＝344.9/346.9/348.9；Found:344.9/346.9/349.0.

Step 2: 3-Bromo-1-[3-(methoxymethyl)phenyl]-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 12-2 (1.00 g, 2.89 mmol) and 2-3 (631 mg, 3.47 mmol) were dissolved in tetrahydrofuran (8 mL) and water (2 mL), and Pd(dppf)Cl ₂ (211 mg, 289 μmol) and potassium phosphate (1.23 g, 5.78 mmol) were added at room temperature. The air was replaced by nitrogen three times, and the system was stirred at 70°C for 2 hours. After cooling, the reaction solution was extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EA＝10:1) to obtain compound 12-3 (640 mg, yield 69.2%, yellow liquid). LCMS calc.for C ₁₅ H ₁₈ BrN ₂ O[M+H] ⁺ :m/z＝321.1/323.1；Found:321.0/323.0.

Step 3: 3-Bromo-5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazole

Compound 12-3 (800 mg, 2.49 mmol) was dissolved in methanol (10 mL), and platinum dioxide (113 mg, 498 μmol) was added at 0°C. The air was replaced by hydrogen three times, and the system was stirred at 0°C for 0.5 hours. Filter, wash the solid with methanol (10 mL), concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (PE: EA = 25: 1) to obtain compound 12-4 (420 mg, yield 52.3%, colorless liquid). LCMS calc. for C ₁₅ H ₂₀ BrN ₂ O [M + H] ⁺ : m / z = 323.1/325.1; Found: 323.1/325.1.

Step 4: 2-[[5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 12-4 (600 mg, 1.86 mmol) and INT-1 (435 mg, 1.86 mmol) were dissolved in toluene (6 mL), t-BuBrettphos Pd G3 (159 mg, 186 μmol) and cesium carbonate (1.51 g, 4.64 mmol) were added at room temperature, and the system was stirred at 120°C for 1 hour under nitrogen atmosphere. Filter and concentrate, and the residue was purified by column chromatography (PE:EA=5:1) to obtain compound 12-5 (117 mg, yield 13.2%, yellow liquid). LCMS calc.for C ₂₆ H ₂₉ N ₄ O ₃ S[M+H] ⁺ :m/z=477.2;Found:477.3.

Step 5: 2-[[5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 12-5 (130 mg, 273 μmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide (39.2 mg, 1.64 mmol) was added at room temperature. The system was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with 2N hydrochloric acid, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain compound Cpd-12 (50.0 mg, yield 39.6%, yellow solid). LCMS calc.for C ₂₅ H ₂₇ N ₄ O ₃ S[M+H] ⁺ :m/z＝463.2；Found:463.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.67(s,1H),8.81(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.56-7.52(m,2H),7.50(t,J＝7.7Hz,1H),7.44-7.34(m,3H), 7.18-7.13(m,1H),6.93(s,1H),4.50(s,2H),3.33(s,3H),2.61(d,J＝7.1Hz,2H),1.83-1.77(s,1H),0.85(d,J＝6.6Hz,6H).

Example 13: 2-[[1-(3-ethoxy-4-methoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-13)

Step 1: 4-Bromo-2-ethoxy-1-methoxybenzene

5-Bromo-2-methoxyphenol 13-1 (2.00 g, 9.85 mmol) was dissolved in DMF (15 mL), ethyl bromide (2.15 g, 19.7 mmol) and potassium carbonate (2.72 g, 19.7 mmol) were added, and the system was stirred at 50°C for 2 hours. After the reaction was completed, water (40 mL) was added for washing, and ethyl acetate (40 mL × 3) was used for extraction. The organic phase was dried and concentrated, and the residue was purified by column chromatography (PE: EA = 5: 1) to obtain compound 13-2 (2.01 g, yield 88.7%, white solid).

Step 2: 3-ethoxy-4-methoxyphenylboronic acid

Under nitrogen protection, compound 13-2 (3.00 g, 13.0 mmol) was dissolved in tetrahydrofuran (30 mL), the system was stirred at -78 ° C for 10 minutes, n-butyl lithium (7.79 mL, 19.5 mmol, 2.5 M tetrahydrofuran solution) was slowly added dropwise, and stirring was continued for 0.5 hours. Trimethyl borate (4.05 g, 39.0 mmol) was added, and after stirring for 0.5 hours, pH was adjusted to 4 with 2N hydrochloric acid, and extracted with ethyl acetate (40 mL × 3). The organic phase was dried and concentrated to obtain a crude product 13-3 (2.00 g, yield 78.5%, yellow solid).

Step 3: 3,5-dibromo-1-(3-ethoxy-4-methoxyphenyl)pyrazole

3,5-Dibromo-1H-pyrazole 2-3 (1.05 g, 4.64 mmol) and compound 13-3 (1.00 g, 5.10 mmol) were dissolved in toluene (10 mL), copper acetate (1.26 g, 6.96 mmol) and pyridine (1.12 mL, 13.9 mmol) were added, and the system was stirred at 90 ° C for 16 hours under an oxygen atmosphere. Cool and filter, concentrate the filtrate, and purify the residue by column chromatography (PE: EA = 9: 1) to obtain compound 13-4 (1.08 g, yield 61.9%, white solid). LCMS calc. for C ₁₂ H ₁₃ Br ₂ N ₂ O ₂ [M+H] ⁺ : m/z = 374.9/376.9/378.9; Found: 375.1/377.1/379.1.

Step 4: 3-Bromo-1-(3-ethoxy-4-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 13-4 (1.20 g, 3.19 mmol) and 2-3 (697 mg, 3.83 mmol) were dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (3 mL), and Pd(dppf)Cl ₂ (233 mg, 319 μmol) and potassium phosphate (1.35 g, 6.38 mmol) were added. The system was stirred at 70°C for 16 hours under nitrogen protection. After cooling, water (15 mL) was added, and the mixture was extracted with ethyl acetate (35 mL×3). The organic phase was dried and concentrated, and the residue was purified by column chromatography (PE:EA＝9:1) to obtain compound 13-5 (190 mg, yield 17.0%, colorless liquid). LCMS calc.for C ₁₆ H ₂₀ BrN ₂ O ₂ [M+H] ⁺ :m/z＝351.1/353.1；Found:351.2/353.2.

Step 5: 3-Bromo-1-(3-ethoxy-4-methoxyphenyl)-5-isobutylpyrazole

Compound 13-5 (200 mg, 569 μmol) was dissolved in methanol (2 mL), and platinum dioxide (25.9 mg, 114 μmol) was added. The system was stirred at 0°C for 1 hour under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=9:1) to obtain compound 13-6 (136 mg, yield 67.9%, colorless liquid). LCMS calc.for C ₁₆ H ₂₂ BrN ₂ O ₂ [M+H] ⁺ :m/z＝353.1/355.1；Found: 353.2/355.2.

Step 6: 2-[[1-(3-ethoxy-4-methoxyphenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 13-6 (160 mg, 454 μmol) and INT-1 (106 mg, 453 μmol) were added to DMF (3 mL) with t-BuBrettphos Pd G3 (39.3 mg, 45.3 μmol) and cesium carbonate (295 mg, 906 μmol). The system was stirred at 125 °C for 4 hours under nitrogen protection. After the reaction, 1N hydrochloric acid was added to adjust the pH to 5, and dichloromethane (30 mL × 3) was used for extraction. The organic phase was dried and concentrated to obtain a crude product, which was purified by preparation to obtain Cpd-13 (76.8 mg, yield 34.3%, yellow solid). LCMS calc.for C ₂₆ H ₂₉ N ₄ O ₄ S[M+H] ⁺ :m/z＝493.2；Found:493.2； ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.62(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.56-7.52(m,2H),7 .15(dd,J＝5.1,3.6Hz,1H),7.05(d,J＝8.6Hz,1H),7.00(d,J＝2.4Hz,1H),6.96(dd, J＝8.5,2.4Hz,1H),6.87(s,1H),4.05(q,J＝7.0Hz,2H),3.82(s,3H),2.54(d,J＝7.2 Hz,2H),1.79(dt,J＝13.7,7.0Hz,1H),1.33(t,J＝6.9Hz,3H),0.85(d,J＝6.6Hz,6H).

Example 14: 2-[[1-(3-ethoxy-5-methoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-14)

Step 1: 1-Bromo-3-ethoxy-5-methoxybenzene

Potassium carbonate (5.44 g, 39.4 mmol) was added to a DMF (20 mL) solution containing 3-bromo-5-methoxyphenol 14-1 (4.00 g, 19.7 mmol) and ethyl bromide (4.29 g, 39.4 mmol), and the system was reacted at 50°C for 2 hours. Water (200 mL) was added, extracted with ethyl acetate (150 mL), dried over sodium sulfate, concentrated, and the residue was purified by column chromatography (PE:EA=19:1) to obtain 14-2 (3.60 g, yield 79.4%, colorless liquid).

Step 2: 3-ethoxy-5-methoxyphenylboronic acid

Under nitrogen protection, compound 14-2 (2.80 g, 12.1 mmol) was dissolved in tetrahydrofuran (30 mL). The system was cooled to -60 ° C, n-butyl lithium (7.27 mL, 18.2 mmol, 2.5 M n-hexane solution) was slowly added dropwise, stirred for 10 minutes, and trimethyl borate (3.78 g, 36.3 mmol) was added. The system was slowly warmed to room temperature and stirred for 1 hour. 4N hydrochloric acid was added until the pH value reached 2-3, and extracted with ethyl acetate (100 mL × 3). The organic layer was washed with saturated sodium chloride aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was slurried by (PE: EA = 10: 1) to obtain 14-3 (1.08 g, yield 45.5%, white solid).

Step 3: 3,5-dibromo-1-(3-ethoxy-5-methoxyphenyl)pyrazole

Compound 2-1 (800 mg, 3.54 mmol) was dissolved in toluene (16 mL), pyridine (0.857 mL, 10.6 mmol), copper acetate (965 mg, 5.31 mmol) and 14-3 (764 mg, 3.90 mmol) were added, and the system was stirred at 45 ° C for 16 hours under an oxygen atmosphere. The reaction solution was filtered, the filter cake was washed with ethyl acetate (100 mL), the filtrate was collected, concentrated, and the crude product was purified by column chromatography (PE: EA = 10: 1) to obtain 14-4 (810 mg, yield 60.8%, colorless liquid). LC-MS calc. for C ₁₂ H ₁₃ Br ₂ N ₂ O ₂ [M+H] ⁺ : m/z = 374.9/376.9/378.9; Found: 375.0/377.0/379.0.

Step 4: 3-Bromo-1-(3-ethoxy-5-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 14-4 (900 mg, 2.39 mmol) and 2-3 (435 mg, 2.39 mmol) were dissolved in tetrahydrofuran (10 mL), and Pd(dppf)Cl ₂ (347 mg, 478 μmol) and potassium phosphate (1.02 g, 4.79 mmol) were added. The system was heated to 70°C and stirred for 2 hours under a nitrogen atmosphere. After cooling, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝10:1) to obtain compound 14-5 (585 mg, yield 69.9%, colorless liquid). LC-MS calc.for C ₁₆ H ₂₀ BrN ₂ O ₂ [M+H] ⁺ :m/z＝351.1/353.1; Found: 351.2/353.2.

Step 5: 3-Bromo-1-(3-ethoxy-5-methoxyphenyl)-5-isobutylpyrazole

Compound 14-5 (600 mg, 1.71 mmol) was dissolved in methanol (10 mL), and platinum dioxide (83.7 mg, 341 μmol) was added. The system was stirred in an ice-water bath under a hydrogen atmosphere for 30 minutes. Filter, wash the filter cake with methanol (20 mL), collect the filtrate and concentrate, and the residue was subjected to column chromatography (PE:EA＝10:1) to obtain compound 14-6 (360 mg, yield 59.8%, colorless liquid). LC-MS calc.for C ₁₆ H ₂₂ BrN ₂ O ₂ [M+H] ⁺ :m/z＝353.1/355.1；Found:353.1/355.1.

Step 6: 2-[[1-(3-ethoxy-5-methoxyphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 14-6 (300 mg, 849 μmol) and INT-1 (298 mg, 1.27 mmol) were dissolved in toluene (5 mL), and then t-BuBrettphos Pd G3 (109 mg, 127 μmol) and cesium carbonate (552 mg, 1.70 mmol) were added. The system was stirred at 120 ° C for 1 hour under nitrogen atmosphere. The reaction solution was concentrated, and the residue was purified by column chromatography (PE: EA = 9: 1) to obtain compound 14-7 (180 mg, yield 41.9%, yellow solid). LC-MS calc. for C ₂₇ H ₃₁ N ₄ O ₄ S [M + H] ⁺ : m / z = 507.2; Found: 507.3.

Step 7: 2-[[1-(3-ethoxy-5-methoxyphenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 14-7 (250 mg, 493 μmol) was dissolved in a mixed solvent of methanol (5 mL), tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (118 mg, 4.93 mmol) was added. The system was heated to 50°C and stirred for 1 hour. 1N hydrochloric acid was added to the reaction solution to adjust the pH to 2-3, and extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain compound Cpd-14 (95.0 mg, yield 39.1%, yellow solid). LC-MS calc.for C ₂₆ H ₂₉ N ₄ O ₄ S[M+H] ⁺ :m/z＝493.2; Found: 493.3. ¹ H NMR (400MHz, DMSO-d ₆ )δ13.89(s,1H),10.64(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz 1H),7.54-7.52(m,2H),7.15-7.13(m,1H),6.90(s,1H),6.60-6.59(m,2H),6.53-6.51(m,1H),4.09-4.05(m ,2H),3.79(s,3H),2.62(d,J＝7.2Hz,2H),1.88-1.78(m,1H),1.33(t,J＝10.7Hz,3H),0.86(d,J＝6.9Hz,6H).

Example 15: 2-[[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-15)

Step 1: 4-Fluoro-3-(trifluoromethoxy)phenylboronic acid

4-Bromo-1-fluoro-2-(trifluoromethoxy)benzene 15-1 (4.50 g, 17.4 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyl lithium (16.3 mL, 26.1 mmol, 1.6 M n-hexane solution) was slowly added dropwise at -78 °C under nitrogen atmosphere. After the addition was complete, the mixture was stirred at -78 °C for 0.5 hours, and then trimethyl borate (5.42 g, 52.1 mmol) was added dropwise, and the mixture was slowly heated to room temperature and stirred for 1 hour. The reaction was quenched with 1N hydrochloric acid (50 mL), and ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 15-2 (3.00 g, yield 77.0%, colorless liquid).

Step 2: 3,5-dibromo-1-[4-fluoro-3-(trifluoromethoxy)phenyl]pyrazole

Compound 15-2 (3.00 g, 13.4 mmol) and 3,5-dibromo-1H-pyrazole 2-1 (3.03 g, 13.4 mmol) were dissolved in toluene (20 mL), copper acetate (4.01 g, 20.1 mmol) and pyridine (3.24 mL, 40.2 mmol) were added at room temperature, and the system was stirred at 90 ° C in an oxygen atmosphere for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA = 10: 1) to obtain 15-3 (742 mg, yield 13.7%, colorless liquid). LCMS calc. for C ₁₀ H ₅ Br ₂ F ₄ N ₂ O [M + H] ⁺ : m / z = 402.9/404.9/406.9; Found: 402.9/404.9/406.9.

Step 3: 3-Bromo-1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 15-3 (900 mg, 2.23 mmol) and 2-3 (406 mg, 2.23 mmol) were dissolved in tetrahydrofuran (6 mL) and water (1 mL), potassium phosphate (946 mg, 4.46 mmol) and Pd(dppf)Cl ₂ (326 mg, 446 μmol) were added at room temperature, and the system was stirred at 75°C under nitrogen atmosphere for 4 hours. After cooling to room temperature, the reaction solution was filtered, separated with ethyl acetate (40 mL) and water (10 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was purified by column chromatography (PE:EA=10:1) to obtain 15-4 (405 mg, yield 48.0%, colorless liquid). LCMS calc.for C ₁₄ H ₁₂ BrF ₄ N ₂ O[M+H] ⁺ :m/z＝379.0/381.0; Found: 379.0/381.0.

Step 4: 3-Bromo-1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazole

Compound 15-4 (300 mg, 793 μmol) was dissolved in methanol (5 mL), and platinum dioxide (53.9 mg, 238 μmol) was added at room temperature. The air was replaced by hydrogen three times, and the system was stirred at 0°C for 0.5 hours. After the reaction was completed, it was filtered with methanol (40 mL), concentrated under reduced pressure, and the crude product was purified by column chromatography (PE: EA = 10: 1) to obtain compound 15-5 (120 mg, yield 39.8%, colorless liquid). LCMS calc. for C ₁₄ H ₁₄ BrF ₄ N ₂ O [M + H] ⁺ : m / z = 381.0/383.0; Found: 381.1/383.1.

Step 5: 2-[[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 15-5 (200 mg, 525 μmol) and INT-1 (123 mg, 525 μmol) were dissolved in DMF (2 mL), t-BuBrettphos Pd G3 (44.8 mg, 52.5 μmol) and cesium carbonate (341 mg, 1.05 mmol) were added at room temperature, and the system was stirred at 120 ° C for 1 hour under nitrogen atmosphere. Cool and filter, the filtrate was separated with ethyl acetate (70 mL) and water (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to column chromatography (PE: EA = 10: 1) to obtain 15-6 (212 mg, yield 75.6%, yellow solid). LCMS calc. for C ₂₅ H ₂₃ F ₄ N ₄ O ₃ S [M + H] ⁺ : m / z = 535.1; Found: 535.2.

Step 6: 2-[[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 15-6 (250 mg, 468 mol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide (56.0 mg, 2.34 mmol) was added at room temperature. The system was stirred at 65°C for 0.5 hours. After the reaction was completed, the mixture was cooled to room temperature and the pH value was adjusted to 5-6 with 1N dilute hydrochloric acid. Ethyl acetate (20 mL×3) was added for extraction and vacuum drying to obtain a crude product. Compound Cpd-15 (118 mg, yield 48.5%, yellow solid) was obtained by preparative purification. LCMS calc.for C ₂₄ H ₂₁ F ₄ N ₄ O ₃ S[M+H] ⁺ :m/z＝521.1；Found:521.1； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.65(s,1H),8.78(d,J＝2.6Hz,1H),8.35(d,J＝2.6Hz,1H),7.79-7.75(m,1H),7.67-7.58(m,2H),7.53-7.49(m,2H) ,7.12(dd,J＝5.1,3.6Hz,1H),6.92(s,1H),2.59(d,J＝7.1Hz,2H),1.73(dt,J＝13.4,6.8Hz,1H),0.81(d,J＝6.6Hz,6H).

Example 16: 2-[[1-(5-ethoxy-2-fluorophenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-16)

Step 1: 3,5-dibromo-1-(5-ethoxy-2-fluorophenyl)pyrazole

Compound 2-1 (2.00 g, 8.85 mmol) and 16-1 (1.71 g, 9.30 mmol) were dissolved in toluene (20 mL), pyridine (2.20 mL, 26.6 mmol) and copper acetate (2.41 g, 13.3 mmol) were added at room temperature, and the air was replaced by oxygen three times. The system was stirred at 90 ° C for 12 hours. Cool and filter, the filtrate was concentrated under reduced pressure to obtain a crude product for column chromatography (PE: EA = 4: 1), and compound 16-2 (510 mg, yield 15.8%, colorless liquid) was obtained. LCMS calc. for C ₁₁ H ₁₀ Br ₂ FN ₂ O [M + H] ⁺ : m / z = 362.9/364.9/366.9; Found: 363.0/365.0/367.0.

Step 2: 3-Bromo-1-(5-ethoxy-2-fluorophenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 16-2 (640 mg, 1.76 mmol) and 2-3 (352 mg, 1.93 mmol) were dissolved in tetrahydrofuran (18 mL) and water (3 mL), and Pd(dppf)Cl ₂ (128 mg, 175 μmol) and potassium phosphate (746 mg, 3.52 mmol) were added at room temperature. The air was replaced by nitrogen three times, and the system was stirred at 70°C for 4 hours. After cooling, the reaction solution was extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EA＝10:1) to obtain compound 16-3 (560 mg, yield 94.1%, yellow liquid). LCMS calc.for C ₁₅ H ₁₇ BrFN ₂ O[M+H] ⁺ :m/z＝339.0/341.0；Found:339.2/341.2.

Step 3: 3-Bromo-1-(5-ethoxy-2-fluorophenyl)-5-isobutyl-pyrazole

Compound 16-3 (560 mg, 1.65 mmol) was dissolved in methanol (10 mL), and platinum dioxide (75.0 mg, 330 μmol) was added at 0°C. After the air was replaced by hydrogen three times, the system was stirred at 0°C for 1 hour. After filtration, the solid was washed with methanol (10 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA = 15: 1) to obtain compound 16-4 (203 mg, yield 36.1%, colorless liquid). LCMS calc.for C ₁₅ H ₁₉ BrFN ₂ O[M+H] ⁺ :m/z＝341.1/343.1; Found: 341.1/343.1; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.38-7.32(m,1H),7.11-7.02(m,2H),6.43(s,1H),4.03-3.98(m,2H),2.33(d ,J＝7.2Hz,2H),1.75-1.65(m,1H),1.27(d,J＝7.0Hz,3H),0.75(d,J＝6.6Hz,6H).

Step 4: 2-[[1-(5-ethoxy-2-fluorophenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 16-4 (200 mg, 586 μmol) and INT-1 (151 mg, 644 μmol) were dissolved in DMF (2 mL), t-BuBrettphos Pd G3 (55.6 mg, 58.6 μmol) and cesium carbonate (382 mg, 1.17 mmol) were added at room temperature, and the system was stirred at 125 ° C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the pH was adjusted to 5 with 2N hydrochloric acid, and ethyl acetate (10 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain compound Cpd-16 (86.2 mg, yield 30.6%, yellow solid). LCMS calc.for C ₂₅ H ₂₆ FN ₄ O ₃ S[M+H] ⁺ :m/z＝481.2；Found:481.2； ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.63(s,1H),8.77(dd,J＝2.6,0.6Hz,1H),8.35(d,J＝2.6Hz,1H),7.54-7.48(m,2H),7.33(t,J＝9.6Hz,1H),7.15-6.98(m, 3H), 6.89 (s, 1H), 4.05-4.00 (m, 2H), 2.38 (d, J = 7.2Hz, 2H), 1.77-1.69 (m, 1H), 1.29 (t, J = 7.0Hz, 3H), 0.79 (d, J = 6.6Hz, 6H).

Example 17: 2-[[1-(3-ethoxy-2-fluorophenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-17)

Step 1: 3,5-dibromo-1-(3-ethoxy-2-fluorophenyl)-1H-pyrazole

Compound 2-1 (2.00 g, 8.85 mmol) was dissolved in toluene (20 mL), 3-ethoxy-2-fluorophenylboronic acid 17-1 (1.79 g, 9.74 mmol), copper acetate (2.41 g, 13.3 mmol) and pyridine (2.20 mL, 26.6 mmol) were added, and the system was stirred at 90 ° C for 16 hours under an oxygen atmosphere. After cooling, the reaction solution was filtered and concentrated, and the residue was purified by chromatography column (PE: EA = 10: 1) to obtain compound 17-2 (560 mg, yield 17.4%, yellow liquid). LCMS calc. for C ₁₁ H ₁₀ Br ₂ FN ₂ O [M + H] ⁺ : m / z = 362.9/364.9/366.9; Found: 363.0/365.0/367.0.

Step 2: 3-Bromo-1-(3-ethoxy-2-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Compound 17-2 (700 mg, 1.92 mmol) was dissolved in tetrahydrofuran (10 mL), and 2-3 (385 mg, 2.12 mmol), Pd(dppf)Cl ₂ (141 mg, 192 μmol) and potassium phosphate (816 mg, 3.85 mmol) were added, and the system was stirred at 70°C for 2 hours under nitrogen protection. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography (PE:EA=20: 1) Compound 17-3 (315 mg, yield 48.5%, colorless liquid) was obtained by purification. LCMS calc. for C ₁₅ H ₁₇ BrFN ₂ O [M+H] ⁺ : m/z = 339.0/341.0; Found: 339.1/341.1.

Step 3: 3-Bromo-1-(3-ethoxy-2-fluorophenyl)-5-isobutyl-1H-pyrazole

Compound 17-3 (350 mg, 1.03 mmol) was dissolved in methanol (8 mL), and platinum dioxide (46.9 mg, 206 μmol) was added. The system was stirred at 0°C for 1 hour under hydrogen. Filtered and concentrated, the residue was purified by column chromatography (PE:EA＝10:1) to obtain compound 17-4 (270 mg, yield 77.1%, colorless liquid). LCMS calc.for C ₁₅ H ₁₉ BrFN ₂ O[M+H] ⁺ :m/z＝341.1/343.1；Found:341.2/343.2.

Step 4: 2-[[1-(3-ethoxy-2-fluorophenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 17-4 (300 mg, 879 μmol) was dissolved in DMF (3 mL), and INT-1 (206 mg, 879 μmol), t-BuBrettphos Pd G3 (75.1 mg, 87.9 μmol) and cesium carbonate (859 mg, 2.64 mmol) were added. The system was stirred at 125 ° C for 3 hours under nitrogen protection. The filtrate was cooled and filtered, and the crude product obtained by concentration of the filtrate was purified by preparation to obtain compound Cpd-17 (174 mg, yield 41.2%, yellow solid). LCMS calc.for C ₂₅ H ₂₆ FN ₄ O ₃ S[M+H] ⁺ :m/z＝481.2；Found:481.2； ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.70(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.56-7.52( m,2H),7.34-7.23(m,2H),7.15(dd,J＝5.1,3.6Hz,1H),7.05(ddd,J＝7.9,6 .5,1.8Hz,1H),6.92(s,1H),4.19(q,J＝7.0Hz,2H),2.39(d,J＝7.2Hz,2H), 1.77(dt,J＝13.5,6.8Hz,1H), 1.38(t,J＝7.0Hz,3H), 0.82(d,J＝6.6Hz,6H).

Example 18: 2-[[1-[3-(Cyclobutyloxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-18)

Step 1: 3-(3-Bromo-5-isobutyl-1H-pyrazol-1-yl)phenol

Compound 6-4 (1.00 g, 3.09 mmol) was dissolved in hydrobromic acid (8 mL) and water (4 mL), and the system was stirred at 120°C for 2 hours. After cooling to room temperature, the reaction solution was extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EA＝5:1) to obtain compound 18-1 (900 mg, yield 99.1%, yellow liquid). LCMS calc.for C ₁₃ H ₁₆ BrN ₂ O[M+H] ⁺ :m/z＝295.0/297.0；Found:295.2/297.2.

Step 2: 3-Bromo-1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazole

Compound 18-1 (200 mg, 678 μmol) and bromocyclobutane (137 mg, 1.02 mmol) were dissolved in DMF (4 mL), potassium carbonate (375 mg, 2.71 mmol) was added at room temperature, and the system was stirred at 100°C for 1 hour. After cooling, the mixture was separated with ethyl acetate (70 mL) and water (50 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=10:1) to obtain compound 18-2 (112 mg, Yield 47.4%, colorless liquid). LCMS calc. for C ₁₇ H ₂₂ BrN ₂ O [M+H] ⁺ : m/z = 349.1/351.1; Found: 349.2/351.1.

Step 3: 2-[[1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 18-2 (100 mg, 286 μmol) and INT-1 (67.1 mg, 286 μmol) were dissolved in DMF (3 mL), t-BuBrettphos Pd G3 (36.7 mg, 43.0 μmol) and cesium carbonate (186 mg, 573 μmol) were added at room temperature, and the system was stirred at 120 ° C in a nitrogen atmosphere for 1 hour. Cool and filter, the filtrate was separated with ethyl acetate (70 mL) and water (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to column chromatography (PE: EA = 10: 1) to obtain compound 18-3 (73.4 mg, yield 51.1%, yellow solid). LCMS calc. for C ₂₈ H ₃₁ N ₄ O ₃ S [M + H] ⁺ : m / z = 503.2; Found: 503.3.

Step 4: 2-[[1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

18-3 (110 mg, 219 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide (26.2 mg, 1.09 mmol) was added at room temperature. The system was stirred at 65°C for 0.5 hours. After cooling to room temperature, the reaction solution was adjusted to pH 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL×3). The organic phase was dried and concentrated, and the crude product was purified by preparative purification to obtain compound Cpd-18 (65.0 mg, yield 60.8%, yellow solid). LCMS calc.for C ₂₇ H ₂₉ N ₄ O ₃ S[M+H] ⁺ :m/z＝489.2；Found:489.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.65(s,1H),8.80(d,J＝2.3Hz,1H),8.38(d,J＝2.5Hz,1H),7.54(t,J＝4.3H z,2H),7.39(t,J＝8.4Hz,1H),7.18-7.12(m,1H),7.02(d,J＝8.2Hz,1H),6.92-6 .83(m,3H),4.83-4.70(m,1H),2.60(d,J＝7.1Hz,2H),2.43(d,J＝9.0Hz,2H),2 .12-2.00(m,2H),1.84-1.73(m,2H),1.72-1.60(m,1H),0.84(d,J＝6.5Hz,6H).

Example 19: 2-[[5-isobutyl-1-[3-(2,2,2-trifluoroethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-19)

Step 1: 3-Bromo-5-isobutyl-1-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole

3-(3-bromo-5-isobutylpyrazol-1-yl)phenol 18-1 (200 mg, 678 μmol) was dissolved in DMF (3 mL), and p-toluenesulfonic acid (2,2,2-trifluoroethyl) ester 19-1 (345 mg, 1.36 mmol) and sodium hydroxide (54.2 mg, 1.36 mmol) were added. The system was stirred at 100 ° C for 3 hours under nitrogen protection. Cool, add water (15 mL), extract with ethyl acetate (30 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and the residue was purified by chromatography column (PE: EA = 10: 1) to obtain compound 19-2 (210 mg, yield 82.3%, colorless liquid). LCMS calc.for C ₁₅ H ₁₇ BrF ₃ N ₂ O[M+H] ⁺ :m/z＝377.0/379.0; Found: 377.1/379.1.

Step 2: 2-[[5-isobutyl-1-[3-(2,2,2-trifluoroethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 19-2 (300 mg, 795 μmol) was dissolved in DMF (3 mL), t-BuBrettphos Pd G3 (67.9 mg, 79.5 μmol) and cesium carbonate (777 mg, 2.39 mmol) were added, and the system was stirred at 120°C for 16 hours under nitrogen protection. After cooling, 1N hydrochloric acid was added to adjust the pH to 5, and dichloromethane (30 mL) was used for extraction. The organic phase was concentrated to obtain a crude product, which was purified by preparative purification to obtain compound Cpd-19 (95.1 mg, yield 23.1%, yellow solid). LCMS calc.for C ₂₅ H ₂₄ F ₃ N ₄ O ₃ S[M+H] ⁺ :m/z＝517.1; Found: 517.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.67(s,1H),8.81(d,J＝2.6Hz,1H),8.39(d,J＝2.6Hz,1H),7.61-7.41(m,3H),7.23-7.08(m,4H),6 .93(s,1H),4.86(q,J＝11.6,10.3Hz,2H),2.62(d,J＝7.8Hz,2H),1.88-1.75(m,1H),0.85(d,J＝6.4Hz, 6H).

Example 20: 2-[[1-[3-(1,1-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-20)

Step 1: 3-Bromo-1-[3-(2-bromo-1,1-difluoro-ethoxy)phenyl]-5-isobutyl-pyrazole

Compound 18-1 (200 mg, 678 μmol) was dissolved in acetonitrile (2 mL) and water (0.8 mL), potassium hydroxide (76.0 mg, 1.36 mmol) was added, 2-bromo-1,1-difluoroethylene 20-1 (484 mg, 3.39 mmol) was added to the system at -5 °C, stirred for 10 minutes, then heated to 65 °C and stirred for 3 hours, and the reaction was completed. After cooling to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 20-2 (220 mg, yield 74.0%, yellow liquid). LCMS calc.for C ₁₅ H ₁₇ Br ₂ F ₂ N ₂ O[M+H] ⁺ :m/z＝437.0/439.0/441.0; Found: 437.0/439.0/441.0.

Step 2: 2-[[1-[3-(1,1-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 20-2 (160 mg, 365 μmol) and INT-1 (89.8 mg, 383 μmol) were dissolved in DMF (3 mL), t-BuBrettphos Pd G3 (86.7 mg, 91.3 μmol) and cesium carbonate (238 mg, 730 μmol) were added at room temperature, and the system was stirred at 120 ° C for 12 hours under nitrogen atmosphere. After cooling to room temperature, the reaction solution was adjusted to pH = 5 with 2N hydrochloric acid, and extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was purified to obtain compound Cpd-20 (14.6 mg, yield 8.03%, yellow solid). LCMS calc.for C ₂₅ H ₂₅ F ₂ N ₄ O ₃ S[M+H] ⁺ :m/z＝499.2; Found: 499.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.69(s,1H),8.84-8.78(m,1H),8.39-8.36(m,1H),7.55-7.51(m,3H),7.45-7.40(m,1H),7.33(s,1H),7.27-7.22(m,1H),7.18 -7.14(m,1H),6.95(d,J＝3.6Hz,1H),2.63(d,J＝7.4Hz,2H),1.99(td,J＝13.9,3.0Hz,3H),1.83-1.75(m,1H),0.85(d,J＝6.6Hz,6H).

Example 21: 2-[[5-isobutyl-1-(3-methoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-21)

Step 1: 3,5-dibromo-1-(3-methoxyphenyl)pyrazole

Compound 2-1 (1.00 g, 4.43 mmol) and 3-methoxyphenylboronic acid 21-1 (740 mg, 4.87 mmol) were dissolved in toluene (20 mL), pyridine (1.07 mL, 13.3 mmol) and copper acetate (1.21 g, 6.64 mmol) were added at room temperature, and the air was replaced by oxygen three times. The system was heated at 90 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography (PE:EA=10:1) to obtain compound 21-2 (1.00 g, yield 67.9%, colorless liquid). LCMS calc.for C ₁₀ H ₉ Br ₂ N ₂ O[M+H] ⁺ :m/z=330.9/332.9/334.9;Found:330.9/333.0/334.9.

Step 2: 3-Bromo-1-(3-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 21-2 (1.00 g, 3.01 mmol) and 2-3 (603 mg, 3.31 mmol) were dissolved in tetrahydrofuran (15 mL) and water (3 mL), and Pd(dppf)Cl ₂ (437 mg, 603 μmol) and potassium phosphate (1.28 g, 6.02 mmol) were added at room temperature, and the air was replaced by nitrogen three times. The system was stirred at 70°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝10:1) to obtain compound 21-3 (540 mg, yield 58.6%, colorless liquid). LCMS calc.for C ₁₄ H ₁₆ BrN ₂ O[M+H] ⁺ :m/z＝307.0/309.0; Found: 307.3/309.3.

Step 3: 3-Bromo-5-isobutyl-1-(3-methoxyphenyl)pyrazole

Compound 21-3 (540 mg, 1.76 mmol) was dissolved in methanol (6 mL), and platinum dioxide (86.2 mg, 352 μmol) was added at room temperature. The air was replaced by hydrogen three times, and the system was stirred at 0°C for 2 hours. Filtered, the solid was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (PE: EA = 10: 1) to obtain compound 21-4 (440 mg, yield 81.1%, colorless liquid). LCMS calc. for C ₁₄ H ₁₈ BrN ₂ O [M + H] ⁺ : m / z = 309.1/311.1; Found: 309.0/311.0.

Step 4: 2-[[5-isobutyl-1-(3-methoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)pyridine-3-carboxylic acid methyl ester

Compound 21-4 (350 mg, 1.13 mmol) and INT-1 (398 mg, 1.70 mmol) were dissolved in DMF (10 mL), t-BuBrettphos Pd G3 (96.7 mg, 113 μmol) and cesium carbonate (736 mg, 2.26 mmol) were added at room temperature, and the system was stirred at 120°C in a nitrogen atmosphere for 1 hour. Cool and filter, add water (30 mL) to the filtrate, extract with ethyl acetate (30 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and filter and concentrate the crude product to obtain compound 21-5 (300 mg, yield 57.4%, yellow liquid) by column chromatography (PE:EA＝4:1). LCMS calc.for C ₂₅ H ₂₇ N ₄ O ₃ S[M+H] ⁺ :m/z＝463.2；Found:463.3.

Step 5: 2-[[5-isobutyl-1-(3-methoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 21-5 (300 mg, 646 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide (77.7 mg, 3.24 mmol) was added at room temperature. The system was stirred at 50°C for 0.5 hours. After cooling to room temperature, the pH value was adjusted to 5-6 with 1N hydrochloric acid, and ethyl acetate (20 mL) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was prepared and purified to obtain compound Cpd-21 (56.4 mg, yield 19.4%, yellow solid). LCMS calc.for C ₂₄ H ₂₅ N ₄ O ₃ S[M+H] ⁺ :m/z＝449.2；Found:449.4； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.75(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.54-7.49(m,2H),7.39(t,J＝8.0Hz,1H),7.15(dd,J＝5.0, 3.7Hz,1H),7.07-6.97(m,3H),6.92(s,1H),3.82(s,3H),2.61(d,J＝7.2Hz,2H),1.86-1.76(m,1H),0.86(d,J＝6.6Hz,6H).

Example 22: 2-((1-(3-ethoxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-22)

Step 1: 3,5-dibromo-1-(3-ethoxy-4-fluorophenyl)-1H-pyrazole

Compound 2-1 (1.50 g, 6.64 mmol), compound 22-1 (1.22 g, 6.64 mmol), copper acetate (1.99 g, 9.96 mmol), pyridine (1.60 mL, 19.9 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred in an oxygen atmosphere at 90 ° C for 2 hours. Cool and filter, add saturated aqueous ammonium chloride solution (30 mL) to the filtrate, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, and purify the crude product obtained after filtration and concentration by column chromatography (PE: EA = 19: 1) to obtain compound 22-2 (1.28 g, yield 52.9%, white solid). LCMS calc.for C ₁₁ H ₁₀ Br ₂ FN ₂ O[M+H] ⁺ :m/z＝362.9/364.9/366.9; Found: 363.1/365.1/367.1.

Step 2: 3-Bromo-1-(3-ethoxy-4-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 22-2 (1.00 g, 2.75 mmol), compound 2-3 (450 mg, 2.47 mmol), Pd(dppf)Cl ₂ (402 mg, 550 μmol), potassium phosphate (1.17 g, 5.49 mmol) and a mixed solvent of dioxane/water (10 mL, 4:1) were added to the reaction flask, and the system was stirred at 120°C for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (30 mL×3), and the combined organic phase was washed with a saturated aqueous sodium chloride solution (30 mL×2). The crude product obtained after the organic phase was concentrated was subjected to column chromatography (PE:EA＝19:1) to obtain compound 22-3 (532 mg, yield 57.2%, white solid). LCMS calc.for C ₁₅ H ₁₇ BrFN ₂ O[M+H] ⁺ :m/z＝339.0/341.0; Found: 339.0/341.0.

Step 3: 3-Bromo-1-(3-ethoxy-4-fluorophenyl)-5-isobutyl-1H-pyrazole

Compound 22-3 (532 mg, 1.57 mmol) was dissolved in methanol (8 mL), and platinum dioxide (71.2 mg, 0.310 mmol) was added. The system was stirred at 0°C for 2 hours under a hydrogen atmosphere. The residue was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=19:1) to obtain compound 22-4 (442 mg, yield 82.8%, white solid). LCMS calc.for C ₁₅ H ₁₉ BrFN ₂ O[M+H] ⁺ :m/z＝341.1/343.1；Found:341.3/343.3.

Step 4: 2-((1-(3-ethoxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 22-4 (200 mg, 588 μmol), INT-1 (178 mg, 761 μmol), t-BuBrettphos Pd G3 (50.0 mg, 52.6 μmol), cesium carbonate (764 mg, 2.34 mmol) and DMF (4 mL) were added to the reaction bottle, and the system was stirred at 125° for 1.5 hours. Cooled to room temperature, diluted with saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with 1N hydrochloric acid (10 mL), and then washed with saturated aqueous sodium chloride solution (10 mL×2), and the crude product obtained after the organic phase was concentrated was subjected to column chromatography (DCM: MeOH = 19: 1) to obtain compound Cpd-22 (55.0 mg, yield 19.4%, yellow solid). LCMS calc.for C ₂₅ H ₂₆ FN ₄ O ₃ S[M+H] ⁺ :m/z＝481.2; Found: 480.8; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.93(s,1H),10.73(s,1H),8.80(d,J＝2.4Hz,1H),8.38(d,J＝2.8Hz,1H),7.58-7.49(m,2H),7.34(dd,J＝11.2,8.4Hz,1H), 7.25(dd,J＝7.6,2.4Hz,1H),7.15(dd,J＝5.2,3.6Hz,1H),7.03(ddd,J＝8.8,3.6,2.4Hz,1H),6.91(s,1H),4.17(q ,J＝7.2Hz,2H),2.58(d,J＝7.2Hz,2H),1.79(dt,J＝13.6,6.8Hz,1H),1.36(t,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,6H).

Example 23: 2-((1-(3-ethoxy-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-23)

Step 1: 3,5-dibromo-1-(3-ethoxy-5-fluorophenyl)-1H-pyrazole

Compound 2-1 (1.50 g, 6.64 mmol), compound 23-1 (1.22 g, 6.64 mmol), copper acetate (1.99 g, 9.96 mmol), pyridine (1.60 mL, 19.9 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred in an oxygen atmosphere at 90 ° C for 2 hours. Cool and filter, add saturated aqueous ammonium chloride solution (20 mL) to the filtrate, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate, and the residue is subjected to column chromatography (PE: EA = 19: 1) to obtain compound 23-2 (1.41 g, yield 58.3%, white solid). LCMS calc.for C ₁₁ H ₁₀ Br ₂ FN ₂ O[M+H] ⁺ :m/z＝362.9/364.9/366.9; Found: 363.1/365.1/367.1.

Step 2: 3-Bromo-1-(3-ethoxy-5-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 23-2 (1.40 g, 3.87 mmol), compound 2-3 (633 mg, 3.48 mmol), Pd(dppf)Cl ₂ (566 mg, 773 μmol), potassium phosphate (1.64 g, 7.73 mmol) and a mixed solvent of dioxane/water (20 mL, 4:1) were added to the reaction flask, and the system was stirred at 120°C for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (30 mL×3), and the combined organic phase was washed with a saturated aqueous sodium chloride solution (30 mL×2). The organic phase was concentrated, and the residue was subjected to column chromatography (PE:EA＝19:1) to obtain compound 23-3 (1.10 g, yield 84.1%, white solid). LCMS calc.for C ₁₅ H ₁₇ BrFN ₂ O[M+H] ⁺ :m/z＝339.0/341.0; Found: 339.1/341.1.

Step 3: 3-Bromo-1-(3-ethoxy-5-fluorophenyl)-5-isobutyl-1H-pyrazole

Compound 23-3 (1.10 g, 3.24 mmol) was dissolved in methanol (8 mL), and platinum dioxide (147 mg, 650 μmol) was added. The system was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝19:1) to obtain compound 23-4 (846 mg, yield 76.7%, white solid). LCMS calc.for C ₁₅ H ₁₉ BrFN ₂ O[M+H] ⁺ :m/z＝341.1/343.1；Found:341.2/343.2.

Step 4: 2-((1-(3-ethoxy-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 23-4 (846 mg, 2.48 mmol), INT-1 (871 mg, 3.72 mmol), t-BuBrettphos Pd G3 (212 mg, 250 μmol), cesium carbonate (3.23 g, 9.92 mmol) and DMF (10 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (40 mL), extract with ethyl acetate (20 mL × 3), and the combined organic phase is washed with saturated aqueous sodium chloride solution (20 mL × 2). The organic phase is concentrated and the residue is purified by column chromatography (DCM: MeOH = 19: 1) Compound Cpd-23 (266 mg, yield 22.3%, white solid) was obtained. LCMS calc. for C ₂₅ H ₂₆ FN ₄ O ₃ S [M+H] ⁺ : m/z = 481.2; Found: 481.2; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.98(s,1H),11.02(s,1H),8.76(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H), 7.53(dd,J＝7.2,4.4Hz,2H),7.15(dd,J＝5.2,3.6Hz,1H),6.95(d,J＝11.4Hz,2 H),6.88(dd,J＝10.0,2.0Hz,2H),4.11(q,J＝6.8Hz,2H),2.66(d,J＝7.2Hz,2H ),1.82(dt,J＝13.6,6.8Hz,1H),1.34(t,J＝7.2Hz,3H),0.87(d,J＝6.8Hz,6H).

Example 24: 2-(1-(3-ethoxyphenyl)-5-neopentyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-24)

Step 1: 1-[5-bromo-2-(3-ethoxyphenyl)pyrazol-3-yl]-2,2-dimethylpropan-1-ol

Under nitrogen protection, 3,5-dibromo-1-(3-ethoxyphenyl)pyrazole 6-2 (3.00 g, 8.67 mmol) was dissolved in tetrahydrofuran (30 mL), the system was stirred at -60 ° C for 5 minutes, isopropylmagnesium chloride (6.5 mL, 13.0 mmol, 2M tetrahydrofuran solution) was slowly added dropwise, and stirred for 1 hour. Then p-valeraldehyde (2.24 g, 26.0 mmol) was added, the system was slowly warmed to room temperature and continued to stir for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 24-1 (2.61 g, yield 85.5%, light yellow liquid). LC-MS calc.for C ₁₆ H ₂₂ BrN ₂ O ₂ [M+H] ⁺ :m/z＝353.1/355.1; Found: 353.3/355.3.

Step 2: 3-Bromo-5-neopentyl-1-(3-ethoxyphenyl)pyrazole

24-1 (1.00 g, 2.83 mmol) was dissolved in trifluoroacetic acid (15 mL), triethylsilane (15 mL) was added, and the system was stirred at 80°C for 48 hours. The reaction solution was concentrated, and the pH value of the solution was adjusted to 7-8 with saturated sodium bicarbonate, and then extracted with dichloromethane (100 ml × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE: EA = 10: 1) to obtain compound 24-2 (315 mg, yield 33.1%, light yellow solid). LC-MS calc. for C ₁₆ H ₂₂ BrN ₂ O [M + H] ⁺ : m / z = 337.1/339.1; Found: 337.3/339.3.

Step 3: 2-[[5-neopentyl-1-(3-ethoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, 24-2 (300 mg, 889 μmol) and INT-1 (312 mg, 1.33 mmol) were dissolved in toluene (5 mL), t-BuBrettphos Pd G3 (114 mg, 133 μmol) and cesium carbonate (578 mg, 1.78 mmol) were added, and the system was stirred at 120°C for 1 hour. The reaction solution was concentrated, and the residue was subjected to column chromatography (PE:EA=4:1) to obtain compound 24-3 (270 mg, yield 61.9%, yellow solid). LC-MS calc.for C ₂₇ H ₃₁ N ₄ O ₃ S[M+H] ⁺ :m/z＝491.2；Found:491.4.

Step 4: 2-(1-(3-ethoxyphenyl)-5-neopentyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

24-3 (250 mg, 509 μmol) was dissolved in a mixed solvent of methanol (5 mL), tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (122 mg, 5.10 mmol) was added. The system was stirred at 75 ° C for 0.5 hours. 1N hydrochloric acid was added to adjust the pH to 3, and extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparation to obtain compound Cpd-24 (105 mg, Yield 43.3%, yellow solid). LC-MS calc. for C ₂₆ H ₂₉ N ₄ O ₃ S [M+H] ⁺ : m/z = 477.2; Found: 477.5; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.92(s,1H),10.75(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.57-7.54(m,2H),7.42-7.40(m,1H),7. 17-7.15(m,1H),7.00-6.97(m,3H),6.92(s,1H),4.08(q,J＝7.3Hz,2H),2.68(s,2H),1.33(t,J＝8Hz,3H),0.78(s,9H).

Example 25: 2-((1-(3-ethoxyphenyl)-5-(1-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-25)

Step 1: 2-[[1-(3-ethoxyphenyl)-5-(1-hydroxy-2,2-dimethylpropyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 24-1 (250 mg, 707 μmol) and INT-1 (248 mg, 1.06 mmol) were dissolved in toluene (5 mL), t-BuBrettphos Pd G3 (90.7 mg, 106 μmol) and cesium carbonate (460 mg, 1.42 mmol) were added, and the system was stirred at 120 ° C for 1 hour under nitrogen atmosphere. The reaction solution was concentrated, and the crude product was subjected to column chromatography (PE: EA = 5: 1) to obtain compound 25-1 (250 mg, yield 69.9%, yellow solid). LC-MS calc. for C ₂₇ H ₃₁ N ₄ O ₄ S [M + H] ⁺ : m / z = 507.2; Found: 507.5.

Step 2: 2-((1-(3-ethoxyphenyl)-5-(1-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

25-1 (200 mg, 394 μmol) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (94.5 mg, 3.95 mmol) was added. The system was stirred at 75°C for 30 minutes. After cooling, the reaction solution was adjusted to pH 5 with 1N hydrochloric acid, extracted with ethyl acetate (50 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative purification to obtain compound Cpd-25 (70.0 mg, yield 36.1%, yellow solid). LC-MS calc.for C ₂₆ H ₂₉ N ₄ O ₄ S[M+H] ⁺ :m/z＝493.2；Found:493.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ13.89(s,1H),10.70(s,1H),8.83(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.54-7.51(m,2H),7.42(t,J＝1.4Hz,1H),7.16-7 .14(m,1H),7.08-6.97(m,4H),5.57(s,1H),4.43(s,1H),4.08(q,J＝11.1,6.9Hz,2H),1.34(t,J＝7.3,6.9Hz,3H),0.75(s,9H).

Example 26: 2-((1-(3-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-26)

Step 1: 3,5-dibromo-1-(3-(difluoromethoxy)phenyl)-1H-pyrazole

Compound 2-1 (1.00 g, 4.43 mmol), compound 26-1 (832 mg, 4.43 mmol), copper acetate (1.33 g, 6.64mmol), pyridine (1.07mL, 13.3mmol) and toluene (20mL), the system was stirred at 90℃ for 2 hours. Cooled to room temperature, filtered, the filtrate was added with saturated aqueous ammonium chloride solution (20mL), extracted with ethyl acetate (30mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝20:1) to obtain compound 26-2 (1.53g, yield 93.8%, colorless liquid). LCMS calc.for C ₁₀ H ₇ Br ₂ F ₂ N ₂ O[M+H] ⁺ :m/z＝366.9/368.9/370.9；Found:367.0/369.0/371.0.

Step 2: 3-Bromo-1-(3-(difluoromethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 26-2 (1.49 g, 4.05 mmol), compound 2-3 (664 mg, 3.64 mmol), Pd(dppf)Cl ₂ (296 mg, 410 μmol), potassium phosphate (1.72 g, 8.10 mmol) and a mixed solvent of 1,4-dioxane/water (20 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (30 mL×3), and the combined organic phase was washed with saturated brine (30 mL×2). The crude product obtained after concentrating the organic phase was subjected to column chromatography (PE:EA＝20:1) to obtain compound 26-3 (862 mg, yield 62.2%, colorless liquid). LCMS calc.for C ₁₄ H ₁₄ BrF ₂ N ₂ O[M+H] ⁺ :m/z＝343.0/345.0; Found: 343.0/345.0.

Step 3: 3-Bromo-1-(3-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazole

Compound 26-3 (862 mg, 2.51 mmol) was dissolved in methanol (10 mL), and platinum dioxide (114 mg, 502 μmol) was added. The system was stirred at 0°C in a hydrogen atmosphere for 2 hours. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝20:1) to obtain compound 26-4 (787 mg, yield 91.1%, colorless liquid). LCMS calc.for C ₁₄ H ₁₆ BrF ₂ N ₂ O[M+H] ⁺ :m/z＝345.0/347.0；Found:344.9/346.9.

Step 4: 2-((1-(3-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 26-4 (787 mg, 2.28 mmol), compound INT-1 (641 mg, 2.74 mmol), t-BuBrettphos Pd G3 (195 mg, 230 μmol), cesium carbonate (2.97 g, 9.12 mmol) and DMF (10 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (40 mL), extract with ethyl acetate (20 mL × 3), and the combined organic phase is washed with saturated aqueous sodium chloride solution (20 mL × 2). The crude product obtained after the organic phase is concentrated is subjected to column chromatography (DCM: MeOH = 93: 7), and then purified by preparation to obtain compound Cpd-26 (356 mg, yield 32.2%, yellow solid). LCMS calc.for C ₂₄ H ₂₃ F ₂ N ₄ O ₃ S[M+H] ⁺ :m/z＝485.1; Found: 485.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.94(s,1H),10.71(s,1H),8.81(d,J＝2.4Hz,1H),8.39(d,J＝2.6Hz,1H),7.60-7.53(m,2H),7.45-7.3 1(m,3H),7.26-7.13(m,2H),6.96(s,1H),2.64(d,J＝7.2Hz,2H),1.87-1.77(m,1H),0.86(d,J＝6.8Hz,6H).

Example 27: 2-((1-cyclohexyl-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-27)

Step 1: 3,5-dibromo-1-cyclohexyl-pyrazole

3,5-Dibromo-1H-pyrazole 2-1 (700 mg, 3.10 mmol) and bromocyclohexane 27-1 (1.01 g, 6.20 mmol) were dissolved in DMF (7 mL), cesium carbonate (2.53 g, 7.75 mmol) was added, and the system was reacted at 100°C for 16 hours. Cool and filter, add water (20 mL) to the filtrate, extract with ethyl acetate (100 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and the crude product was purified by column chromatography (PE:EA=20:1) to obtain product 27-2 (400 mg, yield 41.8%, yellow liquid). LCMS calc.for C ₉ H ₁₃ N ₂ Br ₂ [M+H] ⁺ :m/z＝306.9/308.9/310.9；Found:306.9/309.0/311.0.

Step 2: 3-Bromo-1-cyclohexyl-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 27-2 (350 mg, 1.14 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and 2-3 (207 mg, 1.14 mmol), potassium phosphate (481 mg, 2.27 mmol) and Pd(dppf)Cl ₂ (83.1 mg, 114 mmol) were added, and the system was stirred at 70°C in a nitrogen atmosphere for 4 hours. After cooling, water (20 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=30:1) to obtain compound 27-3 (150 mg, yield 46.6%, yellow liquid). LCMS calc.for C ₁₃ H ₂₀ N ₂ Br[M+H] ⁺ :m/z＝283.1/285.1；Found:283.3/285.3.

Step 3: 3-Bromo-1-cyclohexyl-5-isobutyl-pyrazole

Compound 27-3 (800 mg, 2.82 mmol) was dissolved in methanol (8 mL), and platinum dioxide (64.2 mg, 282 μmol) was added. The system was stirred at 0°C for 0.5 hours in a hydrogen atmosphere. The residue was filtered and concentrated, and purified by column chromatography (PE:EA=10:1) to obtain compound 27-4 (650 mg, yield 81.1%, yellow liquid). LCMS calc.for C ₁₃ H ₂₂ N ₂ Br[M+H] ⁺ :m/z＝285.1/287.1；Found:285.1/287.1.

Step 4: 2-[(1-cyclohexyl-5-isobutyl-pyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid

Compound 27-4 (300 mg, 1.05 mmol) was dissolved in DMF (3 mL), and INT-1 (246 mg, 1.05 mmol), cesium carbonate (514 mg, 1.58 mmol), and t-BuBrettphos Pd G3 (89.9 mg, 105 μmol) were added. The system was stirred at 120 ° C for 2 hours under a nitrogen atmosphere. After cooling, water (5 mL) was added to the reaction solution, and ethyl acetate (30 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative purification to obtain compound Cpd-27 (50.0 mg, yield 11.2%, yellow solid). LCMS calc.for C ₂₃ H ₂₉ N ₄ O ₂ S[M+H] ⁺ :m/z＝425.2；Found:425.2； ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.82(s,1H),10.51(s,1H)8.75(d,J＝2.8Hz,1H),8.34(d,J＝2.8Hz,1H),7.53-7.49(m,2H),7.15-7.13(m,1H),6.58(s,1H),4.04-3 .98(m,1H),2.52(d,J＝7.2Hz,2H),1.86-1.80(m,7H),1.77-1.74(m,1H),1.45-1.35(m,2H),1.25-1.19(m,1H),0.94(d,J＝4.8Hz,6H).

Example 28: 2-[(1-cycloheptyl-5-isobutyl-pyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-28)

Step 1: 3,5-dibromo-1-cycloheptyl-1H-pyrazole

3,5-Dibromo-1H-pyrazole 2-1 (1.28 g, 5.65 mmol) and bromocycloheptane 28-1 (2.00 g, 11.3 mmol) were dissolved in DMF (30 mL). Cesium carbonate (4.60 g, 14.1 mmol) was added. The system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was washed with a saturated sodium chloride aqueous solution (30 mL), and the organic phase was dried and concentrated. The organic phase was purified by column chromatography (PE:EA=10:1) to obtain compound 28-2 (1.62 g, yield 89.0%, colorless liquid). LCMS calc.for C ₁₀ H ₁₅ Br ₂ N ₂ [M+H] ⁺ :m/z＝321.0/323.0/325.0；Found:321.1/323.1/325.1.

Step 2: 3-Bromo-1-cycloheptyl-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Compound 28-2 (1.00 g, 3.11 mmol) was dissolved in tetrahydrofuran (15 mL) and water (3 mL), and 2-3 (678 mg, 3.73 mmol), Pd(dppf)Cl ₂ (227 mg, 311 μmol) and potassium phosphate (1.32 g, 6.21 mmol) were added. The system was stirred at 70°C for 2 hours under nitrogen protection. After the reaction, water (20 mL) was added, and ethyl acetate (50 mL) was used for extraction. The organic phase was dried and concentrated, and purified by column chromatography (PE 100%) to obtain compound 28-3 (693 mg, yield 75.3%, colorless liquid). LCMS calc. for C ₁₄ H ₂₂ BrN ₂ [M+H] ⁺ : m/z＝297.1/299.1；Found:297.3/299.3.

Step 3: 3-Bromo-1-cycloheptyl-5-isobutyl-1H-pyrazole

Compound 28-3 (770 mg, 2.59 mmol) was dissolved in methanol (10 mL), and platinum dioxide (118 mg, 518 μmol) was added. The system was stirred at 0°C for 1 hour under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated, and the residue was purified by chromatography column (PE 100%) to obtain compound 28-4 (475 mg, yield 61.5%, colorless liquid). LCMS calc.for C ₁₄ H ₂₄ BrN ₂ [M+H] ⁺ :m/z＝299.1/231.1；Found:299.2/231.2.

Step 4: 2-((1-cycloheptyl-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, INT-1 (196 mg, 835 μmol), t-BuBrettphos Pd G3 (71.4 mg, 83.5 μmol) and cesium carbonate (544 mg, 1.67 mmol) were added to a DMF (3 mL) solution of 28-4 (250 mg, 835 μmol), and the system was stirred at 120 ° C for 2 hours. After the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL). The organic phase was dried and concentrated, and purified by chromatography column (PE: EA = 5: 1) to obtain compound 28-5 (200 mg, yield 53.0%, yellow liquid). LCMS calc. for C ₂₅ H ₃₃ N ₄ O ₂ S [M + H] ⁺ : m / z = 453.2; Found: 453.3.

Step 5: 2-[(1-cycloheptyl-5-isobutyl-pyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid

Compound 28-5 (200 mg, 442 μmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide (52.9 mg, 2.21 mmol) was added, and stirred at 45°C for 1 hour. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH to 5, and the mixture was extracted with dichloromethane (20 mL). The organic phase was dried and concentrated to obtain a crude product, which was purified by preparation to obtain compound Cpd-28 (147 mg, yield 75.9%, yellow solid). LCMS calc.for C ₂₄ H ₃₁ N ₄ O ₂ S[M+H] ⁺ :m/z＝439.2；Found:439.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.52(s,1H),8.75(d,J＝2.6Hz,1H),8.35(d,J＝2.6Hz,1H),7.52(d,J＝14.1Hz,2H),7.15-7.14(m,1H),6.57(s,1H),4.2 0(d,J＝9.1Hz,1H),2.53(d,J＝3.1Hz,1H),2.03-1.91(m,2H),1.89-1.72(m,6H),1.65-1.45(m,7H),0.94(d,J＝6.6Hz,6H).

Example 29: 2-((1-(1-(tert-Butyloxycarbonyl)piperidin-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-29)

Step 1: tert-Butyl 3-(3,5-dibromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

Under nitrogen protection, compound 2-1 (3.00 g, 13.3 mmol), 29-1 (4.56 g, 17.3 mmol), triphenylphosphine (6.97 g, 26.6 mmol) and tetrahydrofuran (30 mL) were added to the reaction flask. Diisopropyl azodicarboxylate (6.71 g, 33.2 mmol) was added dropwise to the solution under ice bath. The system was stirred and reacted at room temperature for 1 hour, diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (50 mL), and the crude product obtained by concentrating the organic phase was subjected to column chromatography (PE: EA = 19: 1) to obtain compound 29-2 (4.41 g, yield 81.1%, colorless liquid). LCMS calc.for C ₁₃ H ₂₀ Br ₂ N ₃ O ₂ [M+H] ⁺ :m/z＝408.0/410.0/412.0; Found: 408.1/410.1/412.1.

Step 2: tert-Butyl 3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Under nitrogen protection, compound 29-2 (2.00 g, 4.89 mmol), compound 2-3 (890 mg, 4.89 mmol), Pd(dppf)Cl ₂ (257 mg, 490 μmol), potassium phosphate (2.08 g, 9.78 mmol) and a mixed solvent of dioxane/water (25 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. Cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (40 mL×3), the combined organic phase was washed with a saturated sodium chloride aqueous solution (30 mL×2), and then dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was subjected to column chromatography (PE:EA＝19:1) to obtain compound 29-3 (1.35 g, yield 72.1%, colorless liquid). LCMS calc.for C ₁₇ H ₂₇ BrN ₃ O ₂ [M+H] ⁺ :m/z＝384.1/386.1; Found: 384.1/386.1.

Step 3: tert-Butyl 3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

Compound 29-3 (1.00 g, 2.60 mmol) was dissolved in methanol (10 mL), and platinum dioxide (118 mg, 520 μmol) was added at 0°C. The system was stirred for 2 hours under a hydrogen atmosphere. The product was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝19:1) to obtain compound 29-4 (847 mg, yield 84.6%, colorless liquid). LCMS calc.for C ₁₇ H ₂₉ BrN ₃ O ₂ [M+H] ⁺ :m/z＝386.1/388.1；Found:386.3/388.3.

Step 4: 2-((1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 29-4 (800 mg, 2.07 mmol), compound INT-1 (534 mg, 2.28 mmol), t-BuBrettphos Pd G3 (177 mg, 186 μmol), cesium carbonate (1.35 g, 4.14 mmol) and DMF (10 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (40 mL), extract with ethyl acetate (20 mL × 3), and the combined organic phase is washed with saturated aqueous sodium chloride solution (30 mL). The crude product obtained after the organic phase is concentrated is subjected to column chromatography (DCM: MeOH = 19: 1) to obtain compound Cpd-29 (55.0 mg, yield 5.06%, yellow solid). LCMS calc.for C ₂₇ H ₃₆ N ₅ O ₄ S[M+H] ⁺ :m/z＝526.2; Found: 525.9; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.84(s,1H),10.68(s,1H),8.72(s,1H),8.35(d,J＝2.4Hz,1H),7.51(dd,J＝1 0.8,4.4Hz,2H),7.17-7.09(m,1H),6.64(s,1H),4.10-3.85(m,3H),3.10(s,1H) ,2.75(s,1H),2.60(s,1H),2.43-2.36(m,1H),2.07(s,1H),1.98-1.85(m,2H),1 .80-1.72(m,1H),1.61-1.51(m,1H),1.40(s,9H),0.96(dd,J＝15.2,6.8Hz,6H).

Example 30: 2-((5-isobutyl-1-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-30)

Step 1: 3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)piperidine

Compound 29-3 (500 mg, 1.30 mmol) and dichloromethane (4 mL) were added to the reaction flask, and hydrochloric acid (2 mL, 4N dioxane solution) was added dropwise. The system was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the crude product 30-1 (277 mg, yield 74.8%, white solid). LCMS calc.for C ₁₂ H ₁₉ BrN ₃ [M+H] ⁺ :m/z＝284.1/286.1；Found:284.2/286.2.

Step 2: 3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine

Compound 30-1 (277 mg, 975 μmol), potassium carbonate (404 mg, 2.92 mmol) and DMF (5 mL) were added to the reaction flask, and compound 30-2 (452 mg, 1.95 mmol) was added dropwise. The system was stirred at 50°C for 1 hour. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (10 mL×3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (30 mL). The crude product obtained after the organic phase was concentrated was subjected to column chromatography (PE:EA＝19:1) to obtain compound 30-3 (117 mg, yield 32.9%, white solid). LCMS calc.for C ₁₄ H ₂₀ BrF ₃ N ₃ [M+H] ⁺ :m/z＝366.1/368.1；Found:366.3/368.3.

Step 3: 3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine

Compound 30-3 (117 mg, 321 μmol) was dissolved in methanol (4 mL), and platinum dioxide (14.5 mg, 63.8 μmol) was added at 0°C. The system was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝19:1) to obtain compound 30-4 (100 mg, yield 84.9%, white solid). LCMS calc.for C ₁₄ H ₂₂ BrF ₃ N ₃ [M+H] ⁺ :m/z＝368.1/370.1；Found:368.2/370.2.

Step 4: 2-((5-isobutyl-1-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 30-4 (100 mg, 272 μmol), INT-1 (95.4 mg, 407 μmol), t-BuBrettphos Pd G3 (23.2 mg, 27.1 μmol), cesium carbonate (354 mg, 1.09 mmol) and DMF (4 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (10 mL × 3), and the combined organic phase is washed with saturated aqueous sodium chloride solution (20 mL). The crude product obtained after the organic phase is concentrated is subjected to column chromatography (DCM: MeOH = 19: 1) to obtain compound Cpd-30 (35.1 mg, yield 25.5%, yellow solid). LCMS calc.for C ₂₄ H ₂₉ F ₃ N ₅ O ₂ S[M+H] ⁺ :m/z＝508.2; Found: 508.0; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.84(s,1H),10.71(s,1H),8.72(d,J＝2.4Hz,1H),8.34(d,J＝2.4Hz,1H),7.51(dd,J＝1 1.2,4.4Hz,2H),7.14(dd,J＝4.8,3.6Hz,1H),6.62(s,1H),4.14(d,J＝8.8Hz,1H),3.26(t, J＝10.4Hz,2H),2.93(t,J＝10.4Hz,2H),2.77(t,J＝10.4Hz,1H),2.57(dd,J＝15.6,7.6Hz,2 H),2.38(t,J＝10.8Hz,1H),1.92-1.80(m,3H),1.77-1.60(m,2H),0.95(dd,J＝6.4,2.8Hz, 6H).

Example 31: 2-((5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-31-A and Cpd-31-B)

Step 1: 3-Hydroxycyclohexyl p-toluenesulfonate

Under nitrogen protection, compound 31-1 (5.00 g, 43.0 mmol), p-toluenesulfonyl chloride (3.04 g, 43.0 mmol), 4-dimethylaminopyridine (1.05 g, 8.61 mmol) and triethylamine (12 mL, 86.1 mmol) were dissolved in dichloromethane (50 mL), and the system was stirred at room temperature for 1 hour. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE: EA = 4: 1) to obtain compound 31-2 (2.40 g, yield 19.1%, colorless liquid). LCMS calc. for C ₁₃ H ₁₈ O ₄ SNa[M+Na] ⁺ : m/z = 293.1; Found: 293.1.

Step 2: 3-(3,5-dibromo-1H-pyrazol-1-yl)cyclohexanol

Under nitrogen protection, compound 31-2 (2.40 g, 8.88 mmol), compound 2-1 (2.11 g, 9.32 mmol), and cesium carbonate (5.78 g, 17.8 mmol) were dissolved in DMF (20 mL), and the system was stirred at 100 ° C for 1.5 hours. After cooling, the reaction solution was quenched with water (40 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE: EA = 4: 1) to obtain compound 31-3 (1.40 g, yield 48.7%, colorless liquid). LCMS calc. for C ₉ H ₁₃ Br ₂ N ₂ O [M + H] ⁺ : m / z = 322.9/324.9/326.9; Found: 323.1/325.1/327.1.

Step 3: 3,5-dibromo-1-(3-methoxycyclohexyl)-1H-pyrazole

Under nitrogen protection, sodium hydride (320 mg, 8.02 mmol, 60% content) was added to a DMF (10 mL) solution of compound 31-3 (1.30 g, 4.01 mmol) at 0°C. After the system was stirred at this temperature for 0.5 hours, iodomethane (0.50 mL, 8.02 mmol) was added and continued to stir for 1 hour. Water (30 mL) was added to quench the reaction, and ethyl acetate (30 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE: EA = 10: 1) to obtain compound 31-4 (1.10 g, yield 81.2%, colorless liquid). LCMS calc.for C ₁₀ H ₁₅ Br ₂ N ₂ O[M+H] ⁺ :m/z＝337.0/339.0/341.0; Found: 337.0/339.1/340.9.

Step 4: 3-Bromo-1-(3-methoxycyclohexyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 31-4 (801 mg, 2.37 mmol), compound 2-3 (474 mg, 2.60 mmol), Pd(dppf)Cl ₂ (346 mg, 473μmol) and potassium phosphate (1.11g, 5.21mmol) were dissolved in a mixed solvent of dioxane and water (12mL, 5:1), and the system was stirred at 80℃ for 1 hour. After cooling to room temperature, water (30mL) was added to quench the reaction, and ethyl acetate (30mL×3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA＝10:1) to obtain compound 31-5 (450mg, yield 60.9%, yellow liquid). LCMS calc.for C ₁₄ H ₂₂ BrN ₂ O[M+H] ⁺ :m/z＝313.1/315.1；Found:313.3/315.3.

Step 5: 3-Bromo-5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazole

Compound 31-5 (313 mg, 999 μmol) was dissolved in methanol (5 mL). Platinum dioxide (45.4 mg, 200 μmol) was then added, and the system was stirred at 0°C for 1 hour under hydrogen conditions. The mixture was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (PE:EA=10:1) to obtain compound 31-6 (191 mg, yield 60.8%, yellow liquid). LCMS calc.for C ₁₄ H ₂₄ BrN ₂ O[M+H] ⁺ :m/z=315.1/317.1;Found:315.2/317.2.

Step 6: 2-((5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 31-6 (260 mg, 828 μmol), INT-1 (194 mg, 828 μmol), t-BuBrettphos Pd G3 (48.4 mg, 50.8 μmol), cesium carbonate (540 mg, 1.65 mmol) and toluene (5 mL) were added to the reaction bottle, and the system was stirred at 120°C for 2 hours. Cooled to room temperature, water (30 mL) was added, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝5:1) to obtain compound 31-7 (210 mg, yield 54.2%, yellow solid). LCMS calc.for C ₂₅ H ₃₃ N ₄ O ₃ S[M+H] ⁺ :m/z＝469.2；Found:469.3.

Step 7: 2-((5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 31-7 (210 mg, 449 μmol) and lithium hydroxide (76.7 mg, 3.20 mmol) were dissolved in a mixed solution of water (3 mL) and tetrahydrofuran (3 mL). The system was stirred at 50°C for 1 hour and cooled to room temperature. The reaction solution was extracted with ethyl acetate (10 mL×3), then the pH was adjusted to 5 with 1N hydrochloric acid, and then extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative purification to obtain compound Cpd-31-A (45.1 mg, yield 22.1%, yellow solid). LCMS calc.for C ₂₄ H ₃₁ N ₄ O ₃ S[M+H] ⁺ :m/z＝455.2；Found:455.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.57(s,1H),8.76(d,J＝2.6Hz,1H),8.36(d,J＝2.2Hz,1H),7.55-7.50(m,2H),7.14(dd,J＝5.1,3.6Hz,1H),6.59(s,1H),4.20(d,J＝4.6Hz,4H),3.66(s,1H),3.26(s,3H),2.04-1.93(m,2H),1.92-1.72(m,4H),1.70-1.52(m,2H),1.38(t,J＝13.8Hz,1H),0.94(s,6H); compound Cpd-31-B (26.2mg, yield 12.9%), yellow solid was obtained. LCMS calc.for C ₂₄ H ₂₆ N ₅ O ₃ S[M+H] ⁺ :m/z＝455.2; Found: 455.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.51(s,1H),8.75(s,1H),8.35(s,1H),7.55-7.48(m,2H),7.14(s,1H),6.59(s,1H),4.10(q,J＝10.6Hz,1H),3.25(s,3H),2.53(d, J＝8.4Hz,2H),2.07(dd,J＝34.7,11.9Hz,2H),1.94-1.62(m,5H),1.37(d,J＝14.0Hz,1H),1.08(q,J＝13.8Hz,1H),0.94(d,J＝5.6Hz,6H).

Example 32: 2-[[1-[3-(Cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-32)

Step 1: 3,5-dibromo-1-(3-fluoro-5-methoxyphenyl)pyrazole

3,5-Dibromo-1H-pyrazole 2-1 (10.0 g, 44.3 mmol) and (3-fluoro-5-methoxyphenyl) boronic acid 32-1 (8.28 g, 48.7 mmol) were dissolved in toluene (100 mL), copper acetate (12.1 g, 66.4 mmol) and pyridine (10.7 mL, 133 mmol) were added at room temperature, oxygen was replaced three times, and the system was stirred at 90°C for 2 hours. LCMS showed that the reaction was completed, cooled to room temperature, filtered the reaction solution, extracted with ethyl acetate (200 mL) and water (70 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was purified by column chromatography (PE: EA = 10: 1) to obtain compound 32-2 (9.90 g, yield 63.9%, white solid). LCMS calc.for C ₁₀ H ₈ Br ₂ FN ₂ O[M+H] ⁺ :m/z＝348.9/350.9/352.9; Found: 348.7/350.8/352.8.

Step 2: 3-Bromo-1-(3-fluoro-5-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

Compound 32-2 (6.00 g, 17.1 mmol) and 2-3 (3.12 g, 17.1 mmol) were dissolved in THF (60 mL) and water (10 mL), potassium phosphate (7.28 g, 34.3 mmol) and Pd(dppf)Cl ₂ (1.63 g, 2.23 mmol) were added at room temperature, nitrogen was replaced three times, and the system was stirred at 70°C for 5 hours. LCMS showed that the reaction was completed, cooled to room temperature, the reaction solution was filtered, extracted with ethyl acetate (100 mL) and water (30 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was purified by column chromatography (PE:EA=8:1) to obtain compound 32-3 (2.87 g, yield 51.8%, yellow liquid). LCMS calc.for C ₁₄ H ₁₅ BrFN ₂ O[M+H] ⁺ :m/z＝325.0/327.0; Found: 324.9/326.9.

Step 3: 3-Bromo-1-(3-fluoro-5-methoxyphenyl)-5-isobutylpyrazole

Compound 32-3 (4.00 g, 12.3 mmol) was dissolved in methanol (40 mL) solution, and platinum dioxide (559 mg, 2.46 mmol) was added at room temperature. The hydrogen was replaced five times, and the system was stirred at 0°C for 1.5 hours. LCMS showed that the reaction was complete, and the mixture was filtered with methanol (40 mL). The crude product was collected under reduced pressure and purified by column chromatography (PE: EA = 8: 1) to obtain compound 32-4 (2.97 g, yield 74.1%, colorless liquid). LCMS calc. for C ₁₄ H ₁₇ BrFN ₂ O [M + H] ⁺ : m / z = 327.0/329.0; Found: 326.8/328.9.

Step 4: 3-(3-bromo-5-isobutylpyrazol-1-yl)-5-fluorophenol

Compound 32-4 (3.50 g, 10.7 mmol) was dissolved in hydrobromic acid acetic acid solution (15 mL, 33% content) and hydrobromic acid aqueous solution (15 mL, 48% content), and the system was stirred at 120°C for 4 hours. LCMS showed that the reaction was complete, and the mixture was cooled to room temperature, adjusted to alkalinity with saturated sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was The product was purified by column chromatography (PE:EA=4:1) to obtain compound 32-5 (2.25 g, yield 67.4%, yellow liquid). LCMS calc. for C ₁₃ H ₁₅ BrFN ₂ O[M+H] ⁺ : m/z=313.0/315.0; Found: 312.9/314.9.

Step 5: 3-Bromo-1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazole

Compound 32-5 (1.50 g, 4.79 mmol) and bromocyclobutane (647 mg, 4.79 mmol) were dissolved in DMF (10 mL), cesium carbonate (3.12 g, 9.58 mmol) was added at room temperature, and the system was stirred at 100 ° C for 1 hour. LCMS showed that the reaction was completed, cooled to room temperature, filtered the reaction solution, extracted with ethyl acetate (100 mL) and water (100 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product after filtration and concentration was purified by column chromatography (PE: EA = 8: 1) to obtain compound 32-6 (720 mg, yield 41.1%, colorless liquid). LCMS calc. for C ₁₇ H ₂₁ BrFN ₂ O [M + H] ⁺ : m / z = 367.1/369.1; Found: 366.8/368.9.

Step 6: 2-[[1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 32-6 (300 mg, 817 μmol) and INT-1 (191 mg, 817 μmol) were dissolved in toluene (6 mL), t-BuBrettphos Pd G3 (105 mg, 123 μmol) and cesium carbonate (532 mg, 1.63 mmol) were added at room temperature, and the system was stirred at 120 ° C for 1 hour under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (70 mL) and water (50 mL) were added, and the liquid was separated. The organic phase was dried over anhydrous sodium sulfate, and the crude product after filtration and concentration was purified by column chromatography (PE: EA = 8: 1) to obtain compound 32-7 (198 mg, yield 46.6%, yellow liquid). LCMS calc. for C ₂₈ H ₃₀ FN ₄ O ₃ S [M + H] ⁺ : m / z = 521.2; Found: 521.0.

Step 7: 2-[[1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 32-7 (198 mg, 381 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide (55.2 mg, 2.30 mmol) was added at room temperature. The system was stirred at 60°C for 0.5 hours. LCMS showed that the reaction was complete. After cooling to room temperature, the pH value was adjusted to 5-6 with 1N hydrochloric acid water, and ethyl acetate (50 mL) was added for extraction. The organic phase was concentrated and purified by preparative purification to obtain compound Cpd-32 (71.5 mg, yield 37.1%, yellow solid). LCMS calc.for C ₂₇ H ₂₈ FN ₄ O ₃ S[M+H] ⁺ :m/z＝507.2；Found:507.2； ¹ H NMR (400MHz, DMSO-d ₆ )δ13.92(s,1H),10.65(s,1H),8.78(d,J＝2.6Hz,1H),8.35(d,J＝2.6Hz,1H) ,7.55-7.49(m,2H),7.13(dd,J＝5.0,3.6Hz,1H),6.98-6.88(m,2H),6.78-6. 73(m,2H),4.80-4.73(m,1H),2.62(d,J＝7.1Hz,2H),2.48-2.42(m,2H),2.0 8-2.03(m,2H),1.86-1.70(m,2H),1.68-1.56(m,1H),0.83(d,J＝6.6Hz,6H).

Example 33: 2-((1-(3-cyclobutyloxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-33)

Step 1: 3,5-dibromo-1-(4-fluoro-3-methoxyphenyl)-1H-pyrazole

Compound 2-1 (2.66 g, 11.8 mmol), compound 33-1 (2.00 g, 11.8 mmol), copper acetate (3.05 g, 15.3 mmol), pyridine (1.89 mL, 23.5 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred at 90 ° C for 2 hours. Cool to room temperature and Filter, add saturated aqueous ammonium chloride solution (20 mL) to the filtrate, extract with ethyl acetate (40 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and perform column chromatography (PE:EA＝19:1) on the crude product after filtration and concentration to obtain compound 33-2 (2.22 g, yield 53.8%, white solid). LCMS calc.for C ₁₀ H ₈ Br ₂ FN ₂ O[M+H] ⁺ :m/z＝348.9/350.9/352.9；Found:349.3/351.3/353.3.

Step 2: 3-Bromo-1-(4-fluoro-3-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 33-2 (2.22 g, 6.35 mmol), compound 2-3 (1.04 g, 5.72 mmol), Pd(dppf)Cl ₂ (465 mg, 640 μmol), potassium phosphate (2.70 g, 12.7 mmol) and a mixed solvent of 1,4-dioxane/water (20 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (30 mL×2), and the organic phase was concentrated and purified by column chromatography (PE:EA＝19:1) to obtain compound 33-3 (1.73 g, yield 93.3%, white solid). LCMS calc.for C ₁₄ H ₁₅ BrFN ₂ O[M+H] ⁺ :m/z＝325.0/327.0; Found: 325.3/327.3.

Step 3: 3-Bromo-1-(4-fluoro-3-methoxyphenyl)-5-isobutyl-1H-pyrazole

Compound 33-3 (1.73 g, 5.33 mmol) was dissolved in methanol (20 mL), and platinum dioxide (363 mg, 1.60 mmol) was added. The system was stirred at 0°C for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=19:1) to obtain compound 33-4 (1.14 g, yield 65.6%, white solid). LCMS calc.for C ₁₄ H ₁₇ BrFN ₂ O[M+H] ⁺ :m/z＝327.0/329.0；Found:327.2/329.2.

Step 4: 5-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-fluorophenol

Compound 33-4 (1.14 g, 3.48 mmol) was dissolved in 1,2-dichloroethane (20 mL), and boron tribromide (1.31 g, 5.23 mmol) was added. The system was stirred at room temperature for 1 hour. The reaction was quenched with methanol (10 mL), and the reaction solution was concentrated. The crude product was purified by column chromatography (PE:EA=7:3) to obtain compound 33-5 (597 mg, yield 55.0%, white solid). LCMS calc.for C ₁₃ H ₁₅ BrFN ₂ O[M+H] ⁺ :m/z＝313.0/315.0；Found:313.2/315.2.

Step 5: 3-Bromo-1-(3-cyclobutyloxy-4-fluorophenyl)-5-isobutyl-1H-pyrazole

Compound 33-5 (597 mg, 1.91 mmol), cyclobutyl bromide (386 mg, 2.86 mmol) and cesium carbonate (1.24 g, 3.81 mmol) were dissolved in DMF (8 mL), and the system was stirred at 120°C for 1 hour. After cooling to room temperature, water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL × 2), and concentrated. The crude product was purified by column chromatography (PE: EA = 19: 1) to obtain compound 33-6 (699 mg, yield 100%, white solid). LCMS calc. for C ₁₇ H ₂₁ BrFN ₂ O [M + H] ⁺ : m / z = 367.1/369.1; Found: 367.2/369.2.

Step 6: 2-((1-(3-cyclobutyloxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 33-6 (699 mg, 1.90 mmol), compound INT-1 (535 mg, 2.28 mmol), t-BuBrettphos Pd G3 (163 mg, 190 μmol), cesium carbonate (2.48 g, 7.61 mmol) and DMF (10 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 2 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (40 mL), extract with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 2). The crude product obtained after concentrating the organic phase was purified by preparative purification to obtain compound Cpd-33 (72.2 mg, yield 7.51%, light yellow solid). LCMS calc.for C ₂₇ H ₂₈ FN ₄ O ₃ S[M+H] ⁺ :m/z＝507.2; Found: 506.8; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.91(s,1H),10.68(s,1H),8.80(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.59-7.50( m,2H),7.35(dd,J＝11.2,8.4Hz,1H),7.16(dd,J＝5.2,3.6Hz,1H),7.10-6.98(m,2H),6.91 (s,1H),4.91-4.76(m,1H),2.57(d,J＝7.2Hz,2H),2.47-2.39(m,2H),2.16 -2.01(m,2H),1.86-1.71(m,2H),1.70-1.56(m,1H),0.84(d,J＝6.4Hz,6H).

Example 34: 2-((5-isobutyl-1-(3-morpholinophenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-34)

Step 1: 4-(3-(3,5-dibromo-1H-pyrazol-1-yl)phenyl)morpholine

Compound 2-1 (2.18 g, 9.66 mmol), compound 34-1 (1.00 g, 4.83 mmol), copper acetate (1.45 g, 7.25 mmol), pyridine (1.94 mL, 24.2 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred at 90 ° C for 2 hours. Cool to room temperature, filter, add saturated aqueous ammonium chloride solution (30 mL) to the filtrate, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, and filter and concentrate the crude product for column chromatography (PE: EA = 19: 1) to obtain compound 34-2 (1.40 g, yield 74.9%, colorless liquid). LCMS calc.for C ₁₃ H ₁₄ Br ₂ N ₃ O[M+H] ⁺ :m/z＝385.9/387.9/389.9; Found: 386.1/388.1/390.1.

Step 2: 4-(3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)phenyl)morpholine

Under nitrogen protection, compound 34-2 (1.40 g, 3.40 mmol), compound 2-3 (594 mg, 3.26 mmol), Pd(dppf)Cl ₂ (265 mg, 360 μmol), potassium phosphate (1.54 g, 7.25 mmol) and a mixed solvent of 1,4-dioxane/water (20 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (30 mL×2), and the organic phase was concentrated and purified by column chromatography (PE:EA＝19:1) to obtain compound 34-3 (821 mg, yield 69.8%, white solid). LCMS calc.for C ₁₇ H ₂₁ BrN ₃ O[M+H] ⁺ :m/z＝362.1/364.1; Found: 362.2/364.2.

Step 3: 4-(3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)phenyl)morpholine

Compound 34-3 (821 mg, 2.27 mmol) was dissolved in methanol (8 mL), and platinum dioxide (154 mg, 680 μmol) was added. The system was stirred at 0°C for 2 hours under a hydrogen atmosphere. The product was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=19:1) to obtain compound 34-4 (413 mg, yield 50.1%, white solid). LCMS calc.for C ₁₇ H ₂₃ BrN ₃ O[M+H] ⁺ :m/z＝364.1/366.1；Found:364.3/366.3.

Step 4: 2-((5-isobutyl-1-(3-morpholinophenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 34-4 (413 mg, 1.13 mmol), compound INT-1 (266 mg, 1.13 mmol), t-BuBrettphos Pd G3 (97.0 mg, 110 μmol), cesium carbonate (1.48 g, 4.53 mmol) and DMF (4 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (40 mL), extract with ethyl acetate (20 mL × 3), and the combined organic phase is washed with saturated brine (20 mL × 2). After the organic phase is concentrated, it is purified by preparative method to obtain compound Cpd-34 (27.1 mg, yield 4.77%, light yellow solid). LCMS calc.for C ₂₇ H ₃₀ N ₅ O ₃ S[M+H] ⁺ :m/z＝504.2；Found:504.1； ¹ H NMR (400MHz, DMSO-d ₆ )δ13.91(s,1H),10.79(s,1H),8.79(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.57-7.49(m,2H),7.34(t,J＝8.0Hz,1H),7.15(dd,J＝5.2,3.6Hz,1 H),7.02-6.94(m,2H),6.93-6.83(m,2H),3.80-3.68(m,4H),3.21-3.12 (m,4H),2.59(d,J＝7.2Hz,2H),1.87-1.74(m,1H),0.85(d,J＝6.4Hz,7H).

Example 35: 2-((5-isobutyl-1-(3-(piperidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-35)

Step 1: 1-(3-(3,5-dibromo-1H-pyrazol-1-yl)phenyl)piperidine

Compound 2-1 (2.20 g, 9.75 mmol), compound 35-1 (1.00 g, 4.88 mmol), copper acetate (1.46 g, 7.31 mmol), pyridine (1.96 mL, 24.4 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred at 90 ° C for 2 hours. Cool to room temperature, filter, add saturated aqueous ammonium chloride solution (20 mL) to the filtrate, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, and filter and concentrate the crude product for column chromatography (PE: EA = 19: 1) to obtain compound 35-2 (1.31 g, yield 69.7%, white solid). LCMS calc.for C ₁₄ H ₁₆ Br ₂ N ₃ [M+H] ⁺ :m/z＝384.0/386.0/388.0; Found: 384.1/386.1/388.0.

Step 2: 1-(3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)phenyl)piperidine

Under nitrogen protection, compound 35-2 (1.31 g, 3.40 mmol), compound 2-3 (557 mg, 3.06 mmol), Pd(dppf)Cl ₂ (249 mg, 341 μmol), potassium phosphate (1.44 g, 6.80 mmol) and a mixed solvent of 1,4-dioxane/water (20 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (15 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (30 mL×2), and the organic phase was concentrated and purified by column chromatography (PE:EA＝19:1) to obtain compound 35-3 (866 mg, yield 78.8%, white solid). LCMS calc.for C ₁₈ H ₂₃ BrN ₃ [M+H] ⁺ :m/z＝360.1/362.1; Found: 360.0/362.0.

Step 3: 1-(3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)phenyl)piperidine

Compound 35-3 (866 mg, 2.40 mmol) was dissolved in methanol (8 mL), and platinum dioxide (164 mg, 720 μmol) was added. The system was stirred at 0°C for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=19:1) to obtain compound 35-4 (578 mg, yield 66.7%, white solid). LCMS calc.for C ₁₈ H ₂₅ BrN ₃ [M+H] ⁺ :m/z＝362.1/364.1；Found:362.0/364.0.

Step 4: 2-((5-isobutyl-1-(3-(piperidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 35-4 (578 mg, 1.60 mmol), compound INT-1 (374 mg, 1.60 mmol), t-BuBrettphos Pd G3 (137 mg, 161 μmol), cesium carbonate (2.08 g, 6.38 mmol) and DMF (10 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, add saturated ammonium chloride aqueous solution (40 mL) to dilute, extract with ethyl acetate (20 mL × 3), and the combined organic phase is washed with saturated brine (20 mL × 2). After the organic phase is concentrated, it is purified by preparative purification to obtain compound Cpd-35 (264 mg, yield 32.9％, white solid). LCMS calc.for C ₂₈ H ₃₂ N ₅ O ₂ S[M+H] ⁺ :m/z＝502.2；Found:502.0； ¹ H NMR(400MHz,DMSO-d ₆ )δ13.88(s,1H),10.83(s,1H),8.78(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H), 7.53(dd,J＝6.0,4.4Hz,2H),7.30(t,J＝8.0Hz,1H),7.15(dd,J＝5.2,3.6Hz,1H ),7.01-6.85(m,3H),6.84-6.73(m,1H),3.25-3.15(m,4H),2.58(d,J＝7.2Hz ,2H),1.81(dp,J＝13.2,6.8Hz,1H),1.69-1.49(m,6H),0.85(d,J＝6.8Hz,6H).

Example 36: 2-((5-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-36)

Step 1: 3,5-dibromo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

Compound 2-1 (1.00 g, 4.43 mmol), compound 36-1 (912 mg, 4.43 mmol), copper acetate (1.33 g, 6.64 mmol), pyridine (1.07 mL, 13.3 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred at 90 ° C for 2 hours. Cool to room temperature, filter, add saturated aqueous ammonium chloride solution (20 mL) to the filtrate, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, and filter and concentrate the crude product for column chromatography (PE: EA = 20: 1) to obtain compound 36-2 (764 mg, yield 44.7%, colorless liquid). LCMS calc.for C ₁₀ H ₆ Br ₂ F ₃ N ₂ O[M+H] ⁺ :m/z＝384.9/386.9/388.9; Found: 385.1/387.1/389.1.

Step 2: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

Under nitrogen protection, compound 36-2 (764 mg, 1.98 mmol), compound 2-3 (360 mg, 1.98 mmol), Pd(dppf)Cl ₂ (145 mg, 200 μmol), potassium phosphate (821 mg, 5.94 mmol) and a mixed solvent of 1,4-dioxane/water (15 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (30 mL×2), and the organic phase was concentrated and subjected to column chromatography (PE:EA＝20:1) to obtain compound 36-3 (469 mg, yield 65.8%, colorless liquid). LCMS calc.for C ₁₄ H ₁₃ BrF ₃ N ₂ O[M+H] ⁺ :m/z＝361.0/363.0; Found: 361.0/363.0.

Step 3: 3-Bromo-5-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

Compound 36-3 (469 mg, 1.30 mmol) was dissolved in methanol (10 mL), and platinum dioxide (88.0 mg, 390 μmol) was added. The system was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=20:1) to obtain compound 36-4 (340 mg, yield 72.2%, colorless liquid). LCMS calc.for C ₁₄ H ₁₅ BrF ₃ N ₂ O[M+H] ⁺ :m/z＝363.0/365.0；Found:363.0/365.0.

Step 4: 2-((5-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 36-4 (300 mg, 550 μmol), compound INT-1 (179 mg, 760 μmol), t-BuBrettphos Pd G3 (47.1 mg, 55.0 μmol), cesium carbonate (711 mg, 2.18 mmol) and DMF (4 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, add saturated ammonium chloride aqueous solution (20 mL) to dilute, extract with ethyl acetate (15 mL × 3), and combine The organic phase was washed with saturated brine (15 mL x 2), concentrated, and purified to obtain Cpd-36 (40.0 mg, yield 14.5%, yellow solid). LCMS calc.for C ₂₄ H ₂₂ F ₃ N ₄ O ₃ S[M+H] ⁺ :m/z＝503.1; Found: 503.0; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.94(s,1H),10.78(s,1H),8.80(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.68-7.61(m,2H),7.57-7.48(m, 4H),7.16(dd,J＝5.2,3.6Hz,1H),6.96(s,1H),2.63(d,J＝7.2Hz,2H),1.88-1.73(m,1H),0.86(d,J＝6.8Hz,6H).

Example 37: 2-((1-(4-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-37)

Step 1: 3,5-dibromo-1-(4-(difluoromethoxy)phenyl)-1H-pyrazole

Compound 2-1 (1.00 g, 4.43 mmol), compound 37-1 (832 mg, 4.43 mmol), copper acetate (1.33 g, 6.64 mmol), pyridine (1.07 mL, 13.3 mmol) and toluene (20 mL) were added to the reaction flask, and the system was stirred at 90°C for 2 hours. Cooled to room temperature, filtered, saturated aqueous ammonium chloride solution (20 mL) was added to the filtrate, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product after filtration and concentration was subjected to column chromatography (PE: EA = 20: 1) to obtain compound 37-2 (1.63 g, yield 100%, colorless liquid). LCMS calc.for C ₁₀ H ₇ Br ₂ F ₂ N ₂ O[M+H] ⁺ :m/z＝366.9/368.9/370.9; Found: 367.0/369.0/371.0.

Step 2: 3-Bromo-1-(4-(difluoromethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 37-2 (784 mg, 2.13 mmol), compound 2-3 (388 mg, 2.13 mmol), Pd(dppf)Cl ₂ (156 mg, 210 μmol), potassium phosphate (885 mg, 6.40 mmol) and a mixed solvent of dioxane/water (15 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (30 mL×2), and the organic phase was concentrated and purified by column chromatography (PE:EA＝20:1) to obtain compound 37-3 (606 mg, yield 83.2%, colorless liquid). LCMS calc.for C ₁₄ H ₁₄ BrF ₂ N ₂ O[M+H] ⁺ :m/z＝343.0/345.0; Found: 343.1/345.1.

Step 3: 3-Bromo-1-(4-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazole

Compound 37-3 (606 mg, 1.77 mmol) was dissolved in methanol (10 mL), and platinum dioxide (120 mg, 530 μmol) was added. The system was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=20:1) to obtain compound 37-4 (340 mg, yield 55.8%, colorless liquid). LCMS calc.for C ₁₄ H ₁₆ BrF ₂ N ₂ O[M+H] ⁺ :m/z＝345.0/347.0；Found:344.8/346.8.

Step 4: 2-((1-(4-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 37-4 (200 mg, 581 μmol), compound INT-1 (190 mg, 810 μmol), t-BuBrettphos Pd G3 (50.0 mg, 58.5 μmol), cesium carbonate (755 mg, 2.32 mmol) and DMF (3 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, add saturated ammonium chloride aqueous solution (20 mL) to dilute, extract with ethyl acetate (15 mL × 3), and combine The combined organic phase was washed with saturated brine (15 mL×2), and the organic phase was concentrated and purified to obtain Cpd-37 (67.1 mg, yield 23.9%, yellow solid). LCMS calc.for C ₂₄ H ₂₃ F ₂ N ₄ O ₃ S[M+H] ⁺ :m/z＝485.1; Found: 484.8; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.92(s,1H),10.74(s,1H),8.80(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.60-7.49(m,4H),7.36-7.2 6(m,3H),7.20-7.12(m,1H),6.93(s,1H),2.59(d,J＝7.2Hz,2H),1.89-1.74(m,1H),0.85(d,J＝6.8Hz,6H).

Example 38: 2-((5-isobutyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-38)

Step 1: tert-Butyl 4-(3,5-dibromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

Under nitrogen protection at 0°C, diisopropyl azodicarboxylate (11.6 mL, 59.0 mmol) was added dropwise to a solution of compound 2-1 (5.00 g, 24.8 mmol), compound 38-1 (6.73 g, 29.8 mmol) and triphenylphosphine (11.7 g, 44.7 mmol) in tetrahydrofuran (30 mL). After the addition was complete, the system was stirred and reacted at room temperature for 12 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phase was dried, filtered, concentrated and purified by column chromatography (PE: EA = 20: 1) to obtain compound 38-2 (5.00 g, yield 49.3%, off-white solid). LCMS calc.for C ₉ H ₁₂ Br ₂ N ₃ O ₂ [M+2H-tBu] ⁺ :m/z＝351.9/353.9/355.9; Found: 351.8/353.8/355.8.

Step 2: tert-butyl 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

At room temperature, potassium phosphate (3.54 g, 16.7 mmol) and Pd(dppf)Cl 2 (1.11 g, 1.52 mmol) were added to a mixed solution of compound 38-2 (3.10 g, 7.58 mmol) and compound _2-3 (1.52 g, 8.34 mmol) in 1,4-dioxane (30 mL) and water (6 mL), and the system was stirred at 80°C for 1 hour under nitrogen protection. After cooling, ethyl acetate (20 mL) and water (10 mL) were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (PE:EA＝19:1) to obtain compound 38-3 (2.34 g, yield 80.4%, yellow liquid). LCMS calc.for C ₁₃ H ₁₉ BrN ₃ O ₂ [M+2H-tBu] ⁺ :m/z＝328.1/330.1; Found: 328.0/329.9.

Step 3: tert-Butyl 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

At 0°C, platinum dioxide (415 mg, 1.83 mmol) was added to a solution of compound 38-3 (2.34 g, 6.09 mmol) in methanol (25 mL), and the system was stirred and reacted for 1 hour under a hydrogen atmosphere. After filtration, the filtrate was concentrated and purified by column chromatography (PE:EA=9:1) to obtain compound 38-4 (2.20 g, yield 93.8%, yellow liquid). LCMS calc.for C ₁₃ H ₂₁ BrN ₃ O ₂ [M+2H-tBu] ⁺ :m/z＝330.1/332.1；Found:329.9/331.9.

Step 4: 2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

At room temperature, t-BuBrettphos Pd G3 (221 mg, 259 μmol) and cesium carbonate (1.05 g, 3.24 mmol) were added to a toluene (8 mL) solution of compound 38-4 (500 mg, 1.29 mmol) and compound INT-1 (303 mg, 1.29 mmol), and the system was stirred at 120°C for 1 hour under nitrogen protection. After cooling and filtration, the filtrate was concentrated and purified by column chromatography (PE:EA=9:1) to obtain compound 38-5 (495 mg, yield 71.2%, yellow solid). LCMS calc.for C ₂₈ H ₃₈ N ₅ O ₄ S[M+H] ⁺ :m/z＝540.3；Found:540.0.

Step 5: 2-((5-isobutyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compound 38-5 (470 mg, 871 μmol) in dichloromethane (10 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, saturated sodium carbonate aqueous solution was added to adjust the pH to 8-9, extracted with ethyl acetate (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (DCM: MeOH = 10: 1) to obtain compound 38-6 (296 mg, yield 77.4%, yellow solid). LCMS calc. for C ₂₃ H ₃₀ N ₅ O ₂ S [M + H] ⁺ : m / z = 440.2; Found: 440.0.

Step 6: 2-((5-isobutyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

At room temperature, diisopropylethylamine (495 μL, 2.84 mmol) was added to a solution of compound 38-6 (125 mg, 284 μmol) in acetonitrile (2 mL), and then (2,2,2-trifluoroethyl) trifluoromethanesulfonate (99.0 mg, 427 μmol) was added. The system was stirred at room temperature for 16 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 38-7 (135 mg, crude product, yellow solid). LCMS calc. for C ₂₅ H ₃₁ F ₃ N ₅ O ₂ S [M+H] ⁺ : m/z = 522.2; Found: 522.0.

Step 7: 2-((5-isobutyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

At room temperature, lithium hydroxide (27.6 mg, 1.15 mmol) was added to a mixed solution of compound 38-7 (100 mg, 192 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL), and the system was stirred at 50°C for 1 hour. After cooling, 1.5 N hydrochloric acid was added to adjust the pH to 5-6, and ethyl acetate (10 mL) was added for extraction. The organic phase was concentrated and purified by preparative purification to obtain compound Cpd-38 (52.8 mg, yield 54.2%, yellow solid). LCMS calc.for C ₂₄ H ₂₉ F ₃ N ₅ O ₂ S[M+H] ⁺ :m/z＝508.2；Found:508.2； ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.81(s,1H),10.55(s,1H),8.76(d,J＝2.4Hz,1H),8.36(d,J＝2.5Hz,1H),7.61-7.35(m,2H),7.19-7.07(m,1H),6.61(s,1H),4.25-3.9 2(m,1H),3.59-3.36(m,2H),3.14-2.96(m,2H),2.18-2.02(m,2H),1.91-1.81(m,1H),1.73(dd,J＝14.4,4.2Hz,2H),0.96(d,J＝6.5Hz,6H).

Example 39: 2-((1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-39)

Compound 38-5 (297 mg, 550 μmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (1 mL), and lithium hydroxide (79.1 mg, 3.30 mmol) was added, and the system was stirred at 50°C for 1 hour. 1.5 N hydrochloric acid was added to adjust the pH to 5-6, and ethyl acetate (10 mL) was used for extraction. The organic phase was concentrated and purified by preparative purification to obtain compound Cpd-39 (108 mg, yield 37.5%, white solid). LCMS calc.for C ₂₇ H ₃₆ N ₅ O ₄ S[M+H] ⁺ :m/z＝526.2; Found: 526.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.85(s,1H),10.57(s,1H),8.74(d,J＝2.4Hz,1H),8.34(d,J＝2.6Hz,1H),7.55-7.47(m,2H),7.13(dd,J＝5.1,3 .6Hz,1H),6.60(s,1H),4.27(td,J＝11.1,5.5Hz,1H),4.05(s,2H),2.89(s,2H),2.54(d,J＝7.2Hz,2H),1.85(dq,J＝ 19.0, 12.0, 9.3Hz, 3H), 1.77-1.70 (m, 2H), 1.42 (s, 9H), 0.94 (d, J = 6.6Hz, 6H).

Example 40: 2-[1-[2-(difluoromethoxy)-5-pyridinyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-40)

Step 1: [2-(Difluoromethoxy)-5-pyridinyl]boronic acid

Compound 40-1 (2.50 g, 11.2 mmol) and biboronic acid pinacol ester (3.12 g, 12.3 mmol) were dissolved in 1,4-dioxane (25 mL), potassium acetate (3.40 g, 34.6 mmol) and Pd(dppf)Cl ₂ (815 mg, 1.12 mmol) were added, and the system was stirred at 90°C under nitrogen protection for 3 hours. After cooling, ethyl acetate (50 mL) was added and filtered, and the filtrate was concentrated to obtain compound 40-2 (2.61 g, crude product, black oil). LCMS calc. for C ₆ H ₇ BF ₂ NO ₃ [M+3H-Pinacol] ⁺ : m/z＝190.0；Found:190.3.

Step 2: 5-(3,5-dibromopyrazol-1-yl)-2-(difluoromethoxy)pyridine

Compound 2-1 (2.72 g, 12.0 mmol) and compound 40-2 (2.50 g, 13.2 mmol) were dissolved in toluene (25 mL), copper acetate (3.28 g, 18.0 mmol) and pyridine (2.85 g, 36.0 mmol) were added at room temperature, and the system was stirred at 90°C for 16 hours under an oxygen atmosphere. The mixture was cooled and filtered, and the filter cake was washed with ethyl acetate (100 mL). The organic phase was concentrated under reduced pressure and purified by column chromatography (PE:EA=10:1) to obtain compound 40-3 (1.80 g, yield 40.5%, yellow oil). LCMS calc.for C ₉ H ₆ Br ₂ F ₂ N ₃ O[M+H] ⁺ :m/z＝367.9/369.9/371.9；Found:368.0/370.0/372.0.

Step 3: 5-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]-2-(difluoromethoxy)pyridine

Compound 40-3 (1.80 g, 4.88 mmol) and compound 2-3 (1.24 g, 6.83 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), potassium phosphate (2.07 g, 9.76 mmol) and Pd(dppf)Cl ₂ (464 mg, 630 μmol) were added, and the system was stirred at 70°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was cooled, diluted with water (50 mL), extracted with ethyl acetate (60 mL), dried and concentrated, and purified by column chromatography (PE:EA=10:1) to obtain compound 40-4 (250 mg, yield 14.8%, colorless liquid). LCMS calc.for C ₁₃ H ₁₃ BrF ₂ N ₃ O[M+H] ⁺ :m/z＝344.0/346.0；Found:344.0/346.0.

Step 4: 5-(3-bromo-5-isobutylpyrazol-1-yl)-2-(difluoromethoxy)pyridine

Compound 40-4 (250 mg, 729 μmol) was dissolved in methanol (10 mL), and platinum dioxide (50 mg, 220 μmol) was added. The system was stirred at 0°C for 30 minutes under a hydrogen atmosphere. The residue was filtered and concentrated, and purified by column chromatography (PE:EA=10:1) to obtain compound 40-5 (250 mg, yield 99.4%, colorless oil). LCMS calc.for C ₁₃ H ₁₅ BrF ₂ N ₃ O[M+H] ⁺ :m/z＝346.0/348.0；Found:346.2/348.2.

Step 5: 2-[[1-[2-(difluoromethoxy)-5-pyridinyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 40-5 (230 mg, 660 μmol) and compound INT-1 (233 mg, 1.00 mmol) were dissolved in toluene (7 mL), t-BuBrettphos Pd G3 (85.2 mg, 100 μmol) and cesium carbonate (432 mg, 1.33 mmol) were added, and the system was stirred at 120°C for 2 hours under nitrogen protection. After cooling to room temperature, the mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=85:15) to obtain compound 40-6 (220 mg, yield 66.2%, yellow solid). LCMS calc.for C ₂₄ H ₂₄ F ₂ N ₅ O ₃ S[M+H] ⁺ :m/z=500.2;Found:500.2.

Step 6: 2-[1-[2-(difluoromethoxy)-5-pyridinyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 40-6 (210 mg, 420 μmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL), methanol (5 mL) and water (1 mL), and lithium hydroxide (100 mg, 4.20 mmol) was added, and the system was stirred at 50°C for 1 hour. The reaction solution was cooled to room temperature, the pH was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (50 mL×2). The organic phase was dried, concentrated and purified to obtain Cpd-40 (130 mg, yield 63.7%, yellow solid). LCMS calc.for C ₂₃ H ₂₂ F ₂ N ₅ O ₃ S[M+H] ⁺ :m/z＝486.1; Found: 486.1; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.98(s,1H),10.70(s,1H),8.82(s,1H),8.43(d,J＝26.7Hz,2H),8.13-7.78(m,2H),7.57-7.45 (m,2H),7.28-7.16(m,2H),6.98(s,1H),2.55(d,J＝6.1Hz,2H),1.81(m,1H),0.86(d,J＝5.8Hz,6H).

Example 41: 2-((1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-41)

Step 1: 3,5-dibromo-1-(3-methylphenyl)-1H-pyrazole

Under nitrogen protection at -60°C, isopropylmagnesium chloride (8.06mL, 8.06mmol, 1M tetrahydrofuran solution) was added dropwise to a tetrahydrofuran (20mL) solution of compound 40-4 (2.00g, 5.38mmol), and the system was stirred at -60°C for 1 hour. Then, a tetrahydrofuran (4mL) solution of p-fluorobenzaldehyde (801mg, 6.45mmol) was added dropwise to the above reaction solution, the dry ice bath was removed, and the mixture was naturally warmed to room temperature and continued to stir for 1 hour. After the reaction was completed, saturated ammonium chloride solution (50mL) was added to quench, and extracted with ethyl acetate (20mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE:EA＝5:1) to obtain compound 41-1 (1.29g, yield 57.5%, yellow oil). LCMS calc. for C ₂₀ H ₁₉ BrFN ₂ O ₂ [M+H] ⁺ :m/z=417.1/419.1; Found: 416.8/418.8.

Step 2: 3-Bromo-1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazole

A mixture of compound 41-1 (1.24 g, 2.97 mmol), trifluoroacetic acid (2 mL) and triethylsilane (4 mL) was heated to 80°C and stirred for 2 hours. After cooling to room temperature, a saturated sodium carbonate solution was added to adjust the pH to 8-9, and the mixture was extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE:EA＝10:1) to obtain compound 41-2 (1.15 g, yield 96.4%, yellow oil). LCMS calc.for C ₂₀ H ₁₉ BrFN ₂ O[M+H] ⁺ :m/z＝401.1/403.1；Found:401.2/403.2.

Step 3: 2-((1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Compound 41-2 (150 mg, 375 μmol) and compound INT-1 (403 mg, 1.72 mmol) were dissolved in toluene (3 mL), t-BuBrettphos Pd G3 (64.0 mg, 74.9 μmol) and cesium carbonate (304 mg, 93.3 μmol) were added, and the system was stirred at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=10:1) to obtain compound 41-3 (101 mg, yield 48.7%, yellow solid). LCMS calc.for C ₃₁ H ₂₈ FN ₄ O ₃ S[M+H] ⁺ :m/z=555.2;Found:555.4.

Step 5: 2-((1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 41-3 (90.0 mg, 162 μmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide (23.3 mg, 971 μmol) was added. The system was stirred at 50°C for 1 hour. After the reaction was completed, 1.5 N hydrochloric acid was added to adjust the pH to 6, and ethyl acetate (10 mL × 3) was used for extraction. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative method to obtain compound Cpd-41 (70.0 mg, yield 72.3%, yellow solid). LCMS calc.for C ₃₀ H ₂₆ FN ₄ O ₃ S[M+H] ⁺ :m/z＝541.2；Found:541.1； ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.96(s,1H),10.69(s,1H),8.74(d,J＝2.6Hz,1H),8.37(d,J＝2.6Hz,1H),7.54(dd,J＝5.1 ,1.0Hz,2H),7.36(t,J＝8.1Hz,1H),7.19(td,J＝5.8,2.3Hz,2H),7.16-7.10(m,3H),7.06-7.0 2(m,1H),6.90-6.84(m,1H),6.83(t,J＝2.1Hz,1H),6.80(s,1H),4.64(p,J＝7.2Hz,1H),4.11( s,2H),2.37-2.29(m,2H),2.06-1.95(m,2H),1.76(q,J＝10.2,9.1Hz,1H),1.66-1.53(m,1H).

Examples 42 & 43: 2-((5-isobutyl-1-(4-(trifluoromethyl)cyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-42 and Cpd-43)

Step 1: 3,5-dibromo-1-(4-(trifluoromethyl)cyclohexyl)-1H-pyrazole

Under ice bath, diisopropyl azodicarboxylate (13.9 mL, 70.6 mmol) was added dropwise to a tetrahydrofuran (50 mL) solution of compound 42-1 (5.00 g, 29.7 mmol), compound 2-1 (8.06 g, 35.7 mmol) and triphenylphosphine (14.0 g, 53.5 mmol). The reaction solution was slowly warmed to room temperature and stirred for 16 hours under nitrogen protection. After the reaction was completed, water (50 mL) was added, extracted with ethyl acetate (100 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was purified by column chromatography (PE: EA = 10: 1) to obtain compound 42-2 (3.20 g, yield 28.6%, white solid). LCMS calc.for C ₁₀ H ₁₂ Br ₂ F ₃ N ₂ [M+H] ⁺ :m/z＝374.9/376.9/378.9; Found: 375.0/377.0/379.0.

Step 2: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(4-(trifluoromethyl)cyclohexyl))-1H-pyrazole

Compound 42-2 (1.50 g, 3.99 mmol) and compound 2-3 (763 mg, 4.19 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL), potassium phosphate (1.86 g, 8.78 mmol) and Pd(dppf)Cl ₂ (584 mg, 798 μmol) were added, and the system was stirred at 80°C for 1 hour under nitrogen protection. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3), and the organic phase was dried and concentrated. The organic phase was purified by column chromatography (PE:EA＝10:1) to obtain compound 42-3 (900 mg, yield 64.2%, white solid). LCMS calc.for C ₁₄ H ₁₉ BrF ₃ N ₂ [M+H] ⁺ :m/z＝351.1/353.1；Found:351.1/353.1.

Step 3: 3-Bromo-5-isobutyl-1-(4-(trifluoromethyl)cyclohexyl))-1H-pyrazole

Compound 42-3 (900 mg, 2.56 mmol) was dissolved in methanol (10 mL), and platinum dioxide (116 mg, 510 μmol) was added. The system was stirred at 0°C for 1 hour under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated to obtain compound 42-4 (700 mg, crude product, colorless liquid). LCMS calc. for C ₁₄ H ₂₁ BrF ₃ N ₂ [M+H] ⁺ : m/z＝353.1/355.1；Found:353.2/355.2.

Step 4: 2-((5-isobutyl-1-(4-(trifluoromethyl)cyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Compound 42-4 (600 mg, 1.70 mmol) and compound INT-1 (517 mg, 2.21 mmol) were dissolved in toluene (6 mL), t-BuBrettphos Pd G3 (291 mg, 340 μmol) and cesium carbonate (1.38 g, 4.25 mmol) were added, and the system was stirred at 120°C for 1 hour under nitrogen protection. After the reaction was completed, the product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=1:1) to obtain compound 42-5 (560 mg, yield 65.1%, yellow solid). LCMS calc.for C ₂₅ H ₃₀ F ₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝507.2；Found:507.3.

Step 5: 2-((5-isobutyl-1-(cis-4-(trifluoromethyl)cyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid and 2-((5-isobutyl-1-(trans-4-(trifluoromethyl)cyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 42-5 (560 mg, 1.11 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), and lithium hydroxide (159 mg, 6.63 mmol) was added. The system was stirred at 50°C for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 4, and dichloromethane (10 mL×3) was used for extraction. The organic phase was dried, concentrated, purified and separated by SFC to obtain compound Cpd-42 (64.9 mg, yield 11.9%, yellow solid). LCMS calc. for C ₂₄ H ₂₈ F ₃ N ₄ O ₂ S [M+H] ⁺ : m/z = 493.2; Found: 493.3; ¹ H NMR (400 MHz, CDCl ₃ )δ8.70(s,1H),8.30(s,1H),7.30(s,2H),7.07(d,J＝4.2Hz,1H),6.48(s,1H),4.11(s,1H),2.49(d,J＝7.2Hz,2H),2.26(d,J＝12.0Hz,5H),2.02-1.73(m,5H),0.98(s,6H); Compound Cpd-43 (61.2mg, yield 11.2%, yellow solid), LCMS calc.for C ₂₄ H ₂₈ F ₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝493.2;Found:493.3; ¹ H NMR (400MHz,CDCl ₃ )δ8.54(d,J＝29.3Hz,2H),7.28(d,J＝4.9Hz,2H),7.08(d,J＝4.2Hz,1H),6.51(s,1H),3.97(s, 1H), 2.50 (d, J = 7.2Hz, 2H), 2.27-1.87 (m, 8H), 1.52 (d, J = 25.7Hz, 2H), 1.00 (d, J = 6.6Hz, 6H).

Example 44: 2-((1-(3-(difluoromethoxy)-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-44)

Step 1: 3,5-dibromo-1-(3-(difluoromethoxy)-5-fluorophenyl)-1H-pyrazole

Compound 2-1 (1.10 g, 4.86 mmol), compound 44-1 (1.00 mg, 4.86 mmol), copper acetate (1.45 g, 7.28 mmol), pyridine (1.17 mL, 14.6 mmol) and toluene (10 mL) were added to the reaction flask, and the system was stirred at 90°C for 2 hours. Cooled to room temperature, filtered, and the crude product after filtration and concentration was subjected to column chromatography (PE: EA = 20: 1) to obtain compound 44-2 (1.09 g, yield 58.0%, colorless liquid). LCMS calc. for C ₁₀ H ₆ Br ₂ F ₃ N ₂ O [M + H] ⁺ : m / z = 384.9/386.9/388.9; Found: 385.0/387.0/389.0.

Step 2: 3-Bromo-1-(3-(difluoromethoxy)-5-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, compound 44-2 (1.09 g, 2.82 mmol), compound 2-3 (461 mg, 2.53 mmol), Pd(dppf)Cl ₂ (206 mg, 280 μmol), potassium phosphate (1.20 g, 5.63 mmol) and a mixed solvent of 1,4-dioxane/water (15 mL, 4:1) were added to the reaction flask, and the system was stirred at 100°C for 2 hours. After cooling to room temperature, ethyl acetate (30 mL×3) was used for extraction, and the combined organic phase was washed with saturated brine (30 mL×2). The organic phase was concentrated and subjected to column chromatography (PE:EA＝20:1) to obtain compound 44-3 (751 mg, yield 73.8%, colorless liquid). LCMS calc.for C ₁₄ H ₁₃ BrF ₃ N ₂ O[M+H] ⁺ :m/z＝361.0/363.0; Found: 361.1/363.1.

Step 3: 3-Bromo-1-(3-(difluoromethoxy)-5-fluorophenyl)-5-isobutyl-1H-pyrazole

Compound 44-3 (751 mg, 2.08 mmol) was dissolved in methanol (10 mL), and platinum dioxide (142 mg, 620 μmol) was added. The system was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA＝20:1) to obtain compound 44-4 (511 mg, yield 67.7%, colorless liquid). LCMS calc.for C ₁₄ H ₁₅ BrF ₃ N ₂ O[M+H] ⁺ :m/z＝363.0/365.0；Found:363.3/365.3.

Step 4: 2-((1-(3-(difluoromethoxy)-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 44-4 (300 mg, 1.28 mmol), compound INT-1 (465 mg, 1.28 mmol), t-BuBrettphos Pd G3 (110 mg, 128 μmol), cesium carbonate (1.67 g, 5.12 mmol) and DMF (4 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (15 mL × 3), and the combined organic phase was washed with saturated brine (15 mL × 2). The organic phase was concentrated and purified to obtain compound Cpd-44 (23.8 mg, yield 3.69%, yellow solid). LCMS calc.for C ₂₄ H ₂₂ F ₃ N ₄ O ₃ S[M+H] ⁺ :m/z＝503.1; Found: 503.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.97(s,1H),10.78(s,1H),8.81(d,J＝2.5Hz,1H),8.39(d,J＝2.6Hz,1H),7.57-7.51(m,2H),7.42(t,J＝73.2Hz,1H ),7.40-7.32(m,1H),7.26-7.12(m,3H),6.99(s,1H),2.68(t,J＝6.0Hz,2H),1.90-1.70(m,1H),0.87(d,J＝6.6Hz,6H).

Example 45: 2-((5-isobutyl-1'-(2,2,2-trifluoroethyl)-1'H-[1,3'-bipyrazole]-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-45)

Step 1: 3-Bromo-1-(2,2,2-trifluoroethyl)pyrazole

Compound 45-1 (5.00 g, 34.0 mmol) was dissolved in DMF (60 mL), and 2,2,2-trifluoroethyl trifluoromethanesulfonate was added at room temperature. (15.8 g, 68.1 mmol) and cesium carbonate (22.2 g, 68.1 mmol), the reaction solution was stirred at 35°C for 2 hours. The reaction solution was filtered, water (100 mL) was added to the filtrate, and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝2:1) to obtain compound 45-2 (2.43 g, yield 31.2%, yellow oil). LCMS calc.for C ₅ H ₅ BrF ₃ N ₂ [M+H] ⁺ :m/z＝229.0/231.0；Found:228.9/231.0.

Step 2: [1-(2,2,2-trifluoroethyl)pyrazol-3-yl]boronic acid

Compound 45-2 (2.20 g, 9.61 mmol) and biboronic acid pinacol ester (2.93 g, 11.5 mmol) were dissolved in 1,4-dioxane (30 mL), and Pd(dppf)Cl ₂ (702 mg, 960 μmol) and potassium acetate (2.83 g, 28.8 mmol) were added at room temperature, and the system was stirred at 90°C for 16 hours under a nitrogen atmosphere. LCMS showed that the reaction was completed, and the mixture was cooled to room temperature, and water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA=2:1) to obtain compound 45-3 (1.28 g, yield 68.7%, brown oil). LCMS calc.for C ₅ H ₇ BF ₃ N ₂ O ₂ [M+3H-Pinacol] ⁺ :m/z=195.1; Found: 195.2.

Step 3: 3,5-dibromo-1-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyrazole

Compound 2-1 (1.20 g, 5.31 mmol) and 45-3 (1.24 g, 6.39 mmol) were dissolved in acetonitrile (20 mL), 4-dimethylaminopyridine (1.30 g, 10.6 mmol) and copper acetate (1.45 g, 7.97 mmol) were added at room temperature, and the system was stirred at 80 ° C for 3 hours under an oxygen atmosphere. LCMS showed that the reaction was completed, cooled to room temperature, filtered and concentrated, and the residue was subjected to column chromatography (PE: EA = 4: 1) to obtain compound 45-4 (990 mg, yield 50.0%, colorless oil). LCMS calc. for C ₈ H ₆ Br ₂ F ₃ N ₄ [M+H] ⁺ : m/z = 372.9/374.9/376.9; Found: 372.9/374.9/377.0.

Step 4: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyrazole

Compound 45-4 (900 mg, 2.41 mmol) and compound 2-3 (526 mg, 2.89 mmol) were dissolved in 1,4-dioxane (12 mL) and water (2 mL), and Pd(dppf)Cl ₂ (352 mg, 481 μmol) and potassium phosphate (1.02 g, 4.81 mmol) were added at room temperature. The system was heated to 70°C and stirred for 2 hours under nitrogen protection. LCMS showed that the reaction was complete, and the mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA=4:1) to obtain compound 45-5 (595 mg, yield 70.8%, yellow oil). LCMS calc.for C ₁₂ H ₁₃ BrF ₃ N ₄ [M+H] ⁺ :m/z＝349.0/351.0; Found: 349.1/351.0.

Step 5: 3-Bromo-5-isobutyl-1-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyrazole

Compound 45-5 (700 mg, 2.00 mmol) was dissolved in methanol (10 mL), and platinum dioxide (137 mg, 600 μmol) was added at room temperature. The reaction solution was stirred at 0°C for 1 hour under a hydrogen atmosphere. LCMS showed that the reaction was complete, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=4:1) to obtain compound 45-6 (440 mg, yield 63.6%, colorless oil). LCMS calc. _{C 12} H ₁₅ BrF ₃ N ₄ [M+H] ⁺ :m/z＝351.0/353.0；Found:351.1/353.0.

Step 6: 2-((5-isobutyl-1'-(2,2,2-trifluoroethyl)-1'H-[1,3'-bipyrazole]-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Compound 45-6 (300 mg, 855 μmol) and compound INT-1 (240 mg, 1.03 mmol) were dissolved in toluene (6 mL), t-BuBrettPhos Pd G3 (109 mg, 128 μmol) and cesium carbonate (555 mg, 1.71 mmol) were added at room temperature, and the system was stirred at 120 ° C for 4 hours under a nitrogen atmosphere. LCMS showed that the reaction was completed, cooled to room temperature, water (50 mL) was added, and extracted with ethyl acetate (70 mL), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EA = 4: 1) to obtain compound 45-7 (135 mg, yield 31.3%, yellow solid). LCMS calc. _{C 23} H ₂₄ F ₃ N ₆ O ₂ S [M + H] ⁺ : m / z = 505.2; Found: 505.2.

Step 7: 2-((5-isobutyl-1'-(2,2,2-trifluoroethyl)-1'H-[1,3'-bipyrazole]-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 45-7 (135 mg, 268 μmol) was dissolved in a mixed solvent of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide (68.8 mg, 2.87 mmol) was added, and the system was stirred at 75°C for 0.5 hours. LCMS showed that the reaction was complete, and the mixture was cooled to room temperature, and the pH value was adjusted to 5-6 with 1.5N hydrochloric acid, and extracted with ethyl acetate (20 mL×2), and the organic phase was concentrated and purified by preparative purification to obtain compound Cpd-45 (41.5 mg, yield 31.6%, white solid). LCMS calc.for C ₂₂ H ₂₂ F ₃ N ₆ O ₂ S[M+H] ⁺ :m/z＝491.1; Found: 491.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.95(s,1H),10.67(s,1H),8.81(s,1H),8.38(s,1H),7.95(s,1H),7.70-7.47(m,2H),7.22-7.06(m,1H),6. 90(s,1H),6.54(s,1H),5.17(q,J＝9.4Hz,2H),2.81(d,J＝6.6Hz,2H),1.94-1.78(m,1H),0.85(d,J＝5.7Hz,6H).

Example 46: 2-((1-((1R,3s,5S)-8-(tert-butyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-46)

Step 1: (1R,3s,5S)-3-(3,5-dibromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

In an ice-water bath, diisopropyl azodicarboxylate (8.90 g, 43.9 mmol) was added dropwise to a tetrahydrofuran (80 mL) solution of compound 2-1 (4.37 g, 19.4 mmol), compound 46-1 (4.00 g, 17.6 mmol) and triphenylphosphine (9.23 g, 35.2 mmol). The reaction solution was slowly warmed to room temperature and stirred for 16 hours under nitrogen protection. LCMS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA = 1: 5) to obtain compound 46-2 (5.40 g, yield 70.5%, yellow solid). LCMS calc.for C ₁₁ H ₁₄ Br ₂ N ₃ O ₂ [M+2H-tBu] ⁺ :m/z＝377.9/379.9/381.9; Found: 377.8/379.8/381.8.

Step 2: (1R, 3s, 5S)-3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Compound 46-2 (3.00 g, 6.89 mmol) and compound 2-3 (1.88 g, 10.3 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), potassium phosphate (2.93 g, 13.8 mmol) and Pd(dppf)Cl ₂ (1.01 g, 1.38 mmol) were added, and the reaction system was stirred at 100°C for 2 hours under nitrogen protection. LCMS showed that the reaction was complete, and the reaction solution was cooled to room temperature and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝1:5) to obtain compound 46-3 (720 mg, yield 25.5%, yellow oil). LCMS calc.for C ₁₅ H ₂₁ BrN ₃ O ₂ [M+2H-tBu] ⁺ :m/z＝354.1/356.1; Found: 353.9/355.9.

Step 3: (1R, 3s, 5S)-3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Compound 46-3 (800 mg, 1.95 mmol) was dissolved in methanol (10 mL), and platinum dioxide (133 mg, 580 μmol) was added. The reaction system was stirred at 0°C for 1 hour under a hydrogen atmosphere. LCMS showed that the reaction was complete, and the catalyst was removed by filtration and concentrated under reduced pressure to obtain compound 46-4 (544 mg, crude product, colorless oil). LCMS calc.for C ₁₅ H ₂₃ BrN ₃ O ₂ [M+2H-tBu] ⁺ :m/z＝356.1/358.1；Found: 355.9/357.9; ¹ H NMR (400MHz, DMSO-d ₆ )δ6.09(s,1H),4.60-4.47(m,1H),4.12(s,2H),2.53(d,J＝7.0Hz,2H),2.11-1.98(m,2 H),1.94-1.87(m,2H),1.84-1.76(m,3H),1.74-1.65(m,2H),1.41(s,9H),0.88(s,6H).

Step 4: 2-((1-((1R,3s,5S)-8-(tert-butyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 46-4 (680 mg, 1.65 mmol) and compound INT-1 (406 mg, 1.73 mmol) were dissolved in toluene (1 mL), cesium carbonate (1.61 g, 4.95 mmol) and t-BuBrettPhos Pd G3 (141 mg, 165 μmol) were added, and the reaction solution was heated to 120 ° C and stirred for 1 hour. LCMS showed that the reaction was completed, the reaction solution was cooled to room temperature and diluted with water (50 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EA＝3:1) to obtain compound 46-5 (450 mg, yield 48.2%, yellow solid). LCMS calc.for C ₃₀ H ₄₀ N ₅ O ₄ S[M+H] ⁺ :m/z＝566.3；Found:566.3.

Step 5: 2-((1-((1R,3s,5S)-8-(tert-butyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 46-5 (260 mg, 460 μmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide (88.1 mg, 3.68 mmol) was added at room temperature. The system was stirred at 70°C for 2 hours. LCMS showed that the reaction was complete, and the mixture was cooled to room temperature. The pH value was adjusted to 5-6 with 1N hydrochloric acid, and ethyl acetate (20 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain compound Cpd-46 (121 mg, yield 47.9%, yellow solid). LCMS calc.for C ₂₉ H ₃₈ N ₅ O ₄ S[M+H] ⁺ :m/z＝552.3；Found:552.0； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.58(s,1H),8.77-8.71(m,1H),8.36-8.32(m,1H),7.55-7.48(m,2H),7.16-7.10(m,1H),6.57(d,J＝4.2Hz,1H),4.56- 4.48(m,1H),4.15(s,2H),2.58-2.54(m,2H),2.21-2.11(m,2H),1.97-1.67(m,7H),1.47-1.44(m,9H),0.97-0.94(m,6H).

Example 47: 2-((5-isobutyl-1-((1R,3s,5S)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-47)

Step 1: 2-((1-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Trifluoroacetic acid (1 mL) was added to a dichloromethane (5 mL) solution of compound 46-5 (120 mg, 218 μmol), and the system was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete, and the reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate aqueous solution, and dichloromethane (10 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 47-1 (95.0 mg, crude product, yellow oil). LCMS calc. for C ₂₅ H ₃₂ N ₅ O ₂ S [M + H] ⁺ : m / z = 466.2; Found: 466.3.

Step 2: 2-((5-isobutyl-1-((1R,3s,5S)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

At room temperature, N,N-diisopropylethylamine (264 mg, 2.04 mmol) and trifluoromethanesulfonic acid (2,2,2-trifluoroethyl) ester (142 mg, 610 μmol) were added to a solution of compound 47-1 (95.0 mg, 204 μmol) in acetonitrile (4 mL). The reaction solution was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure and column chromatography (PE:EA=15:1) was performed to obtain compound 47-2 (70.0 mg, yield 62.6%, yellow solid). LCMS calc.for C ₂₇ H ₃₃ F ₃ N ₅ O ₂ S[M+H] ⁺ :m/z=548.2;Found:548.2.

Step 3: 2-((5-isobutyl-1-((1R,3s,5S)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 47-2 (70.0 mg, 128 μmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide (3.06 mg, 128 μmol) was added at room temperature. The reaction solution was stirred at 70°C for 1 hour. LCMS showed that the reaction was completed, and the mixture was cooled to room temperature. The pH value was adjusted to 5-6 with 1N hydrochloric acid aqueous solution, and ethyl acetate (10 mL×3) was added for extraction. The organic phase was concentrated and purified by preparative purification to obtain compound Cpd-47 (26.6 mg, yield 39.0%, yellow solid). LCMS calc.for C ₂₆ H ₃₁ F ₃ N ₅ O ₂ S[M+H] ⁺ :m/z＝534.2；Found:534.1； ¹ H NMR (400MHz, DMSO-d ₆ )δ13.83(s,1H),10.56(s,1H),8.71(d,J＝2.4Hz,1H),8.31(d,J＝2.4Hz,1H),7.51-7.4 5(m,2H),7.10(dd,J＝5.1,3.6Hz,1H),6.55(s,1H),4.32-4.14(m,1H),3.35-3.29(m,2 H),3.15(q,J＝10.0Hz,2H),2.51(d,J＝7.0Hz,2H),2.14(t,J＝11.9Hz,2H),1.95-1.86( m,2H),1.84-1.76(m,1H),1.71-1.65(m,2H),1.59-1.53(m,2H),0.92(d,J=6.6Hz,6H).

Example 48: 2-((1-(2-(difluoromethoxy)pyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-48)

Step 1: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-methoxypyridine

At room temperature, (2-methoxypyridin-4-yl)boric acid (4.06 g, 26.6 mmol), copper acetate (6.63 g, 33.2 mmol) and pyridine (5.34 mL, 66.4 mmol) were added to a toluene (100 mL) solution of 3,5-dibromopyrazole (5.00 g, 22.1 mmol), and the system was stirred at 90 ° C for 3 hours under an oxygen atmosphere. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA = 5: 1) to obtain compound 48-1 (4.80 g, yield 65.1%, white solid). LCMS calc. for C ₉ H ₈ Br ₂ N ₃ O [M + H] ⁺ : m / z = 331.9/333.9/335.9; found: 331.9/333.9/335.9.

Step 2: 4-(3,5-dibromo-1H-pyrazol-1-yl)pyridin-2-ol

Compound 48-1 (2.50 g, 7.51 mmol) and hydrobromic acid acetic acid solution (10 mL, 33% content) were added to the reaction flask, and the system was stirred at 100°C for 0.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated brine (30 mL ×2), the organic phase was concentrated and purified by column chromatography (PE:EA＝1:1) to obtain compound 48-2 (1.20 g, yield 50.2%, white solid). LCMS calc.for C ₈ H ₆ Br ₂ N ₃ O[M+H] ⁺ :m/z＝317.9/319.9/321.9;Found:317.9/319.9/321.8.

Step 3: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-(difluoromethoxy)pyridine

Compound 48-2 (720 mg, 2.26 mmol) was dissolved in acetonitrile (15 mL), sodium difluorochloroacetate (418 mg, 2.71 mmol) was added, and the system was stirred at 80°C for 16 hours. After cooling and filtration, the filtrate was concentrated and then subjected to column chromatography (PE:EA＝5:1) to obtain compound 48-3 (450 mg, yield 54.0%, white solid). LCMS calc.for C ₉ H ₆ Br ₂ F ₂ N ₃ O[M+H] ⁺ :m/z＝367.9/369.9/371.9；Found:367.9/370.0/371.9.

Step 4: 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-2-(difluoromethoxy)pyridine

Under argon protection, a mixture of compound 48-3 (450 mg, 1.22 mmol), compound 2-3 (211 mg, 1.16 mmol), Pd(dppf)Cl ₂ (99.6 mg, 120 μmol) and potassium phosphate (517 mg, 2.44 mmol) in 1,4-dioxane/water (12.5 mL, 4:1) was heated to 100°C and stirred for 5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (30 mL×3), and the organic phase was washed with saturated brine (30 mL×2). After the organic phase was concentrated, it was purified by column chromatography (PE:EA＝5:1) to obtain compound 48-4 (330 mg, yield 78.6%, colorless liquid). LCMS calc.for C ₁₃ H ₁₃ BrF ₂ N ₃ O[M+H] ⁺ :m/z＝344.0/346.0; Found: 344.0/346.1.

Step 5: 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-(difluoromethoxy)pyridine

Compound 48-4 (330 mg, 962 μmol) was dissolved in methanol (15 mL), and platinum dioxide (65.3 mg, 290 μmol) was added. The system was stirred at 0°C for 2 hours under a hydrogen atmosphere. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction solution was filtered and concentrated to obtain compound 48-4 (200 mg, crude product, colorless liquid). The crude product was directly used for the next reaction. LCMS calc.for C ₁₃ H ₁₅ BrF ₂ N ₃ O[M+H] ⁺ :m/z＝346.0/348.0；Found:346.0/348.0.

Step 6: 2-((1-(2-(difluoromethoxy)pyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under argon protection, compound 48-4 (200 mg, 580 μmol), compound INT-1 (153 mg, 690 μmol), t-BuBrettphos Pd G3 (49.4 mg, 57.8 μmol), cesium carbonate (941 mg, 2.89 mmol) and DMF (8 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 2 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (15 mL × 3), and the combined organic phase was washed with saturated brine (15 mL × 2). After the organic phase was concentrated, Cpd-48 (49.0 mg, yield 17.4%, yellow solid) was obtained by preparative purification. LCMS calc.for C ₂₃ H ₂₂ F ₂ N ₅ O ₃ S[M+H] ⁺ :m/z＝486.1; Found: 486.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ14.05(s,1H),10.94(s,1H),8.80(d,J＝2.4Hz,1H),8.40(d,J＝2.4Hz,1H),8.35(d,J＝5.6Hz,1H),7.77(t,J＝72.8Hz,1H),7.56-7.52(m, 3H),7.27(d,J＝1.6Hz,1H),7.16(dd,J＝4.0,5.2Hz,1H),7.07(s,1H),2.82(d,J＝6.8Hz,2H),1.94-1.84(m,1H),0.93(s,3H),0.91(s,3H).

Example 49: 2-((1-(2-ethoxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-49)

Step 1: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-ethoxypyridine

At room temperature, (2-ethoxypyridin-4-yl)boric acid (1.77 g, 10.6 mmol), copper acetate (2.65 g, 13.3 mmol) and pyridine (2.14 mL, 26.6 mmol) were added to a toluene (40 mL) solution of compound 2-1 (2.00 g, 8.85 mmol). The system was stirred at 90 ° C for 3 hours under an oxygen atmosphere. The mixture was cooled and filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE: EA = 4: 1) to obtain compound 49-1 (2.60 g, yield 84.6%, white solid). LCMS calculated value C ₁₀ H ₁₀ Br ₂ N ₃ O [M + H] ⁺ : m / z = 345.9/347.9/349.9; detected value: 346.0/348.0/350.0.

Step 2: 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-2-ethoxypyridine

Under argon protection, a mixture of compound 49-1 (1.00 g, 2.88 mmol), compound 2-3 (500 mg, 2.74 mmol), Pd(dppf)Cl ₂ (240 mg, 290 μmol) and potassium phosphate (1.22 g, 5.76 mmol) in 1,4-dioxane/water (25 mL, 4:1) was heated to 100°C for 5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with saturated brine (30 mL×2). After the organic phase was concentrated, it was purified by column chromatography (PE:EA＝5:1) to obtain compound 49-2 (760 mg, crude product, colorless liquid). LCMS calc.for C ₁₄ H ₁₇ BrN ₃ O[M+H] ⁺ :m/z＝322.1/324.1；Found:322.0/324.0.

Step 3: 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-ethoxypyridine

Compound 49-2 (760 mg, 2.36 mmol) was dissolved in methanol (30 mL), and platinum dioxide (270 mg, 1.18 mmol) was added. The system was stirred for 2 hours under a hydrogen atmosphere. The mixture was filtered and concentrated to obtain compound 49-3 (480 mg, crude product, colorless liquid). LCMS calc. for C ₁₄ H ₁₉ BrN ₃ O[M+H] ⁺ :m/z＝324.1/326.1；Found:324.1/326.1.

Step 4: 2-((1-(2-ethoxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under argon protection, compound 49-3 (200 mg, 619 μmol), compound INT-1 (173 mg, 740 μmol), t-BuBrettphos Pd G3 (52.8 mg, 61.8 μmol), cesium carbonate (804 mg, 2.47 mmol) and DMF (8 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 2 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (15 mL × 3), the organic phase is washed with saturated brine (15 mL × 2), and the organic phase is concentrated and purified by preparative purification to obtain Cpd-49 (96.0 mg, yield 33.4%, yellow solid). LCMS calc.for C ₂₄ H ₂₆ N ₅ O ₃ S[M+H] ⁺ :m/z＝464.2；Found:464.5； ¹ H NMR (400 MHz, DMSO-d ₆ )δ14.02(s,1H),10.89(s,1H),8.79(d,J＝2.8Hz,1H),8.39(d,J＝2.8Hz,1H),8 .23(d,J＝5.6Hz,1H),7.56-7.54(m,2H),7.21(dd,J＝6.0,2.0Hz,1H),7.17-7. 15(m,1H),7.02(s,1H),6.92(d,J＝1.6Hz,1H),4.39-4.34(m,2H),2.77(d,J＝7 .2Hz,2H),1.93-1.83(m,1H),1.35(t,J=6.8Hz,3H),0.91(s,3H),0.89(s,3H).

Example 50: 2-((1-(4-trifluoromethylphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-50)

Step 1: 3,5-dibromo-1-(4-trifluoromethylphenyl)-1H-pyrazole

At room temperature, 4-trifluoromethylphenylboronic acid (2.00 g, 10.5 mmol), copper acetate (4.58 g, 21.1 mmol) and pyridine (2.54 mL, 31.6 mmol) were added to a toluene (30 mL) solution of compound 2-1 (3.57 g, 15.80 mmol), and the system was stirred at 90 ° C for 2 hours in an oxygen atmosphere. Cool and filter, concentrate the filtrate, and purify the crude product by column chromatography (PE: EA = 10: 1) to obtain compound 50-1 (1.36 g, yield 34.9%, colorless liquid). LCMS calculated value C ₁₀ H ₆ Br ₂ F ₃ N ₂ [M+H] ⁺ : m/z = 368.9/370.9/372.9; detected value: 369.0/371.0/373.0.

Step 2: 3-Bromo-1-(4-trifluoromethylphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Under nitrogen protection, a mixture of compound 50-1 (1.36 g, 3.68 mmol), compound 2-3 (669 mg, 3.68 mmol), Pd(dppf)Cl ₂ (269 mg, 370 μmol) and potassium phosphate (1.56 g, 7.35 mmol) in 1,4-dioxane/water (15 mL, 4:1) was heated to 100°C and reacted for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (30 mL×3), and the combined organic phase was washed with saturated brine (30 mL×2). The organic phase was concentrated and subjected to column chromatography (PE:EA＝20:1) to obtain compound 50-2 (792 mg, yield 62.4%, colorless liquid). LCMS calc.for C ₁₄ H ₁₃ BrF ₃ N ₂ [M+H] ⁺ :m/z＝345.0/347.0; Found: 345.1/347.1.

Step 3: 3-Bromo-1-(4-trifluoromethylphenyl)-5-isobutyl-1H-pyrazole

Compound 50-2 (792 mg, 2.29 mmol) was dissolved in methanol (10 mL), and platinum dioxide (208 mg, 920 μmol) was added. The system was stirred for 2 hours under a hydrogen atmosphere. Filtered and concentrated, the crude product was purified by column chromatography (PE:EA=20:1) to obtain compound 50-3 (735 mg, yield 92.4%, colorless liquid). LCMS calc.for C ₁₄ H ₁₅ BrF ₃ N ₂ [M+H] ⁺ :m/z＝347.0/349.0；Found:347.0/349.0.

Step 4: 2-((1-(4-trifluoromethylphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Under nitrogen protection, compound 50-3 (375 mg, 1.08 mmol), compound INT-1 (304 mg, 1.30 mmol), t-BuBrettphos Pd G3 (101 mg, 118 μmol), cesium carbonate (1.40 g, 4.32 mmol) and DMF (8 mL) were added to the reaction bottle, and the system was stirred at 120 ° C for 1.5 hours. Cool to room temperature, dilute with saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (15 mL × 2). After the organic phase was concentrated, it was purified by preparative purification to obtain compound Cpd-50 (85.8 mg, yield 15.8%, yellow solid). LCMS calc.for C ₂₄ H ₂₂ F ₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝487.1; Found: 487.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.98(s,1H),10.91(s,1H),8.80(d,J＝2.4Hz,1H),8.39(d,J＝2.4Hz,1H),7.88(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),7.5 4(t,J＝4.6Hz,2H),7.16(dd,J＝5.2,3.6Hz,1H),7.01(s,1H),2.70(d,J＝7.2Hz,2H),1.89-1.79(m,1H),0.87(d,J＝6.8Hz,6H).

Example 51: 2-((5-isobutyl-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-51)

Step 1: Iodinated mesitylene di[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate]

Under nitrogen atmosphere, compound 51-2 (910 mg, 2.50 mmol) and compound 51-1 (900 mg, 5.00 mmol) were dissolved in toluene solution (10 mL), and the system was stirred at 55° C. for 0.5 hours. After concentration, compound 51-3 (1.70 g, crude product, white solid) was obtained.

Step 2: 3,5-dibromo-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole

Under nitrogen protection, compound 51-3 (1.70 g, 2.81 mmol), compound 2-1 (0.70 g, 3.09 mmol), copper acetylacetonate (220 mg, 840 μmol) and tris(2-phenylpyridine)iridium (18.4 mg, 28.1 μmol) were dissolved in 1,4-dioxane (20 mL). The system was stirred at room temperature for 20 hours under 465 nm (18 V) light source, and then the system was exposed to air for five minutes and quenched with saturated aqueous sodium carbonate solution (20 mL). It was extracted with dichloromethane (20 mL × 3), and the combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the crude product after filtration and concentration was purified by column chromatography (PE: EA = 5: 1) to obtain compound 51-4 (431 mg, yield 42.4%, yellow solid). LCMS calc.for C ₉ H ₈ Br ₂ F ₃ N ₂ [M+H] ⁺ :m/z＝358.9/360.9/362.9; Found: 359.0/361.0/363.0.

Step 3: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole

Under nitrogen protection, compound 51-4 (431 mg, 1.20 mmol), compound 2-3 (220 mg, 1.20 mmol), Pd(dppf)Cl ₂ (171 mg, 240 μmol) and potassium phosphate (631 mg, 2.98 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (6 mL, 5:1), and the system was stirred at 70°C for 2 hours. After cooling and filtration, the filtrate was extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL×2). The organic phase was concentrated and subjected to column chromatography (PE:EA＝5:1) to obtain compound 51-5 (191 mg, yield 47.7%, colorless oil). LCMS calc.for C ₁₃ H ₁₅ BrF ₃ N ₂ [M+H] ⁺ :m/z＝335.0/337.0; Found: 335.1/337.1.

Step 4: 3-Bromo-5-isobutyl-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole

Compound 51-5 (191 mg, 572 μmol) was dissolved in methanol (2 mL), and platinum dioxide (25.9 mg, 110 μmol) was added at 0°C, and then the system was stirred for 0.5 hours under a hydrogen atmosphere. The mixture was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=5:1) to obtain compound 51-6 (170 mg, yield 90.0%, colorless oil). LCMS calc.for C ₁₃ H ₁₇ BrF ₃ N ₂ [M+H] ⁺ :m/z＝337.0/339.0；Found:337.2/339.2.

Step 5: 2-((5-isobutyl-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 51-6 (170 mg, 506 μmol), compound INT-1 (131 mg, 550 μmol), t-BuBrettphos Pd G3 (130 mg, 152 μmol) and cesium carbonate (411 mg, 1.26 mmol) were dissolved in toluene (2 mL), and the system was stirred at 120°C for 1.5 hours. After cooling and filtration, the filtrate was concentrated and subjected to column chromatography (PE:EA=3:1) to obtain compound 51-7 (182 mg, yield 73.4%, yellow solid). LCMS calc.for C ₂₄ H ₂₆ F ₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝491.2；Found:491.2.

Step 6: 2-((5-isobutyl-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 51-7 (182 mg, 371 μmol) and lithium hydroxide (87.9 mg, 3.67 mmol) were dissolved in a mixed solvent of tetrahydrofuran and water (3 mL, 2:1), and the system was stirred at 50°C for 0.5 hours. After cooling to room temperature, the pH value was adjusted to 3 with 1N hydrochloric acid, and extracted with dichloromethane (10 mL×3). The organic phase was concentrated and purified by preparative purification to obtain Cpd-51 (41.1 mg, yield 23.5%, yellow solid). LCMS calc.for C ₂₃ H ₂₄ F ₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝447.2; Found: 477.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.93(s,1H),10.57(s,1H),8.77(d,J＝2.6Hz,1H),8.35(d,J＝2.6Hz,1H),7.57-7.49(m,2H),7.14 (dd,J＝5.1,3.6Hz,1H),6.71(s,1H),2.58(d,J＝4.0Hz,8H),1.90-1.81(m,1H),0.97(d,J＝6.6Hz,6H).

Example 52: 2-[[5-isobutyl-1-[2-(trifluoromethoxy)-5-pyridyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-52)

Step 1: [2-(Trifluoromethoxy)-5-pyridinyl]boronic acid

Under nitrogen protection at -60°C, n-butyl lithium (3.10 mL, 4.96 mmol, 1.6 M tetrahydrofuran solution) was slowly dripped into a THF (8 mL) solution of compound 52-1 (800 mg, 3.31 mmol). After the addition was completed, the system was stirred for 30 minutes, and then trimethyl borate (1.03 g, 9.92 mmol) was added. The reaction solution was warmed to room temperature and continued to stir for 1.5 hours. The reaction was quenched with saturated ammonium chloride solution (150 mL), the pH was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 52-2 (650 mg, crude product, white solid). LCMS calc.for C ₆ H ₆ BF ₃ NO ₃ [M+H] ⁺ :m/z＝208.0；Found:208.1.

Step 2: 5-(3,5-dibromopyrazol-1-yl)-2-(trifluoromethoxy)pyridine

Compound 2-1 (645 mg, 2.86 mmol) and compound 52-2 (650 mg, 3.14 mmol) were dissolved in toluene (10 mL), copper acetate (778 mg, 4.28 mmol) and pyridine (677 mg, 8.57 mmol) were added at room temperature, and the system was stirred at 90 ° C for 16 hours under an oxygen atmosphere. The reaction solution was filtered, the filter cake was washed with EA (100 mL), the organic phase was concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10: 1) to obtain compound 52-3 (370 mg, yield 33.4%, yellow oil). LCMS calc. for C ₉ H ₅ Br ₂ F ₃ N ₃ O [M+H] ⁺ : m/z = 385.9/387.9/389.9; Found: 386.0/388.0/390.0.

Step 3: 5-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]-2-(trifluoromethoxy)pyridine

Compound 52-3 (350 mg, 904 μmol) and compound 2-3 (247 mg, 1.36 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), potassium phosphate (384 mg, 1.81 mmol) and Pd(dppf)Cl ₂ (86.0 mg, 118 μmol) were added, and the system was stirred at 70°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was cooled, water (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and purified by column chromatography (PE:EA=8:1) to obtain compound 52-4 (300 mg, yield 91.5%, yellow liquid). LCMS calc.for C ₁₃ H ₁₂ BrF ₃ N ₃ O[M+H] ⁺ :m/z＝362.0/364.0；Found:362.0/364.0.

Step 4: 5-(3-bromo-5-isobutylpyrazol-1-yl)-2-(trifluoromethoxy)pyridine

Compound 52-4 (280 mg, 776 μmol) was dissolved in methanol (10 mL), and platinum dioxide (35.1 mg, 154 μmol) was added. The system was stirred at 0°C for 30 minutes under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=8:1) to obtain compound 52-5 (140 mg, yield 49.7%, colorless oil). LCMS calc.for C ₁₃ H ₁₄ BrF ₃ N ₃ O[M+H] ⁺ :m/z＝364.0/366.0；Found:364.1/366.1.

Step 5: 2-[5-isobutyl-1-[2-(trifluoromethoxy)-5-pyridinyl]amino]-5-(thiophen-2-yl)nicotinate

Compound 52-5 (130 mg, 358 μmol) and compound INT-1 (125 mg, 540 μmol) were dissolved in toluene (4 mL), t-BuBrettphos Pd G3 (45.8 mg, 53.6 μmol) and cesium carbonate (232 mg, 712 μmol) were added, and the system was stirred at 110°C for 1 hour under nitrogen protection. After the reaction was completed, the mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA=8:1) to obtain compound 52-6 (55.0 mg, yield 29.7%, yellow solid). LCMS calc.for C ₂₄ H ₂₃ F ₃ N ₅ O ₃ S[M+H] ⁺ :m/z＝518.1；Found:518.1.

Step 6: 2-[[5-isobutyl-1-[2-(trifluoromethoxy)-5-pyridyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 52-6 (50.0 mg, 96.7 μmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide (23.1 mg, 970 μmol) was added. The system was stirred at 50°C for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 4, and ethyl acetate (50 mL×2) was used for extraction. The organic phase was dried and concentrated to obtain a crude product, which was purified by preparative method to obtain compound Cpd-52 (22.0 mg, yield 45.2%, yellow solid). LCMS calc.for C ₂₃ H ₂₁ F ₃ N ₅ O ₃ S[M+H] ⁺ :m/z＝504.1；Found:504.1； ¹ H NMR(400MHz,DMSO-d ₆ )δ13.98(s,1H),10.75(s,1H),8.78(d,J＝2.5Hz,1H),8.55(d,J＝2.7Hz,1H),8.35(d,J＝2.5Hz,1H),8.20(dd,J＝8.7,2.7Hz,1H),7.55 -7.49(m,2H),7.44(d,J＝8.7Hz,1H),7.14-7.10(m,1H),6.97(s,1H),2.61(d,J＝7.1Hz,2H),1.84-1.73(m,1H),0.83(d,J＝6.6Hz,6H).

Example 53: 2-((5-isobutyl-1-(2-isopropylpyridin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-53)

Step 1: (2-isopropyl-4-pyridyl)boronic acid

Compound 53-1 (1.80 g, 11.5 mmol) and biboronic acid pinacol ester (3.23 g, 12.7 mmol) were dissolved in 1,4-dioxane (25 mL), potassium acetate (3.52 g, 35.8 mmol) and Pd(dppf)Cl ₂ (845 mg, 1.16 mmol) were added, and the system was stirred at 90°C under nitrogen protection for 5 hours. The mixture was cooled and filtered, and the filtrate was concentrated to obtain compound 53-2 (1.80 g, crude product, black oil). LCMS calc. for C ₈ H ₁₃ BNO ₂ [M+3H-Pinacol] ⁺ : m/z＝166.1；Found:166.3.

Step 2: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-isopropylpyridine

Compound 2-1 (2.71 g, 12.0 mmol) and compound 53-2 (1.80 g, 10.9 mmol) were dissolved in toluene (25 mL), copper acetate (2.97 g, 16.3 mmol) and pyridine (2.59 g, 32.7 mmol) were added, and the system was stirred at 90°C for 16 hours under an oxygen atmosphere. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=10:1) to obtain compound 53-3 (1.10 g, yield 29.2%, colorless oil). LCMS calc.for C ₁₁ H ₁₂ Br ₂ N ₃ [M+H] ⁺ :m/z＝343.9/345.9/347.9；Found:344.1/346.1/348.1.

Step 3: 4-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]-2-isopropylpyridine

Compound 53-3 (1.00 g, 2.90 mmol) and compound 2-3 (1.58 g, 8.69 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), potassium phosphate (1.23 g, 5.80 mmol) and Pd(dppf)Cl ₂ (424 mg, 580 μmol) were added, and the system was stirred at 70°C under nitrogen protection for 2 hours. Cool, add water (50 mL), extract with ethyl acetate (50 mL), dry and concentrate the organic phase, and purify by column chromatography (PE:EA＝10:1) to obtain compound 53-4 (500 mg, yield 53.8%, colorless oil). LCMS calc.for C ₁₅ H ₁₉ BrN ₃ [M+H] ⁺ :m/z＝320.1/322.1；Found:320.1/322.1.

Step 4: 4-(3-bromo-5-isobutylpyrazol-1-yl)-2-isopropylpyridine

Compound 53-4 (500 mg, 1.56 mmol) was dissolved in methanol (10 mL), and platinum dioxide (100 mg, 441 μmol) was added. The system was stirred at 0°C for 1.5 hours under a hydrogen atmosphere. The mixture was filtered and concentrated, and the filtrate was purified by column chromatography (PE:EA=10:1) to obtain compound 53-5 (300 mg, yield 59.6%, colorless oil). LCMS calc.for C ₁₅ H ₂₁ BrN ₃ [M+H] ⁺ :m/z＝322.1/324.1；Found:322.2/324.2.

Step 5: 2-((5-isobutyl-1-(2-isopropylpyridin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 53-5 (260 mg, 810 μmol) and compound INT-1 (284 mg, 1.21 mmol) were dissolved in DMF (8 mL), t-BuBrettphos Pd G3 (104 mg, 122 μmol) and cesium carbonate (526 mg, 1.61 mmol) were added, and the system was stirred at 120 ° C for 1 hour under nitrogen protection. Cool to room temperature, dilute with water (50 mL), adjust pH to 5-6 with 1N hydrochloric acid, extract with ethyl acetate (50 mL×3), and dry and concentrate the organic phase to obtain a crude product. The crude product was purified by preparative purification to obtain compound Cpd-53 (100 mg, yield 26.8%, yellow solid). LCMS calc.for C ₂₅ H ₂₈ N ₅ O ₂ S[M+H] ⁺ :m/z＝462.2；Found:462.4. ¹ H NMR (400 MHz, DMSO-d ₆ )δ14.05(s,1H),10.79(s,1H),8.82(d,J＝2.5Hz,1H),8.58(d,J＝5.5Hz,1H),8.40 (d,J＝2.5Hz,1H),7.57-7.55(m,2H),7.47(d,J＝1.6Hz,1H),7.41(dd,J＝5.5,2.2Hz ,1H),7.16(dd,J＝4.9,3.6Hz,1H),7.03(s,1H),3.17-3.07(m,1H),2.78(d,J＝7.1 Hz, 2H), 1.86 (m, J＝13.4, 6.7Hz, 1H), 1.28 (d, J＝6.9Hz, 6H), 0.90 (d, J＝6.6Hz, 6H).

Example 54: 2-[[1-(4-cyclopropylphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-54)

Step 1: 3,5-dibromo-1-(4-cyclopropylphenyl)pyrazole

Compound 2-1 (2.30 g, 10.2 mmol) and 4-cyclopropylphenylboronic acid (1.81 g, 11.2 mmol) were dissolved in toluene (30 mL), copper acetate (2.77 g, 15.3 mmol) and pyridine (2.42 g, 30.6 mmol) were added at room temperature, and the mixture was stirred at 90 ° C in an oxygen atmosphere for 12 hours. LCMS showed that the reaction was completed, and the reaction solution was cooled to room temperature, filtered and concentrated, and column chromatography (PE: EA = 1: 4) was performed to obtain compound 54-1 (1.92 g, yield 55.1%, yellow solid). LCMS calc. for C ₁₂ H ₁₁ Br ₂ N ₂ [M+H] ⁺ : m/z = 340.9/342.9/344.9; Found: 340.9/342.9/344.9.

Step 2: 3-Bromo-1-(4-cyclopropylphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

Under nitrogen protection, compound 54-1 (1.70 g, 4.97 mmol) and compound 2-3 (1.09 g, 5.96 mmol) were dissolved in tetrahydrofuran (12 mL) and water (2 mL), and Pd(dppf)Cl ₂ (363 mg, 496 μmol) and potassium phosphate (2.11 g, 9.94 mmol) were added at room temperature, and the reaction solution was stirred at 70°C for 16 hours. LCMS showed that the reaction was completed, and the mixture was cooled to room temperature, and ethyl acetate (100 mL) and water (20 mL) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was purified by column chromatography (PE:EA=4:1) to obtain compound 54-2 (850 mg, yield 53.9%, yellow oil). LCMS calc.for C ₁₆ H ₁₈ BrN ₂ [M+H] ⁺ :m/z＝317.0/319.0; Found: 317.1/319.0.

Step 3: 3-Bromo-1-(4-cyclopropylphenyl)-5-isobutylpyrazole

Compound 54-2 (1.20 g, 3.78 mmol) was dissolved in methanol (12 mL), and platinum dioxide (258 mg, 1.13 mmol) was added at room temperature. The system was stirred at 0°C under a hydrogen atmosphere for 1 hour. LCMS showed that the reaction was complete, methanol (40 mL) was added, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=4:1) to obtain compound 54-3 (810 mg, yield 67.1%, colorless oil). LCMS calc.C ₁₆ H ₂₀ BrN ₂ [M+H] ⁺ :m/z＝319.1/321.1；Found:319.1/321.1.

Step 4: 2-[[1-(4-cyclopropylphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 54-3 (300 mg, 940 μmol) and compound INT-1 (220 mg, 940 μmol) were dissolved in toluene (6 mL), t-BuBrettphos Pd G3 (121 mg, 142 μmol) and cesium carbonate (612 mg, 1.88 mmol) were added at room temperature, and the system was stirred at 120 ° C for 4 hours under a nitrogen atmosphere. LCMS showed that the reaction was completed, cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (70 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product after filtration and concentration was purified by column chromatography (PE: EA = 4: 1) to obtain compound 54-4 (127 mg, yield 28.7%, yellow oil). LCMS calc. _{C 27} H ₂₉ N ₄ O ₂ S [M + H] ⁺ : m / z = 473.2; Found: 473.3.

Step 5: 2-[[1-(4-cyclopropylphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 54-4 (150 mg, 318 μmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide (45.6 mg, 1.90 mmol) was added at room temperature. The system was stirred at 60 ° C for 0.5 hours. LCMS showed that the reaction was complete. After the reaction solution was cooled to room temperature, the pH was adjusted to 5-6 with 1.5N hydrochloric acid, and ethyl acetate (20 mL × 2) was added for extraction. The organic phase was dried and concentrated. The crude product was purified by preparation to obtain Cpd- 54 (61.1 mg, yield 41.2%, yellow solid). LCMS calc. for C ₂₆ H ₂₇ N ₄ O ₂ S [M+H] ⁺ : m/z = 459.2; Found: 459.3; ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.93(s,1H),10.66(s,1H),8.80(d,J＝2.6Hz,1H),8.38(d,J＝2.6Hz,1H),7.57-7.51(m,2H),7.33(d,J＝8.4Hz,2H),7.23-7.13(m,3H) ,6.89(s,1H),2.55(d,J＝7.2Hz,2H),2.02-1.96(m,1H),1.82-1.76(m,1H),1.03-0.97(m,2H),0.83(d,J＝6.6Hz,6H),0.75-0.69(m,2H).

Example 55: 2-[1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-55)

Step 1: 2-Bromo-1-isobutyl-4-nitroimidazole

Compound 55-1 (10.0 g, 52.1 mmol) and isobutyl iodide (14.4 g, 78.1 mmol) were dissolved in acetonitrile (100 mL), cesium carbonate (16.9 g, 52.1 mmol) was added at room temperature, and the system was stirred at 80°C for 16 hours. LCMS showed that the reaction was complete, cooled to room temperature, filtered and concentrated, and the residue was subjected to column chromatography (PE:EA＝1:4) to obtain compound 55-2 (8.19 g, yield 63.4%, yellow solid). LCMS calc.for C ₇ H ₁₁ BrN ₃ O ₂ [M+H] ⁺ :m/z＝248.0/250.0；Found:248.0/250.0.

Step 2: 1-isobutyl-4-nitro-2-[4-(trifluoromethyl)phenyl]imidazole

Compound 55-2 (5.00 g, 20.2 mmol) and 4-trifluoromethylphenylboronic acid (4.59 g, 24.2 mmol) were dissolved in 1,4-dioxane (60 mL) and water (10 mL), and cesium carbonate (16.4 g, 50.4 mmol) and Pd(PPh ₃ ) ₄ (2.33 g, 2.02 mmol) were added at room temperature, and the system was stirred at 100° C. for 2 hours under nitrogen protection. LCMS showed that the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA=4:1) to obtain compound 55-3 (4.05 g, yield 64.1%, yellow solid). LCMS calc.for C ₁₄ H ₁₅ F ₃ N ₃ O ₂ [M+H] ⁺ :m/z=314.1; Found: 314.2.

Step 3: 1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-amine

Compound 55-3 (500 mg, 1.60 mmol) was dissolved in methanol (20 mL), and hydrochloric acid (0.50 mL, 3.00 mmol, 6N aqueous solution) was added at room temperature, and then palladium hydroxide (224 mg, 10% content) and palladium carbon (194 mg, 10% content) were added, and the system was stirred at 30°C for 2 hours under hydrogen conditions. LCMS showed that the reaction was complete, and methanol (40 mL) was added for filtration. The filtrate was decompressed to obtain compound 55-4 (400 mg, crude product, yellow oil). LCMS calc. _{C 14} H ₁₇ F ₃ N ₃ [M+H] ⁺ :m/z＝284.1；Found:284.2.

Step 4: 2-[1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]amino]-5-(thiophen-2-yl)nicotinate

Compound 55-4 (310 mg, 1.09 mmol) and compound INT-2 (278 mg, 1.09 mmol) were dissolved in toluene (5 mL), and XantPhos Pd G2 (146 mg, 165 μmol) and cesium carbonate (1.07 g, 3.28 mmol) were added at room temperature. The system was stirred at 100 ° C for 1 hour under nitrogen protection. LCMS showed that the reaction was completed, cooled to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EA = 4: 1) to obtain compound 55-5 (144 mg, yield 26.3%, yellow oil). LCMS calc. _{C 25} H ₂₄ F ₃ N ₄ O ₂ S [M + H] ⁺ : m / z = 501.2; Found: 501.1.

Step 5: 2-[1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 55-5 (130 mg, 260 μmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide (37.3 mg, 1.55 mmol) was added at room temperature, and the system was stirred at 60°C for 0.5 hours. LCMS showed that the reaction was complete, and the mixture was cooled to room temperature, and the pH value was adjusted to 5-6 with 1N hydrochloric acid, and ethyl acetate (20 mL) was added for extraction. The organic phase was concentrated and purified by preparative purification to obtain Cpd-55 (59.6 mg, yield 47.1%, yellow solid). LCMS calc.for C ₂₄ H ₂₂ F ₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝487.1; Found: 487.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.89(s,1H),10.58(s,1H),8.81(d,J＝2.5Hz,1H),8.38(d,J＝2.6Hz,1H),7.93-7.82(m,4H),7.68(s,1H),7.57-7 .50(m,2H),7.15(dd,J＝5.1,3.6Hz,1H),3.99(d,J＝7.5Hz,2H),1.96(dt,J＝13.6,6.9Hz,1H),0.77(d,J＝6.6Hz,6H).

Example 56: 2-[[5-isobutyl-1-[4-(pentafluorosulfuryl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-56)

Step 1: (4-pentafluorosulfuryl)phenylboronic acid

Under ice bath conditions, add a solution of tetrafluoroboric acid (4.32mL, 25.6mmol, 48% aqueous solution) in acetonitrile (10mL) to a solution of compound 56-1 (2.25g, 10.2mmol) in acetonitrile (10mL). After stirring for 5 minutes, add a solution of tert-butyl nitrite (1.11g, 10.7mmol) in acetonitrile (10mL), and continue stirring for 15 minutes. Add a solution of bis(boric acid pinacol) (2.61g, 10.2mmol) in acetonitrile (10mL) and cool to -20°C. Slowly add a solution of pyridine (3.25g, 41.1mmol) in acetonitrile (10mL), and the mixture slowly warms to room temperature and stirs for 1.5 hours. Adjust the pH to 2-3 with 1N hydrochloric acid and extract with ethyl acetate (100mL×2). The organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 56-2 (3.31 g, crude product, gray solid).

Step 2: [4-(3,5-dibromopyrazol-1-yl)phenyl]-sulfur pentafluoride

Compound 2-1 (2.26 g, 10.0 mmol) and compound 56-2 (3.30 g, 10.0 mmol) were dissolved in toluene (30 mL), copper acetate (2.72 g, 14.9 mmol) and pyridine (2.37 g, 29.9 mmol) were added, and the system was stirred at 90 ° C for 16 hours under an oxygen atmosphere. Cool and filter, the filtrate was concentrated and purified by column chromatography (PE: EA = 10: 1) to obtain compound 56-3 (1.50 g, yield 35.1%, yellow oil). LCMS calc. for C ₉ H ₆ Br ₂ F ₅ N ₂ S [M + H] ⁺ : m / z = 426.9/428.8/430.8; Found: 426.9/428.9/430.9.

Step 3: [4-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]phenyl]-sulfur pentafluoride

Compound 56-3 (1.45 g, 3.39 mmol) and compound 2-3 (740 mg, 4.07 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL), potassium phosphate (1.44 g, 6.78 mmol) and Pd(dppf)Cl ₂ (491 mg, 680 μmol) were added, and the system was stirred at 70°C under nitrogen protection for 2 hours. After cooling, water (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was dried, concentrated, and purified by column chromatography (PE:EA=10:1) to obtain compound 56-4 (1.33 g, yield 98.0%, yellow oil). LCMS calc.for C ₁₃ H ₁₃ BrF ₅ N ₂ S[M+H] ⁺ :m/z＝403.0/405.0；Found:403.0/405.0.

Step 4: [4-(3-bromo-5-isobutylpyrazol-1-yl)phenyl]-sulfur pentafluoride

Compound 56-4 (1.33 g, 3.31 mmol) was dissolved in methanol (15 mL), and platinum dioxide (350 mg, 1.54 mmol) was added. Stir at 0°C for 30 minutes under an atmosphere of nitrogen. Filter and concentrate, and purify the crude product by reverse phase column chromatography (H ₂ O:CH ₃ CN=0-80%) to obtain compound 56-5 (650 mg, yield 43.1%, white solid). LCMS calc. for C ₁₃ H ₁₅ BrF ₅ N ₂ S[M+H] ⁺ :m/z=405.0/407.0; Found:405.1/407.1.

Step 5: 2-[[5-isobutyl-1-[4-(pentafluorosulfuryl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

Compound 56-4 (350 mg, 866 μmol) and compound INT-1 (303 mg, 1.30 mmol) were dissolved in DMF (7 mL), t-BuBrettphos Pd G3 (110 mg, 129 μmol) and cesium carbonate (561 mg, 1.73 mmol) were added, and the system was stirred at 120 ° C for 1 hour under nitrogen protection. After the reaction, 1N hydrochloric acid was added to adjust the pH to 5-6, water (50 mL) was added to dilute and extracted with ethyl acetate (50 mL×3), and the organic phase was dried and concentrated to obtain a crude product, which was purified by preparation to obtain compound Cpd-56 (58.0 mg, yield 12.3%, yellow solid). LCMS calc.for C ₂₃ H ₂₂ F ₅ N ₄ O ₂ S ₂ [M+H] ⁺ :m/z＝545.1；Found:545.1； ¹ H NMR (400 MHz, DMSO-d ₆ )δ14.00(s,1H),10.77(s,1H),8.82(d,J＝2.2Hz,1H),8.40(d,J＝2.2Hz,1H),8.05(d,J＝9.1Hz,2H),7.79(d,J＝8.8Hz,2 H),7.55-7.45(m,2H),7.17-7.15(m,1H),7.03(s,1H),2.73(d,J＝7.1Hz,2H),1.89-1.75(m,1H),0.89(d,J＝6.3Hz,6H).

Example 57: 2-((5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-57)

Step 1: Spiro[2.5]octan-6-ol

Under an ice-water bath, sodium borohydride (1.22 g, 32.2 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 57-1 (2.00 g, 16.1 mmol), and the reaction solution was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 57-2 (1.87 g, crude product, yellow oil).

Step 2: 3,5-dibromo-1-(spiro[2.5]octan-6-yl)-1H-pyrazole

Under nitrogen protection, compound 57-2 (1.00 g, 7.92 mmol), compound 2-1 (2.15 g, 9.51 mmol) and triphenylphosphine (3.74 g, 14.2 mmol) were dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarboxylate (2.88 g, 14.3 mmol) was added dropwise at 0°C, and the system was stirred for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the crude product after filtration and concentration was purified by column chromatography (PE: EA = 20: 1) to obtain compound 57-3 (1.20 g, yield 45.3%, yellow solid). LCMS calc.for C ₁₁ H ₁₅ Br ₂ N ₂ [M+H] ⁺ :m/z＝333.0/335.0/337.0; Found: 333.1/335.0/337.1.

Step 3: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(spiro[2.5]octan-6-yl)-1H-pyrazole

Under nitrogen protection, compound 57-3 (1.20 g, 3.59 mmol), compound 2-3 (780 mg, 4.31 mmol), Pd(dppf)Cl ₂ (530 mg, 720 μmol) and potassium phosphate (1.53 g, 7.18 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (12 mL, 5:1). The mixture was stirred at 80°C for 2 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE: EA = 5: 1) to obtain compound 57-4 (430 mg, yield 38.7%, colorless oil). LCMS calc. for C ₁₅ H ₂₂ BrN ₂ [M+H] ⁺ : m/z = 309.1/311.1; Found: 309.2/311.2.

Step 4: 3-Bromo-5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazole

Compound 57-4 (400 mg, 1.30 mmol) was dissolved in methanol (2 mL), and platinum dioxide (56.8 mg, 250 μmol) was added at 0°C. The system was stirred for 0.5 hours under a hydrogen atmosphere. Compound 57-5 (361 mg, crude product, colorless oil) was obtained by filtration and concentration. LCMS calc. for C ₁₅ H ₂₄ BrN ₂ [M+H] ⁺ : m/z＝311.1/313.1；Found:311.2/313.2.

Step 5: 2-((5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, compound 57-5 (300 mg, 968 μmol), compound INT-1 (291 mg, 1.23 mmol), t-BuBrettphos Pd G3 (161 mg, 188 μmol) and cesium carbonate (786 mg, 2.41 mmol) were dissolved in DMF (3 mL), and the system was stirred at 120°C for 1.5 hours. After cooling and filtration, the crude product obtained after the filtrate was concentrated was purified by column chromatography (PE:EA=5:1) to obtain compound 57-6 (171 mg, yield 37.9%, yellow solid). LCMS calc.for C ₂₆ H ₃₃ N ₄ O ₂ S[M+H] ⁺ :m/z＝465.2；Found:465.3.

Step 6: 2-((5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 57-6 (160 mg, 345 μmol) and lithium hydroxide (49.5 mg, 2.07 mmol) were dissolved in a mixed solvent of tetrahydrofuran and water (3 mL, 2:1), and the system was stirred at 50°C for 0.5 hours. After cooling to room temperature, 1N hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was concentrated and purified by preparative purification to obtain Cpd-57 (110 mg, yield 71.1%, yellow solid). LCMS calc.for C ₂₅ H ₃₁ N ₄ O ₂ S[M+H] ⁺ :m/z＝451.2；Found:451.3； ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.87(s,1H),10.56(s,1H),8.75(d,J＝2.6Hz,1H),8.35(d,J＝2.6Hz,1H),7.53-7.50(m,2H),7.14(dd,J＝5.1,3.6Hz,1H),6.59( s,1H),4.08(td,J＝10.9,3.6Hz,1H),2.54(s,2H),2.06-1.81(m,5H),1.77-1.68(m,2H),0.95(d,J＝6.6Hz,8H),0.36-0.26(m,4H).

Example 58: 2-[[5-isobutyl-1-[2-(trifluoromethoxy)-4-pyridinyl]amino]-5-(2-thienyl)pyridine-3-carboxylic acid

Step 1: 4-(3,5-dibromopyrazol-1-yl)-2-(trifluoromethoxy)pyridine

Compound 48-2 (4.20 g, 13.1 mmol) and 1-(trifluoromethyl)-1,2-benzimidoyl-3(1H)-one (16.6 g, 52.6 mmol) were added to nitromethane (50 mL), and the system was stirred at 100°C for 5 hours. After cooling to room temperature, water (300 mL) was added to dilute, and extracted with ethyl acetate (200 mL×2). The organic phase was washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EA＝10:1) to obtain compound 58-1 (2.10 g, yield 41.2%, light yellow solid). LCMS calc.for C ₉ H ₅ Br ₂ F ₃ N ₃ O[M+H] ⁺ :m/z＝385.9/387.9/389.9；Found:385.9/387.9/389.9.

Step 2: 4-[3-bromo-5-(2-methylpropyl-1-enyl)pyrazol-1-yl]-2-(trifluoromethoxy)pyridine

Compound 58-1 (2.10 g, 5.43 mmol) and compound 2-3 (1.48 g, 8.14 mmol) were dissolved in tetrahydrofuran (25 mL) and water (5 mL), potassium phosphate (2.30 g, 10.8 mmol) and Pd(dppf)Cl ₂ (516 mg, 710 μmol) were added, and the system was stirred at 70°C under nitrogen protection for 2 hours. After cooling, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL×2), the organic phase was dried and concentrated, and purified by column chromatography (PE:EA＝10:1) to obtain compound 58-2 (1.60 g, yield 81.4%, colorless liquid). LCMS calc.for C ₁₃ H ₁₂ BrF ₃ N ₃ O[M+H] ⁺ :m/z＝362.0/364.0；Found:362.0/364.0.

Step 3: 4-(3-bromo-5-isobutylpyrazol-1-yl)-2-(trifluoromethoxy)pyridine

Compound 58-2 (1.60 g, 4.42 mmol) was dissolved in methanol (16 mL), and platinum dioxide (300 mg, 1.32 mmol) was added. The system was stirred at 0°C for 30 minutes under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=10:1) to obtain compound 58-3 (900 mg, yield 55.9%, colorless oil). LCMS calc.for C ₁₃ H ₁₄ BrF ₃ N ₃ O[M+H] ⁺ :m/z=364.0/366.0;Found:364.1/366.1.

Step 4: 2-[5-isobutyl-1-[2-(trifluoromethoxy)-4-pyridinyl]pyrazol-3-yl]amino]-5-(2-thienyl)pyridine-3-carboxylic acid methyl ester

Compound 58-3 (900 mg, 2.47 mmol) and compound INT-1 (864 mg, 3.71 mmol) were dissolved in toluene (10 mL), t-BuBrettphos Pd G3 (317 mg, 370 μmol) and cesium carbonate (1.61 g, 4.94 mmol) were added, and the system was stirred at 120°C for 2 hours under nitrogen protection. After cooling, filtration and concentration, the residue was dissolved in ethyl acetate (50 mL) and purified by column chromatography (PE:EA=10:1) to obtain compound 58-4 (500 mg, yield 31.6%, yellow solid). LCMS calc.for C ₂₄ H ₂₃ F ₃ N ₅ O ₃ S[M+H] ⁺ :m/z=518.1;Found:518.2.

Step 5: 2-[[5-isobutyl-1-[2-(trifluoromethoxy)-4-pyridinyl]amino]-5-(2-thienyl)pyridine-3-carboxylic acid

Compound 58-4 (200 mg, 387 μmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL), methanol (15 mL) and water (5 mL), and lithium hydroxide (92.5 mg, 3.86 mmol) was added. The system was stirred at 60°C for 0.5 hours. After cooling, 1N hydrochloric acid was added to adjust the pH to 2-4, and water (50 mL) was added for dilution and extraction with ethyl acetate (50 mL×2) was performed. The organic phase was dried and concentrated to obtain a crude product, which was purified by preparative method to obtain compound Cpd-58 (105 mg, yield 53.9%, white solid). LCMS calc.for C ₂₃ H ₂₁ F ₃ N ₅ O ₃ S[M+H] ⁺ :m/z＝504.1；Found:504.3； ¹ H NMR (400 MHz, DMSO-d ₆ )δ14.05(s,1H),10.79(s,1H),8.81(d,J＝2.5Hz,1H),8.45-8.34(m,2H),7.68(dd,J＝5.5,1.6Hz,1H),7.57-7.54(m,2H),7.47 (s,1H),7.16(dd,J＝4.9,3.8Hz,1H),7.09(s,1H),2.84(d,J＝6.9Hz,2H),1.90(qd,J＝13.4,6.8Hz,1H),0.93(d,J＝6.6Hz,6H).

Example 59: 2-((1-(2-cyclobutyloxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Step 1: 4-Bromo-2-cyclobutoxypyridine

Dissolve 59-1 (5.00 g, 28.4 mmol) in tetrahydrofuran (50 mL), add cyclobutanol (2.67 mL, 34.1 mmol) and potassium tert-butoxide (9.56 g, 85.2 mmol), and stir the reaction mixture at 80 ° C for 3 hours. Cool, dilute with water (50 mL), and extract with ethyl acetate (30 mL × 2). Combine the organic phases, dry with sodium sulfate, filter and concentrate, and the residue is purified by column chromatography (PE: EA = 10: 1) to obtain compound 59-2 (3.20 g, yield 49.4%, white solid). LCMS calc. for C ₉ H ₁₁ BrNO [M + H] ⁺ : m / z = 228.0/230.0; Found: 228.2/230.2.

Step 2: (2-cyclobutyloxypyridin-4-yl)boronic acid

Under nitrogen protection at -78°C, n-butyl lithium (14.0 mL, 22.4 mmol, 1.6 M THF solution) was slowly added dropwise to a tetrahydrofuran (30 mL) solution of compound 59-2 (3.00 g, 13.2 mmol), and stirring was continued for 30 minutes after the addition was completed. Then trimethyl borate (4.40 mL, 39.5 mmol) was slowly added dropwise to the above system, and then the mixture was warmed to room temperature and stirred for 1 hour. LCMS detected that the raw material was completely reacted, and the system was concentrated to obtain a crude product 59-3 (2.50 g, colorless oil). It was directly used in the next step without further treatment. LCMS calc.for C ₉ H ₁₃ BNO ₃ [M+H] ⁺ :m/z＝194.1；Found:194.0.

Step 3: 2-cyclobutyloxy-4-(3,5-dibromo-1H-pyrazol-1-yl)pyridine

Compound 59-3 (2.00 g, 10.4 mmol) was dissolved in toluene (20 mL), and compound 2-1 (1.87 g, 8.29 mmol), copper acetate (2.82 g, 15.5 mmol) and pyridine (2.51 mL, 31.1 mmol) were added. The system was stirred overnight at 90 °C under oxygen protection. Filter, dilute the filtrate with water (50 mL), and extract with ethyl acetate (30 mL × 2). The organic phases were combined, dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EA = 10: 1) to obtain compound 59-4 (1.20 g, yield 31.0%, yellow solid). LCMS calc. for C ₁₂ H ₁₂ Br ₂ N ₃ O [M + H] ⁺ : m / z = 371.9/373.9/375.9; Found: 372.0/374.0/376.0.

Step 4: 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-2-cyclobutoxypyridine

Under nitrogen atmosphere, a mixture of compound 59-4 (1.20 g, 3.22 mmol), compound 2-3 (761 mg, 4.18 mmol), potassium phosphate (1.37 g, 6.43 mmol) and Pd(dppf)Cl ₂ (236 mg, 320 μmol) in tetrahydrofuran (12 mL) and water (3 mL) was stirred at 70°C for 2 hours. The reaction solution was cooled and diluted with water (20 mL), and extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝8:1) to obtain compound 59-5 (750 mg, yield 66.9%, yellow solid). LCMS calc.for C ₁₆ H ₁₉ BrN ₃ O[M+H] ⁺ :m/z＝348.1/350.1; Found: 348.1/350.1.

Step 5: 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-cyclobutoxypyridine

A mixture of compound 59-5 (700 mg, 2.25 mmol) and platinum dioxide (255 mg, 1.12 mmol) in methanol (10 mL) was stirred at 0°C for 1 hour. The mixture was filtered and concentrated to obtain compound 59-6 (600 mg, yield 92.3%, yellow solid). LCMS calc. for C ₁₆ H ₂₁ BrN ₃ O [M+H] ⁺ : m/z = 350.1/352.1; Found: 350.1/352.1.

Step 6: 2-((1-(2-cyclobutyloxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Under nitrogen protection, a mixture of compound 59-6 (550 mg, 1.57 mmol), compound INT-1 (405 mg, 1.73 mmol), t-BuBrettphos Pd G3 (403 mg, 472 μmol) and cesium carbonate (1.28 g, 3.93 mmol) in N,N-dimethylformamide (6 mL) was stirred at 120°C for 3 hours. After cooling, filtration and concentration, the residue was purified by column chromatography (PE:EA=10:1) to obtain compound 59-7 (300 mg, yield 37.9%, yellow solid). LCMS calc.for C ₂₇ H ₃₀ N ₅ O ₃ S[M+H] ⁺ :m/z＝504.2；Found:504.2.

Step 7: 2-((1-(2-cyclobutyloxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 59-7 (300 mg, 596 μmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide (114 mg, 4.77 mmol) was added. The system was stirred at room temperature for 1 hour. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH to 2-4, and water (50 mL) was added to dilute and extract with ethyl acetate (50 mL×2). The organic phase was dried and concentrated to obtain a crude product, which was purified by preparation to obtain compound Cpd-59 (115 mg, yield 39.4%, light yellow solid). LCMS calc.for C ₂₆ H ₂₈ N ₅ O ₃ S[M+H] ⁺ :m/z＝490.2；Found:490.2； ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.73(s,1H),8.82(d,J＝2.6Hz,1H),8.39(d,J＝2.6Hz,1H),8.21(d,J＝5.7Hz,1H) ,7.57-7.55(m,2H),7.21(dd,J＝5.7,1.9Hz,1H),7.16(dd,J＝5.0,3.7Hz,1H),7.02(s ,1H),6.90(d,J＝1.8Hz,1H),5.23-5.13(m,1H),2.76(d,J＝7.0Hz,2H),2.45-2.38(m, 2H),2.14-2.03(m,2H),1.91-1.73(m,2H),1.72-1.59(m,1H),0.90(d,J＝6.6Hz,6H).

Example 60: 2-[(1,5-diisobutylpyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid

Step 1: 3,5-dibromo-1-isobutylpyrazole

Compound 2-1 (4.00 g, 17.7 mmol) and isobutyl iodide (3.26 g, 17.7 mmol) were dissolved in N,N-dimethylformamide (50 mL), cesium carbonate (5.76 g, 17.7 mmol) was added, and the system was stirred at 50°C for 16 hours. After cooling, water (50 mL) was added, and ethyl acetate (50 mL×3) was used for extraction. The organic phase was dried and concentrated, and purified by column chromatography (PE:EA＝10:1) to obtain product 60-1 (3.20 g, yield 64.1%, light yellow oil). LCMS calc.for C ₇ H ₁₁ Br ₂ N ₂ [M+H] ⁺ :m/z＝280.9/282.9/284.9；Found:280.9/283.0/285.0.

Step 2: 3-Bromo-5-(2-methylprop-1-enyl)-1-isobutylpyrazole

Compound 60-1 (1.00 g, 3.55 mmol) and 2-3 (678 mg, 3.72 mmol) were dissolved in tetrahydrofuran (12 mL) and water (3 mL), and Potassium phosphate (1.51 g, 7.09 mmol) and Pd(dppf)Cl ₂ (259 mg, 355 μmol) were added, and the system was stirred at 70°C for 2 hours under nitrogen. After cooling, water (15 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated, and purified by column chromatography (PE:EA=10:1) to obtain product 60-2 (720 mg, yield 78.9%, colorless oil). LCMS calc.for C ₁₁ H ₁₈ BrN ₂ [M+H] ⁺ :m/z=257.1/259.1;Found:257.1/259.2.

Step 3: 1,5-diisobutyl-3-bromopyrazole

Compound 60-2 (900 mg, 3.50 mmol) was dissolved in methanol (20 mL), and platinum dioxide (159 mg, 700 μmol) was added. The system was stirred at 0°C for 1 hour under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated to obtain a crude product 60-3 (256 mg, yield 28.2%, colorless oil). LCMS calc.for: C ₁₁ H ₂₀ BrN ₂ [M+H] ⁺ :m/z＝259.1/261.1；Found:259.1/261.1.

Step 4: 2-((1,5-diisobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

60-3 (300 mg, 1.16 mmol) was dissolved in toluene (8 mL), and INT-1 (298 mg, 1.27 mmol), cesium carbonate (1.13 g, 3.47 mmol), and t-BuBrettphos Pd G3 (98.9 mg, 116 μmol) were added. The system was stirred at 120°C for 3 hours under nitrogen protection. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=2:1) to obtain the product 60-4 (152 mg, yield 31.8%, yellow solid). LCMS calc.for: C ₂₂ H ₂₉ N ₄ O ₂ S[M+H] ⁺ :m/z＝413.2；Found:413.2.

Step 5: 2-[(1,5-diisobutylpyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid

60-4 (190 mg, 460 μmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide (66.2 mg, 2.76 mmol) was added. The system was stirred at room temperature for 0.5 hours. 2N hydrochloric acid was added to adjust the pH to 5, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by reverse phase preparative chromatography to obtain Cpd-60 (21.3 mg, yield 11.1%, white solid). LCMS calc.for C ₂₁ H ₂₇ N ₄ O ₂ S[M+H] ⁺ :m/z＝399.2；Found:399.3； ¹ H NMR (400MHz, DMSO-d ₆ )δ10.59(s,1H),8.77(d,J＝2.6Hz,1H),8.36(d,J＝2.6Hz,1H),7.56-7.49(m,2H),7.14(dd,J＝5.0,3.6Hz,1H),6.62(s,1H ),3.74(d,J＝7.4Hz,2H),2.51(s,2H),2.20-2.09(m,1H),1.97-1.79(m,1H),0.95(d,J＝6.6Hz,6H),0.85(d,J＝6.7Hz,6H).

Example 61: 2-[[5-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutyl-1H-pyrazol-3-yl]amino]-5-(thiophen-2-yl)pyridine-3-carboxylic acid

Step 1: 5-Bromo-1-isobutyl-1H-pyrazole-3-carboxylic acid methyl ester

Potassium carbonate (10.1 g, 73.2 mmol) and isobutyl iodide (6.73 g, 36.6 mmol) were added to a solution of compound 61-1 (5.00 g, 24.4 mmol) in acetonitrile (50 mL), and the system was stirred at 80°C for 16 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=9:1) to obtain compound 61-2 (3.20 g, yield 47.7%, colorless oil). LCMS calc.for C ₉ H ₁₄ BrN ₂ O ₂ [M+H] ⁺ :m/z＝261.0/263.0；Found:261.1/263.1.

Step 2: 5-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutyl-1H-pyrazole-3-carboxylic acid methyl ester

Tetrakis(triphenylphosphine)palladium (442mg, 383μmol) and sodium carbonate (1.22g, 11.5mmol) were added to a mixed solution of compound 61-2 (1.00g, 3.83mmol) and 1-3 (883mg, 3.83mmol) in dioxane (10mL) and water (2mL), and the system was stirred at 100℃ for 1 hour under nitrogen protection. Cool, add water (15mL), extract with ethyl acetate (50mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify the residue by column chromatography (PE:EA＝17:3) to obtain compound 61-3 (650mg, yield 46.3%, yellow oil). LCMS calc.for C ₁₈ H ₂₄ ClN ₂ O ₄ [M+H] ⁺ :m/z＝367.1；Found:367.1.

Step 3: 5-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-pyrazole-3-carboxylic acid

Lithium hydroxide (81.0 mg, 3.38 mmol) was added to a mixed solution of compound 61-3 (620 mg, 1.69 mmol) in methanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL), and the system was stirred at room temperature for 1 hour. Concentrated, pH was adjusted to 5-6 with 1.5 N hydrochloric acid, extracted with dichloromethane (5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EA = 17: 3) to obtain compound 61-4 (390 mg, yield 65.4%, yellow solid). LCMS calc. for C ₁₇ H ₂₂ ClN ₂ O ₄ [M+H] ⁺ : m/z = 353.1; Found: 353.1.

Step 4: tert-Butyl (5-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-pyrazol-3-yl)carbamate

To a solution of compound 61-4 (338 mg, 958 μmol) in tert-butyl alcohol (5 mL) were added diphenylphosphoryl azide (466 mg, 1.92 mmol) and triethylamine (194 mg, 1.92 mmol), and the system was stirred at 50°C for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EA=7:3) to obtain compound 61-5 (175 mg, yield 43.1%, yellow oil). LCMS calc.for C ₂₁ H ₃₁ ClN ₃ O ₄ [M+H] ⁺ :m/z＝424.2；Found:424.2.

Step 5: 5-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-pyrazol-3-amine

Trifluoroacetic acid (1 mL) was added to a solution of compound 61-5 (175 mg, 413 μmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, dichloromethane (5 mL) was added, and the pH was adjusted to 8-9 with a saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 61-6 (142 mg, crude product, yellow oil). LCMS calc. for C ₁₆ H ₂₃ ClN ₃ O ₂ [M+H] ⁺ : m/z＝324.1；Found:324.1.

Step 6: 2-((5-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Xphos (74.8 mg, 157 μmol), cesium carbonate (319 mg, 980 μmol) and Pd ₂ (dba) ₃ (71.8 mg, 78.4 μmol) were added to a toluene (3 mL) solution of compound 61-6 (127 mg, 392 μmol) and INT-2 (99.5 mg, 392 μmol). The system was stirred at 100°C for 1 hour under nitrogen protection. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=13:7) to obtain compound 61-7 (152 mg, yield 64.5%, yellow solid). LCMS calc.for C ₂₇ H ₃₀ ClN ₄ O ₄ S[M+H] ⁺ :m/z＝541.2；Found:541.2.

Step 7: 2-[[5-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutyl-1H-pyrazol-3-yl]amino]-5-(thiophen-2-yl)pyridine-3-carboxylic acid

Lithium hydroxide (37.2 mg, 1.55 mmol) was added to a mixed solution of compound 61-7 (140 mg, 259 μmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and the system was stirred at 75°C for 1 hour. After cooling and concentration, dichloromethane (5 mL) was added, and the pH was adjusted to 5-6 with 1.5N hydrochloric acid, and extracted with dichloromethane/methanol (10 mL, 10:1). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain compound Cpd-61 (71.5 mg, yield 51.4%, yellow solid). LCMS calc.for C ₂₆ H ₂₈ ClN ₄ O ₄ S[M+H] ⁺ :m/z＝527.1；Found:527.1； ¹ H NMR (400MHz, DMSO-d ₆ )δ14.15(s,1H),10.62(s,1H),8.80(s,1H),8.41(s,1H),7.80(s,1H),7.68(d,J＝8.7Hz,1H),7.56(dd,J＝8.9,5.0Hz,2H),7.27-7.13(m,2 H),6.97(d,J＝2.8Hz,1H),4.26-4.11(m,2H),3.90(d,J＝7.1Hz,2H),3.75-3.63(m,3H),3.35(s,3H),2.27-2.14(m,1H),0.95-0.90(m,6H).

Example 62: 2-[[4-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-1H-imidazol-2-yl]amino]-5-(thiophen-2-yl)pyridine-3-carboxylic acid

Step 1: 2-(Cyanamido)-5-(thiophen-2-yl)pyridine-3-carboxylic acid methyl ester

Compound INT-2 (1.40 g, 3.86 mmol) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (6.33 g, 11.6 mmol) and cyanamide (324 mg, 7.73 mmol) were added, and the system was stirred at 80°C for 2 hours. After cooling and concentration, methanol (3 mL) and dichloromethane (6 mL) were added, and then filtered, and the solid after filtration was collected to obtain compound 62-1 (500 mg, crude product, yellow solid). LCMS calc. for C ₁₂ H ₁₀ N ₃ O ₂ S [M+H] ⁺ m/z = 260.0; Found: 260.1.

Step 2: tert-butyl N-[1-[methoxy(methyl)carbamoyl]-3-methylbutyl]carbamate

Compound 62-2 (5.00 g, 21.6 mmol) was dissolved in dichloromethane (100 mL), 1-hydroxybenzotriazole (2.92 g, 21.6 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.22 g, 32.4 mmol) were added at -10 °C, the system was stirred for 30 minutes, N-methoxymethylamine hydrochloride (2.13 g, 21.8 mmol) and diisopropylethylamine (6.97 g, 54.1 mmol) were added, the system was stirred at this temperature for 30 minutes, then the temperature was raised to room temperature and stirred for 1 hour. The reaction was quenched with 1N hydrochloric acid (200 mL), and the organic phase was separated. The organic layer was washed with saturated sodium bicarbonate aqueous solution (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column (PE:EA=9:1) to obtain compound 62-3 (5.00 g, yield 75.9%, light yellow oil). LCMS calc.for C ₉ H ₁₉ N ₂ O ₄ [M- ^t- Bu+H] ⁺ m/z=219.1;Found:219.1.

Step 3: N-[1-[3-chloro-4-(2-methoxyethoxy)benzoyl]-3-methylbutyl]carbamic acid tert-butyl ester

Under nitrogen protection, n-butyl lithium (16 mL, 1.6 M n-hexane solution) was added dropwise to a solution of 4-bromo-2-chloro-1-(2-methoxyethoxy)benzene (6.62 g, 24.9 mmol) in tetrahydrofuran (100 mL) at -70 °C. The system was stirred at -70 °C for 1 hour, and then a solution of 62-3 (1.80 g, 6.56 mmol) in tetrahydrofuran (20 mL) was slowly added. The system was stirred for 30 minutes, and then stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and extracted with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column (PE: EA = 17: 3) to obtain compound 62-4 (2.00 g, yield 68.6%, colorless oil). LCMS calc.for C ₁₆ H ₂₃ ClNO ₅ [M- ^{t -} Bu+H] ⁺ m/z=344.1; Found: 344.2.

Step 4: 2-amino-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-4-methyl-pentan-1-one

To a solution of compound 62-4 (400 mg, 1.00 mmol) in dichloromethane (3 mL) was added hydrochloric acid (1 mL, 4N 1,4-dioxane solution), and the system was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound 62-5 (400 mg, crude product, light yellow solid). LCMS calc. for C ₁₅ H ₂₃ ClNO ₃ [M+H] ⁺ m/z＝300.1；Found:300.2.

Step 5: 2-[[4-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-1H-imidazol-2-yl]amino]-5-(thiophen-2-yl)pyridine-3-carboxylic acid

Triethylamine (156 mg, 1.54 mmol) was added to a mixed solvent of ethanol (10 mL) and N,N-dimethylacetamide (2 mL) of compound 62-1 (200 mg, 771 μmol) and 62-5 (231 mg, 771 μmol), and the system was stirred at 90°C for 3 hours. After cooling, the pH was adjusted to 2-3 with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative purification to obtain Cpd-62 (5.00 mg, yield 1.23%, yellow solid). LCMS calc.for C ₂₆ H ₂₈ ClN ₄ O ₄ S[M+H] ⁺ m/z＝527.1; Found: 527.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ11.22(s,1H),8.95(s,1H),8.33(s,1H),8.04(s,2H),7.58(m,2H),7.35(m,1H),7.14(m,1H),5.65(s,1H),4 .35-4.33(m,2H),3.74-3.72(m,2H),3.35(s,3H),1.86-1.50(m,3H),1.01(d,J＝4Hz,3H),0.90(d,J＝4Hz,3H).

Example 63: 2-((1-(tert-butyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)pyridine-3-carboxylic acid

Step 1: 3,5-dibromo-1-(tert-butyl)-1H-pyrazole

Compound 2-1 (30.0 g, 133 mmol) was dissolved in tert-butyl alcohol (252 mL, 2.63 mol), sulfuric acid (8.72 mL, 159 mmol, 98% content) was slowly added dropwise at 0°C, and the system was stirred at 100°C for 16 hours. After the reaction, the pH was adjusted to neutral with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (300 mL×2), the organic phase was dried with sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝50:1) to obtain compound 63-1 (28.0 g, yield 74.8%, colorless liquid). LCMS calc.for C ₇ H ₁₁ Br ₂ N ₂ [M+H] ⁺ :m/z＝280.9/282.9/284.9；Found:281.1/283.1/285.1.

Step 2: 3-Bromo-1-(tert-butyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Compound 63-1 (6.00 g, 21.3 mmol) and 2-3 (3.87 g, 21.3 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL), potassium phosphate (13.6 g, 63.8 mmol) and Pd(dppf)Cl ₂ (1.56 g, 2.13 mmol) were added at room temperature, and the system was stirred at 70°C for 2 hours under nitrogen atmosphere. The mixture was cooled and filtered, and water (60 mL) was added, and the mixture was extracted with ethyl acetate (60 mL×2). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝8:1) to obtain compound 63-2 (2.50 g, yield 45.7%, colorless oil). LCMS calc.for C ₁₁ H ₁₈ BrN ₂ [M+H] ⁺ :m/z＝257.1/259.1; Found: 257.0/259.0.

Step 3: 3-Bromo-1-(tert-butyl)-5-isobutyl-1H-pyrazole

Compound 63-2 (4.29 g, 16.7 mmol) was dissolved in methanol (45 mL), and platinum dioxide (949 mg, 4.18 mmol) was added at 0°C. The system was stirred at 0°C for 0.5 hours in a hydrogen atmosphere. LCMS detected that the raw material had reacted completely, and the filtrate was filtered and concentrated to obtain the crude product 63-3 (3.79 g, yield 87.7%, colorless oil). LCMS calc.for C ₁₁ H ₂₀ BrN ₂ [M+H] ⁺ :m/z＝259.1/261.1；Found:259.1/261.1.

Step 4: 2-((1-(tert-butyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Compound 63-3 (1.00 g, 3.86 mmol) and INT-1 (723 mg, 3.09 mmol) were dissolved in toluene (6 mL), t-BuBrettphos Pd G3 (330 mg, 386 μmol) and cesium carbonate (3.14 g, 9.65 mmol) were added, and the system was stirred at 120 ° C for 2 hours under nitrogen protection. Cool to room temperature, filter and concentrate, wash the residue with ethyl acetate (50 mL), and concentrate the organic phase to obtain a crude product. The crude product was purified by column chromatography (PE: EA = 10: 1) to obtain compound 63-4 (500 mg, yield 31.4%, yellow solid). LCMS calc. for C ₂₂ H ₂₉ N ₄ O ₂ S [M + H] ⁺ : m / z = 413.2; Found: 413.1.

Step 5: 2-((1-(tert-butyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)pyridine-3-carboxylic acid

Compound 63-4 (500 mg, 1.21 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (1 mL) and water (2 mL), and lithium hydroxide (145 mg, 6.06 mmol) was added. The system was stirred at 30 ° C for 0.5 hours. After the reaction was completed, 2N hydrochloric acid was added to adjust the pH to 2-4, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by reverse phase preparation to obtain chemical Compound Cpd-63 (150 mg, yield 31.1%, yellow solid). LCMS calc.for C ₂₁ H ₂₇ N ₄ O ₂ S[M+H] ⁺ :m/z＝399.2; Found: 399.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ13.8(s,1H),10.44(s,1H),8.75(d,J＝2.4Hz,1H),8.34(d,J＝2.4Hz,1H),7.53-7.50(m,2H),7.15-7 .13(m,1H),6.67(s,1H),2.67(d,J＝6.8Hz,2H),2.00-1.91(m,1H),1.57(s,9H),1.00(d,J＝6.4Hz,6H).

Example 64: 2-((5-isobutyl-1-(1-methylcyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Step 1: 3,5-dibromo-1-(1-methylcyclohexyl)-1H-pyrazole

Compound 2-1 (10.0 g, 44.3 mmol) and 1-methylcyclohexanol (25.3 g, 221 mmol) were dissolved in toluene (100 mL), cooled to 0°C, and sulfuric acid (2.91 mL, 53.1 mmol, 98% content) was slowly added dropwise, and then the system was stirred at 100°C for 16 hours. After the reaction was completed, the pH was adjusted to neutral with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (100 mL×2), the organic phase was dried with sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝50:1) to obtain compound 64-1 (12.0 g, yield 84.2%, colorless liquid). LCMS calc.for C ₁₀ H ₁₅ Br ₂ N ₂ [M+H] ⁺ :m/z＝321.0/323.0/325.0；Found:321.0/323.0/325.0.

Step 2: 3-Bromo-1-(1-methylcyclohexyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

Compound 64-1 (2.00 g, 6.21 mmol) and 2-3 (1.02 g, 5.59 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), potassium phosphate (3.95 g, 18.6 mmol) and Pd(dppf)Cl ₂ (454 mg, 621 μmol) were added, and the system was stirred at 70°C for 2 hours under nitrogen atmosphere. The mixture was cooled and filtered, and the filtrate was added with water (40 mL), extracted with ethyl acetate (40 mL×2), the organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EA＝10:1) to obtain compound 64-2 (1.50 g, yield 81.3%, colorless oil). LCMS calc.for C ₁₄ H ₂₂ BrN ₂ [M+H] ⁺ :m/z＝297.1/299.1; Found: 297.2/299.2.

Step 3: 3-Bromo-5-isobutyl-1-(1-methylcyclohexyl)-1H-pyrazole

Compound 64-2 (500 mg, 1.68 mmol) was dissolved in methanol (5 mL), and platinum dioxide (76.4 mg, 336 μmol) was added at 0°C. The system was stirred for 0.5 hours under a hydrogen atmosphere. LCMS detected that the raw material reaction was complete. Filter and concentrate to obtain a crude product 64-3 (3.80 g, yield 87.8%, colorless oil). LCMS calc. for C ₁₄ H ₂₄ BrN ₂ [M+H] ⁺ : m/z＝299.1/301.1; Found: 299.1/301.1.

Step 4: 2-((5-isobutyl-1-(1-methylcyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

Compound 64-3 (200 mg, 668 μmol) and INT-1 (141 mg, 602 μmol) were dissolved in toluene (2 mL), t-BuBrettphos Pd G3 (57.2 mg, 66.8 μmol) and cesium carbonate (544 mg, 1.67 mmol) were added, and the system was stirred at 120 ° C for 2 hours under nitrogen protection. After the reaction was completed, the residue was filtered and concentrated, and the residue was dissolved in ethyl acetate (20 mL) and purified by column chromatography (PE: EA = 10: 1) to obtain compound 64- 4 (160 mg, yield 52.9%, yellow solid). LCMS calc. for C ₂₅ H ₃₃ N ₄ O ₂ S [M+H] ⁺ : m/z = 453.2; Found: 453.2.

Step 5: 2-((5-isobutyl-1-(1-methylcyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

Compound 64-4 (200 mg, 442 μmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (1 mL) and water (2 mL), and lithium hydroxide (52.9 mg, 2.21 mmol) was added. The system was stirred at 30°C for 0.5 hours. After the reaction was completed, water (20 mL) was added for dilution, and the pH was adjusted to 2-4 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL×2). The organic phase was dried and concentrated to obtain a crude product, which was purified by preparative purification to obtain compound Cpd-64 (100 mg, yield 51.6%, yellow solid). LCMS calc.for C ₂₄ H ₃₁ N ₄ O ₂ S[M+H] ⁺ :m/z＝439.2；Found:439.3； ¹ HNMR(400MHz,DMSO-d ₆ )δ10.51(s,1H),8.74(d,J＝2.5Hz,1H),8.34(d,J＝2.5Hz,1H),7.58-7.48(m,2H),7.14(dd,J＝4.9,3.6Hz,1H),6.68(s,1H),2.64 (d,J＝7.0Hz,2H),2.42-2.30(m,2H),1.97(dt,J＝13.3,6.6Hz,1H),1.78-1.66(m,2H),1.57-1.34(m,9H),0.99(d,J＝6.5Hz,6H).

Biological experiments

1. HTRF test:

Homogeneous time-resolved fluorescence (HTRF) assay was used to measure the inhibitory effect of compounds on eIF4E and eIF4G protein-protein interactions. The recombinant GST-tagged eIF4E full-length protein used in the HTRF assay was expressed in E. coli. It was purified to 90% purity by affinity column. The biotin-tagged eIF4E used in the HTRF assay was synthesized by GenScript, and the specific sequence was Bio-EKKRYDREFLLGFQFIFASMQKPEGLPHISDVVL.

Binding of recombinant GST-tagged eIF4E protein and biotin-tagged eIF4G polypeptide was measured using fluorescence resonance energy transfer (FRET). For the FRET assay, binding of eIF4E protein and biotin-tagged eIF4G polypeptide was measured by detecting the fluorescence of the interaction between an anti-GST antibody conjugated to XL665 (Cisbio, 61GSTXLB) and Tb-conjugated streptavidin (Cisbo, 610SATLA) bound to a biotin-tagged DNA molecule. Compounds were prepared as 20 mM stocks and serially diluted 1:3 in DMSO for 10 concentrations. 50 nL of compound solution was transferred row by row to a 384 assay plate using an Echo, with 2 replicates per column, and centrifuged at 1000 rpm. 2.5 μL of eIF4E protein solution was added to the assay plate and incubated for 60 minutes. 2.5 μL of eIF4G biotinylated polypeptide solution was added to the assay plate and incubated for 10 minutes. Add 5 μL of detection solution (GST-XL665 antibody and streptavidin-Tb) to each well of the detection plate and centrifuge at 1000 rpm. Incubate at 25°C for 60 minutes. Read fluorescence on a BMG (BMG LRBTECH).

Calculate the ratio for each well (Ratio_665nm/615nm - Ratio_background). The activity % is calculated as follows:

%inh＝(High control-cmpds)/(High control-Low control)*100%

_IC50 was calculated by fitting the logarithm of % activity and compound concentration to a non-linear regression (dose response - slope of variable) using Graphpad 8.0.

Table 1: Activity of compounds inhibiting the binding of eIF4E to eIF4G

Ref.1 is Selected from patent WO2021178488A1, compound number I-327.

Ref.2 is Selected from patent WO2023028235A1, compound number I-79.

Ref.3 is Selected from patent WO2024112894A1, compound number I-11.

*+ means 0<IC ₅₀ ≤1000 nM, ++ means 1000 nM<IC ₅₀ ≤5000 nM, +++ means 5000 nM<IC ₅₀ ≤10000 nM, and ++++ means IC ₅₀ >10000 nM.

The experimental results show that the compounds of the present invention have the ability to inhibit the binding between eIF4E and eIF4G.

2. CTG cell proliferation test:

The antiproliferative effect of the compounds on human breast cancer cell lines was evaluated by ATP quantification, and the activity correlated well with the number of viable cells. Cell line ZR-75-1 (ATCC, CRL-1500) was cultured in RPMI 1640 (Invitrogen, 11875-085) medium supplemented with 10% (v/v) fetal bovine serum (BI, 04-002-1A). Cell lines were cultured according to the standard instructions of the American Type Culture Collection. Cell lines were identified by short tandem repeat profiles.

In the proliferation assay, 7000 ZR-75-1 cells were seeded in 96-well flat-bottomed transparent TC-treated plates (Corning, 3903) in 200 μL of culture medium per well and cultured overnight in culture medium to recover. Compounds were added in increasing concentration gradients, and DMSO treatment was used as a positive control. After 7 days of treatment, the plates were equilibrated to room temperature for 30 minutes, and the number of viable cells was measured by adding CellTiter-Glo reagent (Promega, G7572). Chemiluminescence readings were measured on Enspire (Perkin elme). The relative survival of each group was expressed as a percentage change relative to the positive control group and then fitted to a four-parameter logit nonlinear curve using the program XLFit (IDBS).

Table 2: Proliferation inhibition activity of compounds on ZR-75-1 cells

Ref.1 is Selected from patent WO2021178488A1, compound number I-327.

Ref.2 is Selected from patent WO2023028235A1, compound number I-79.

Ref.3 is Selected from patent WO2024112894A1, compound number I-11.

*+ means 0<IC ₅₀ ≤50 nM, ++ means 50 nM<IC ₅₀ ≤250 nM, +++ means 250 nM<IC ₅₀ ≤1000 nM, ++++ means IC ₅₀ >1000 nM.

The experimental results show that the compound of the present invention has good ZR-75-1 cell proliferation inhibitory activity and is significantly better than the reference compound.

3. m ⁷ GTP pull down test:

The ^m7 GTP pull down assay is used to detect the effect of compounds on the interaction between eIF4E and eIF4G or 4E-BP1 in cells. Regulation. ZR-75-1 cells (ATCC, CRL-1500) were cultured in RPMI 1640 (Invitrogen, 11875-085) medium supplemented with 10% (v/v) fetal bovine serum (BI, 04-002-1A). Cell lines were cultured according to the standard instructions of the American Type Culture Collection. Cell lines were identified by short tandem repeat profiles.

2.2×10 ⁶ ZR-75-1 cells were plated in a 6 cm cell culture dish and cultured overnight in culture medium to recover. Compounds were added in increasing concentration gradients, and DMSO treatment was used as a positive control. After incubation of treated cells at 37 degrees Celsius and 5% carbon dioxide for 2 hours, the cells were lysed using IP lysis buffer (Thermo fisher, 87787) supplemented with 1× protease and phosphatase inhibitors (Thermo fisher, 78442). Protein concentration was then quantified using a BCA quantification kit (Thermo fisher, 23227). 40 μL of completely resuspended m7GTP agarose gel (Jenabioscience, AC-155S) was taken into a centrifuge tube and washed 3 times with 1 mL of IP lysis buffer. Add the same amount of protein to the cell lysate in a centrifuge tube and gently incubate with m7GTP agarose gel at 4 degrees Celsius overnight. After centrifugation to remove the supernatant, use 1mL IP lysis buffer to wash the m7GTP agarose gel (a total of 4 times, 3 minutes each time). After centrifugation to remove the supernatant, add 100μL 1×SDS loading buffer, heat in a metal bath at 37 degrees Celsius for 40 minutes to elute the protein on the m7GTP agarose gel, centrifuge the supernatant and heat in a metal bath at 85 degrees Celsius for 10 minutes to denature the protein.

The above samples (10 μL) were transferred to PVDF membranes after electrophoresis through 4%-12% Bis-Tris precast gels (Thermo fisher, NP0336BOX). After blocking with 5% skim milk (BD, 232100) at room temperature for 1 hour, the PVDF membranes were incubated with primary antibodies against eIF4G (CST, #2498), eIF4E (Santa cruz, sc-271480) and 4E-BP1 (CST, #9644) at 4 degrees Celsius overnight on a shaker. The next day, the membranes were washed 3 times with TBST buffer for 5 minutes each time; then incubated with goat anti-rabbit or goat anti-mouse secondary antibodies at room temperature for 1 hour. The membranes were then washed 3 times with TBST buffer for 5 minutes each time. The membranes were quickly incubated with HRP substrate (Millipore, WBKLS0500) and exposed in an Amersham ImageQuant 800 developer. The bands were quantified in grayscale using Image J software and normalized using eIF4E as a control. The quantitative protein levels were plotted and fitted using Graphpad Prism 10. IC ₅₀ represents the compound concentration at which the interaction is inhibited by 50%, EC ₅₀ represents the compound concentration at which 50% of the maximum interaction is activated, and SC ₁₅₀ represents the compound concentration at which 150% of the interaction is activated.

Table 3. Activity of compounds in pull-down assay of eIF4E and interacting proteins

FIG1 depicts the protein levels of eIF4E, and eIF4G and 4EBP1 bound thereto in ZR-75-1 cell lysates bound to m7GTP detected by immunoblotting, characterizing the effects of the compounds on the protein-protein interactions between eIF4E and eIF4G, and eIF4E and 4EBP1.

The experimental results show that the compounds of the present invention inhibit the protein-protein interaction between eIF4E and eIF4G, and promote the The binding of 4EBP1 inhibited the translation activity of eIF4E, and the activity was significantly better than that of the reference compound.

IV. Immunoblotting assay:

Immunoblotting was used to detect the effects of compounds on the expression levels of downstream proteins regulated by eIF4E, such as cMYC and Cyclin D1, in ZR-75-1 cells. ZR-75-1 cells (ATCC, CRL-1500) were cultured in RPMI 1640 (Invitrogen, 11875-085) medium supplemented with 10% (v/v) fetal bovine serum (BI, 04-002-1A). Cell lines were cultured according to the standard instructions of the American Type Culture Collection. Cell lines were identified by short tandem repeat profiles.

4x10 ⁵ ZR-75-1 cells were seeded per well in a 6-well plate and cultured overnight in culture medium to recover. Compounds were added in increasing concentration gradients, and DMSO treatment was used as a positive control. After the treated cells were incubated at 37 degrees Celsius and 5% carbon dioxide for 24 hours, the cells were lysed using RIPA lysis buffer (Epizyme, PC101) supplemented with 1× protease and phosphatase inhibitors (Thermo fisher, 78442). The protein concentration was then quantified using a BCA quantification kit (Thermo fisher, 23227). According to the quantitative results, an appropriate amount of 5× SDS loading buffer was added and the protein was denatured by heating in a metal bath at 85 degrees Celsius for 10 minutes.

The above samples (6 μg total protein per well) were transferred to PVDF membrane after electrophoresis on 4%-12% Bis-Tris precast gel (Thermo fisher, NP0336BOX). After blocking with 5% skim milk (BD, 232100) at room temperature for 1 hour, the PVDF membrane was incubated with primary antibodies of c-Myc (CST, #18583), Cyclin D1 (CST, #55506), and Beta-Actin (CST, #3700) at 4 degrees Celsius overnight on a shaker. The next day, the membrane was washed 3 times with TBST buffer for 5 minutes each time; then incubated with goat anti-rabbit or goat anti-mouse secondary antibodies at room temperature for 1 hour. The membrane was then washed 3 times with TBST buffer for 5 minutes each time. The membrane was quickly incubated with HRP substrate (Millipore, WBKLS0500) and exposed in Amersham ImageQuant 800 developer. The bands were quantified in grayscale using Image J software and normalized using Beta-Actin as a control. The quantitative protein levels were plotted and fitted using Graphpad Prism 10.

Table 4. Inhibitory activity of compounds on translation of downstream proteins of eIF4E

Figure 2 depicts the expression levels of c-Myc and Cyclin D1 proteins in ZR-75-1 cells treated with compounds detected by immunoblotting.

The experimental results show that the compounds of the present invention inhibit the translation activity of eIF4E and the translation of its downstream tumor driving proteins c-Myc and Cyclin D1, reduce the protein levels of c-Myc and Cyclin D1, and their activity is significantly better than that of the reference compounds.

5. In vivo efficacy experiment of ZR-75-1 orthotopic xenograft tumor mouse model:

1. Experimental purpose: To test the drug activity of the compound in the orthotopic xenograft tumor model of human breast cancer (ZR-75-1) in NOD SCID mice. Effective activity.

2. Experimental materials:

Animals: 7-week-old female NOD SCID mice;

Reagents:

Solvent: PEG400/Solutol HS15/pH 7.4 buffer (0.05M PBS buffer)=10/10/80%;

3. Experimental methods:

Cell culture: ZR-75-1 cells were cultured in RPMI-1640 medium containing 10% FBS. ZR-75-1 cells in the exponential growth phase were collected and resuspended in PBS and Matrigel (1:1) to a suitable concentration for orthotopic inoculation into the mammary glands of NOD SCID mice.

Modeling and grouping: One day before cell inoculation, an estrogen rod (β-estradiol mouse implant-90 days (0.36 mg per implant); Suzhou Xinlu Biotechnology Co., Ltd.) was implanted subcutaneously on the left back of each mouse. On the first day (recorded as Day 1), 0.2 mL of ZR-75-1 cell (1 x 10 ⁷ cells) suspension was inoculated under the third breast pad on the right side of each animal to establish a breast orthotopic transplant tumor model. After cell inoculation, the health status of the mice and the growth of the tumor were observed daily. On the 19th day after inoculation, 78 animals were selected and grouping began. The average tumor volume of the animals in the group was 153.4 mm ^3. The experiment was divided into 13 groups, with 6 mice in each group, and drug administration began (see Table 5).

4. Experimental design: Table 5 shows the grouping and dosing information of the efficacy experiment. The mice in group G1 were orally administered with the vehicle control (PEG400/Solutol HS15/pH 7.4 buffer (0.05M PBS buffer) = 10/10/80%) once a day for 22 days. The mice in group G2 were orally administered with Ref.2 once a day at a dose of 100 mg/kg for 22 days. The mice in group G3 were orally administered with Ref.2 twice a day at a dose of 50 mg/kg for 22 days. The mice in group G4 were orally administered with Cpd-32 once a day at a dose of 25 mg/kg for 22 days. The mice in group G5 were orally administered with Cpd-32 twice a day at a dose of 25 mg/kg for 22 days. The mice in group G6 were orally administered with Cpd-32 twice a day at a dose of 12.5 mg/kg for 22 days.

Table 5. Design of in vivo efficacy experiment in ZR-75-1 xenograft mouse model

5. Experimental observation and result judgment:

Experimental observation: The health status and mortality of animals were monitored daily. Routine examinations included observing the effects of tumor growth and drug treatment on the daily behavior of animals, such as behavioral activities, food and water intake, weight changes, physical signs or other abnormal conditions. The number of deaths and side effects of animals in each group were recorded based on the number of animals in each group. The clinical symptoms observed during the experiment were recorded in the original data. The formula for calculating tumor volume: tumor volume (mm ³ ) = 0.5 × (tumor long diameter × tumor short diameter ² ). During the study, the entire drug administration process and tumor and body weight measurements were carried out in a clean bench.

Data processing: Tumor volume inhibition rate TGI _TV (%): TGI%=(1-△T/△C)×100%; wherein, △C is the tumor volume of the control group C _t -C ₀ , C ₀ is the average tumor volume of the control group when grouped, and C _t is the average tumor volume of the control group after treatment; △T is the tumor volume of the treatment group T _t -T ₀ , T0 is the average tumor volume of the treatment group when grouped, and T _t is the average tumor volume of the treatment group after treatment.

Statistical analysis: The tumor volume and animal weight results are expressed as Mean ± SEM (mean standard error). The tumor volumes between different groups were statistically compared and analyzed. All statistical analyses were completed in https://d2k.bio/Efficacy/Invivo. The t.test method was used to compare whether there was a significant difference in tumor volume or tumor weight between the groups, where p ≥ 0.05 was no significant difference, p < 0.05 was a significant difference, and p < 0.01 was a very significant difference.

6. Experimental results:

Pharmacodynamic evaluation of the compound in the ZR-75-1 human breast cancer orthotopic xenograft model of NOD SCID mice The tumor growth curves of the control group and each experimental group are shown in Figure 3. The relative weight changes of mice in the ZR-75-1 human breast cancer orthotopic xenograft model are shown in Figure 4. The average tumor volume of each group of animals at the end of the experiment and the comparison results are shown in Table 6.

On the 22nd day after grouping, the average tumor volume of Group-1 (Vehicle group) was 753.4 mm ³ , and the average tumor volumes of Group-2 (Ref.2, 100 mg/kg, QD), Group-3 (Ref.2, 50 mg/kg, BID), Group-4 (Cpd-32, 25 mg/kg, QD), Group-5 (Cpd-32, 25 mg/kg, BID) and Group-6 (Cpd-32, 12.5 mg/kg, BID) were 328.5 mm ³ , 305.3 mm ³ , 466.8 mm ³ , 222.8 mm ³ and 396.0 mm ³ , respectively, and the corresponding tumor volume inhibition rates TGI _TV were 71%, 75%, 48%, 88% and 60%, respectively. Statistical analysis showed that the average tumor volume of each drug administration group was significantly smaller than that of the Vehicle group (p values were all <0.01). The above results show that compounds Ref.2 and Cpd-32 exhibited good activity in inhibiting the proliferation of ZR-75-1 orthotopic transplanted tumors in mice at each tested dose, and were dose-dependent. At the same time, Cpd-32 had a tumor inhibitory activity (TGI _TV = 88%) at a lower dose (such as 25 mg/kg, 10 mL/kg, po, BID) that was superior to the efficacy (TGI _TV = 75%) of compound Ref.2 at a dose of twice that of compound Ref.2 (50 mg/kg, 10 mL/kg, po, BID), indicating that Cpd-32 had better anti-tumor activity than Ref.2.

Table 6. In vivo efficacy test results of ZR-75-1 xenograft mouse model

Note: P value ^a : P value of the comparison analysis between the average tumor volume of each drug-treated group and the average tumor volume of Group-1.

Claims (15)

A compound as represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, characterized in that the compound of formula (I) is selected from the following structures:
in, ^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;
R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; ^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, ^cyano , ^-NR7R8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group C, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group C, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group C; ^R7 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R ⁸ is selected from hydrogen, C1-C6 alkyl; C group substituents include: oxo, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, ^-NRx1Ry1 , C3-C6 ^cycloalkyl , 3-8 membered heterocyclyl, -C(O) ^ORz ; ^Rx1 and ^Ry1 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; ^Rz is hydrogen or C1-C6 alkyl; ^R2 is selected from C1-C8 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkenyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, A benzo 5-10 membered heteroaryl group substituted by one or more substituents selected from Group A; Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, _C2 -C6 alkenyl, C2- _C6 alkynyl, carboxyl, _thiol , _-SF5 ^, _{-S - CH3} , _-CONH2 , - ₍ CH2)iSO2R9, -( ^CH2 ) _iSO2NH2 , - ₍ CH2)iSO2NR13R11, _- ( _CH2 )iP(O ⁾ _R9R10 , -( ^CH2 _{) iC} (O) ^-OR11 , _- ( _CH2 ) _iOC (O) ^{R11 ,} -CONR13R11 ^{, -NR13CO} - ^{R11 ,} -NR13R11 ^{, -O} ( _CH2 ) _iR12 , ^- ( _CH2 ) ^iR12 _; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S; The compound of formula (I) is not any of the following compounds:
The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that it is the following scheme 1, 2 or 3: Scenario 1: The compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, the compound represented by formula (I) is selected from the following structures:
in, ^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ; ^R3 , ^R4 , ^R5 and ^R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted with one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted with one or more substituents selected from Group A, C6-C10 aromatic which is unsubstituted or substituted with one or more substituents selected from Group A, substituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, unsubstituted or substituted by one or more substituents selected from Group A;
for R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; ^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, or C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, _carboxyl , cyano ^{, -CONR7R8} , -NR8CO- ^{R7 , -NR7R8} , ^-SO2R7 , _-SO2NR7R8 , C2- ^{C6 alkenyl} , C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^R R ⁷ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C6-C10 aryl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R ⁸ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl; ^R2 is selected from C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2- _C6 alkynyl, carboxyl, _thiol , _-SF5 , _{-S - CH3} , _-CONH2 , -(CH2)iSO2R9 ^, - ₍ ^{CH2 )} _iSO2NH2 , -(CH2) ^{iSO2NR13R11 ,} -(CH2) _iP (O) ^R9R10 , -( _CH2 ) _iC (O) ^-OR11 _{, -CONR13R11 , -NR13CO -} ^{R11 , -NR13R11 ,} _-O ( _CH2 ) _iR12 ^, -( ^CH2 ) _iR12 ^; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 ^alkyl , halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, ^halogenated C1-C6 alkoxy, C3-C6 ^{cycloalkyloxy} , -NRxRy, -CONRxRy, -NRxCO ^{- Ry} , -SO2Rx, _-SO2NRxRy , C6- _C10 ^aryl , C3-C6 ^cycloalkyl , ^3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^Rx and ^Ry are each independently H, ^deuterium , C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S; Scenario 2: The compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or its pharmaceutical preparation The acceptable salt of formula (I) is selected from the following structures:
in, ^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;
for R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; ^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted; the substituted C1-C6 alkyl in ^R1 refers to substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, ^cyano , ^-NR7R8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group C, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group C, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group C; ^R7 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R ⁸ is selected from hydrogen, C1-C6 alkyl; C group substituents include: oxo, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, -NR ^x1 R ^y1 , C3-C6 cycloalkyl; R ^x1 and R ^y1 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; ^R2 is selected from C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; The substituents of Group A include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF ₅ , -S-CH ₃ , -CONH ₂ , -(CH ₂ ) _i SO ₂ R ⁹ , -(CH ₂ ) _i SO ₂ NH ₂ , -(CH ₂ ) _i SO ₂ NR ¹³ R ¹¹ , -(CH ₂ ) _i P(O)R ⁹ R ¹⁰ , -(CH ₂ ) _i C(O)-OR ¹¹ , -CONR ¹³ R ¹¹ , -NR ¹³ CO-R ¹¹ , -NR ¹³ R ¹¹ , -O(CH ₂ ) _i R ¹² , -(CH ₂ ) _i R ¹² ; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S; Scenario 3: The compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, the compound represented by formula (I) is selected from the following structures:
in, ^X1 is N or ^CR3 , ^X2 is N or ^CR4 , ^X3 is N or ^CR5 , and ^X4 is N or ^CR6 ; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl which is unsubstituted or substituted by one or more substituents selected from Group A, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents selected from Group A, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;
for R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; ^R1 is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted ^; The substituted C1-C6 alkyl group refers to a group substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, cyano, -NR ⁷ R ⁸ , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group C, C3-C6 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group C, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group C, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group C; R ⁷ is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R ⁸ is selected from hydrogen, C1-C6 alkyl; C group substituents include: oxo, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyloxy, ^-NRx1Ry1 , C3-C6 ^cycloalkyl , 3-8 membered heterocyclyl, -C(O) ^ORz ; ^Rx1 and ^Ry1 are each independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; ^Rz is hydrogen or C1-C6 alkyl; ^R2 is selected from C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C12 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 3-8 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, benzo 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, _-SF5 , -S _{- CH3} ^, _-CONH2 , -( _CH2 )iSO2R9, -(CH2)iP( ^O _{) R9R10} , -(CH2) _iC ( ^O ) ^-OR11 , -( _CH2 ) _iOC ⁽ O) ^{R11 ,} _{-CONR13R11 ,} ^-NR13CO -R11 _, ^{-NR13R11 ,} -O( _CH2 ) ^iR12 , ^- ( _CH2 ) _iR12 ^; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen or C1-C6 alkyl; R ¹³ is hydrogen or C1-C6 alkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S. The compound of formula (I) according to claim 1 or 2, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that ^X1 is N or ^CR3 , ^X2 is ^CR4 , ^X3 is ^CR5 , and ^X4 is N or ^CR6 . The compound of formula (I) as claimed in claim 3, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that the compound of formula (I) is selected from the following structures:
Wherein, R ⁰ , R ¹ , R ² and R ⁵ are as defined in claim 3; Alternatively, when formula (I) is formula (I-1) or (I-4), ^R2 is selected from unsubstituted C1-C8 alkyl, ^R1 is selected from C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl; ^R0 and ^R5 are defined as described in claim 3. The compound of formula (I) as claimed in claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1) ^R0 , ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 , ^R12 , ^R13 , ^Rz , ^Rx , ^{Ry ,} the substituents in Group C, the substituents in Group B and the substituents in Group A, the C1-C6 alkyl group, the C1-C6 alkyl group among the unsubstituted or substituted C1-C6 alkyl groups, the C1-C6 alkyl group among the unsubstituted or substituted C1-C6 alkyl groups, the C1-C6 alkyl group among the halogenated C1-C6 alkyl groups, and the C1-C6 alkyl group among the C3-C6 cycloalkyl groups that are unsubstituted or substituted with C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; (2) In R ² , the C1-C8 alkyl group in the unsubstituted or substituted C1-C8 alkyl group selected from Group A is a C1-C6 alkyl group or a C6-C8 alkyl group; the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; (3) Among R ³ , R ⁴ , R ⁵ , R ⁶ , the substituents in the substituted C1-C6 alkyl group, the substituents in Group B and the substituents in Group C, the C1-C6 alkoxy group, the C1-C6 alkoxy group in the halogenated C1-C6 alkoxy group and the C1-C6 alkoxy group in the unsubstituted or substituted C1-C6 alkoxy group with one or more substituents selected from Group A are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; (4) Among R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² and the substituents in Group B, the C6-C10 aryl group, the C6-C10 aryl group in the C6-C10 aryl group which is unsubstituted or substituted with one or more substituents selected from Group A, the C6-C10 aryl group in the C6-C10 aryl group which is unsubstituted or substituted with one or more substituents selected from Group C, and the C6-C10 aryl group in the C6-C10 aryl group which is unsubstituted or substituted are independently phenyl or naphthyl; (5) ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R11 , ^R12 , the substituents in the substituted C1-C6 alkyl and the substituents in Group B, the 5-10 membered heteroaryl, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group A, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group C, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group A, the 5-10 membered heteroaryl in the 5-10 membered heteroaryl which is unsubstituted or substituted, and the 5-10 membered heteroaryl in the benzo 5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from Group A are independently 5-6 membered monocyclic heteroaryl groups, wherein the heteroatoms are N and / or S, the number is 1, 2 or 3, preferably pyridyl, pyridazinyl, 1H-pyrazolyl or thienyl; (6) Among ^R1 , ^R11 , ^R12 , the substituents in the substituted C1-C6 alkyl group, the substituents in Group B and the substituents in Group C, the C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group in the C3-C6 cycloalkyl group that is unsubstituted or substituted with a C1-C6 alkyl group and the C3-C6 cycloalkyl group in the C3-C6 cycloalkyl group that is unsubstituted or substituted with one or more substituents selected from Group C are independently C3-C6 monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) In ^R2 , the unsubstituted or substituted C3-C12 cycloalkyl group selected from Group A is a C3-C8 monocyclic alkyl group, a 6-8-membered bicyclic spirocyclic group or a bridged cycloalkyl group, preferably a cyclopropyl group, a cyclohexyl group, a cycloheptyl group, a spiro[2.5]octyl group, a bicyclo[3.2.1]octyl group or a bicyclo[1.1.1]pentyl group; and (8) R ² , the 3-8 membered heterocyclic group in the 3-8 membered heterocyclic group which is unsubstituted or substituted by one or more substituents selected from Group A is independently a 3-6 membered monocyclic heterocyclic group or a 6-8 membered bicyclic bridged heterocyclic group, the heteroatoms are N and/or O, the number of which is 1, 2 or 3, and is preferably piperidinyl, 8-azabicyclo[3.2.1]octanyl or -8-oxabicyclo[3.2.1]octanyl. The compound of formula (I) as described in any one of claims 1 to 5, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1) R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; more preferably, R ⁰ is selected from hydrogen, halogen, methyl, ethyl; most preferably, R ⁰ is hydrogen; (2) ^R1 is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in ^R1 refers to a substituent selected from the following: deuterium, halogen, amino, hydroxyl, cyano, C6-C10 aryl unsubstituted or substituted with one or more substituents selected from Group C, C3-C6 cycloalkyl, 3-8 membered heterocyclyl unsubstituted or substituted with -C(O)O C1-C6 alkyl, and 5-10 membered heteroaryl; Preferably, R ¹ is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in R ¹ refers to a substituent selected from the following: deuterium, halogen, amino, hydroxyl, cyano, phenyl, halophenyl, pyridine, halopyridyl, cyclopropyl, cyclohexyl and piperidinyl substituted by -C(O)O C1-C6 alkyl; More preferably, ^R1 is selected from methyl, ethyl, n-propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl, (3) In formula (I) and (I-1) to (I-6), ^R4 and ^R6 are each independently selected from hydrogen, hydroxyl, carboxyl, cyano or amino, preferably hydrogen; (4) In formula (I) and (I-1) to (I-6), R ⁵ is selected from a 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more substituents selected from Group A; the substituents in Group A are preferably selected from halogen and -(CH ₂ ) _i R ¹² ; R ¹² is a C1-C6 alkyl group; Preferably, ^R5 is and (5) In formula (I) and (I-1) to (I-6), R ² is selected from C1-C6 alkyl or halogenated C1-C6 alkyl, in, n is 0, 1, 2, 3 or 4; each ^Ra is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2- _C6 alkenyl, C2- ^C6 alkynyl, _carboxyl , _thiol , -SF5, -S- _CH3 , _-CONH2 , - _{( CH2} )iSO2R9, ^- (CH2)iSO2NH2, -(CH2)iSO2NR13R11, -(CH2 _{) iP (} ^{O )} _{R9R10 , -} ( ^CH2 ) _iC (O) ^{-OR11 ,} -( _CH2 ⁾ _iOC (O ^{) R11} , _{-CONR13R11 ,} ^{-NR13CO - R11} _{, -NR13R11} , ^-O ( _CH2 ) ^iR12 , -( _CH2 ) _iR12 ; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S; R ^d is selected from hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl; Preferably, R ² is selected from any of the following structures:

The compound of formula (I) as claimed in claim 1 or 2, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: R ⁰ is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; R ¹ is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl in R ¹ refers to substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, phenyl, C3-C6 cycloalkyl; ^R5 is a 5-10 membered heteroaryl group which is unsubstituted or substituted by one or more substituents selected from Group A; The definition of substitution in Group A is the same as that in the corresponding claim 1 or 2; Preferably, R ⁰ is selected from hydrogen, halogen, methyl, ethyl; ^R1 is selected from methyl, ethyl, propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl, ^R5 is The compound of formula (I) as claimed in claim 1 or 2, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: the compound of formula (I) is any one of general formulas (II) to (XII) general formula:
In formula (II) to formula (V), n is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; r is 0, 1, 2, or 3; q is 0, 1, 2, or 3; R ⁰ is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl; each ^Ra and ^Rb are independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, _carboxyl , _thiol , ^-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) ^iSO2R9 , _- ( _CH2 ) _iSO2NH2 , -(CH2)iSO2NR13R11 _, -( _CH2 ) ^iP (O) ^R9R10 _, - ⁽ _CH2 ) _iC (O) ^-OR11 _, - ⁽ _CH2 ) _iOC ( ^{O )R11 , -CONR13R11} _{, -NR13CO -} R11 _, ^-NR13R11 , _-O ( _CH2 ) ^iR12 , -( _CH2 ) ^{iR 12} ; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S;
In formula (IV) to formula (X) and (XIII), s is 0, 1, 2, or 3; t is 0, 1, 2, or 3; p1 is 0, 1, or 2; R ⁰ is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl; R ^e is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OC(O)C(CH ₃ ) ₃ ; R ^a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl; each ^Ra1 and ^Rb1 are independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, _carboxyl , thiol, _-SF5 ^, -S- _CH3 , _-CONH2 , -( _CH2 ) ^iSO2R9 , _- ( _CH2 ) _iSO2NH2 , -(CH2)iSO2NR13R11 _, -( _CH2 ) ^{iP (} O)R9R10 _, - ⁽ _CH2 ) _iC (O) ^-OR11 _, - ⁽ _CH2 ) _iOC (O ^{)R11 , -CONR13R11} _{, -NR13CO} -R11 _, ^-NR13R11 , _-O ( _CH2 ) ^iR12 , ^- ( _CH2 ) ⁱ _i R ¹² ; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; The substituents of Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 ^alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 alkoxy, C3-C6 ^{cycloalkyloxy} , -NRxRy, -CONRxRy, -NRxCO ^{- Ry} , -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered ^heterocyclyl , 5-10 membered heteroaryl; ^{Rx and Ry are} each independently H, deuterium _, C1-C6 alkyl, Halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S;
In formula (XI) to formula (XII), s is 0, 1, 2, or 3; t is 0, 1, 2, or 3; R ⁰ is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl; each ^Ra1 and ^Rb1 are independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, _carboxyl , thiol, _-SF5 ^, -S- _CH3 , _-CONH2 , -( _CH2 ) ^iSO2R9 , _- ( _CH2 ) _iSO2NH2 , -(CH2)iSO2NR13R11 _, -( _CH2 ) ^{iP (} O)R9R10 _, - ⁽ _CH2 ) _iC (O) ^-OR11 _, - ⁽ _CH2 ) _iOC (O ^{)R11 , -CONR13R11} _{, -NR13CO} -R11 _, ^-NR13R11 , _-O ( _CH2 ) ^iR12 , ^- ( _CH2 ) ⁱ _i R ¹² ; i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R ¹³ is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, ^halogenated C1-C6 ^alkoxy , C3-C6 cycloalkyloxy, -NRxRy ^, -CONRxRy, ^{-NRxCO - Ry ,} -SO2Rx, -SO2NRxRy, C6-C10 ^aryl , C3-C6 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl; ^{Rx and Ry} are each independently H, deuterium, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S. The compound of formula (I) as claimed in claim 8, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: In formula (II) to formula (V), n is 0, 1 or 2; m is 0 or 1; p is 1 or 2; r is 0 or 1; q is 1 or 2; R ⁰ is hydrogen; R ^b is methyl, ethyl or halogen; each ^Ra is independently selected from the group consisting of oxo, deuterium, halogen, cyano ^, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O)R9R10 ^, -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^{-CONR13R11 , -NR13CO} - ^{R11 ,} _-NR13R11 , _-O ( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;} i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen or C1-C6 alkyl; R ¹³ is hydrogen or C1-C6 alkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S; In formula (IV) to formula (X) and (XIII), s is 0, 1, or 2; t is 0 or 1; p1 is 1 or 2; R ⁰ is hydrogen; R ^e is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or -OC(O)C(CH ₃ ) ₃ ; R ^b1 is methyl, ethyl or halogen; R ^a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl; each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O) ^{R9R10 ,} -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^-CONR13R11 _, ^{-NR13CO - R11 ,} _-NR13R11 , -O( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;} i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen or C1-C6 alkyl; R ¹³ is hydrogen or C1-C6 alkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S; In formula (XI) to formula (XII), s is 0, 1, or 2; t is 0, 1, or 2; R ⁰ is hydrogen; R ^b1 is methyl, ethyl or halogen; R ^a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl; each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O) ^{R9R10 ,} -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^-CONR13R11 _, ^{-NR13CO - R11 ,} _-NR13R11 , -O( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;} i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen or C1-C6 alkyl; R ¹³ is hydrogen or C1-C6 alkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C6-C10 aryl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; The heteroatoms in the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2 or 3 of N, O and S. The compound of formula (I) according to claim 9, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: In formula (IV) to formula (X) and (XIII), s is 0 or 1; t is 0 or 1; p1 is 1; R ⁰ is hydrogen; R ^e is hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl or -OC(O)C(CH ₃ ) ₃ ; R ^b1 is methyl, ethyl or halogen; R ^a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl; each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O) ^{R9R10 ,} -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^-CONR13R11 _, ^{-NR13CO - R11 ,} _-NR13R11 , -O( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;} i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen or C1-C6 alkyl; R ¹³ is hydrogen or C1-C6 alkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; the substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; In formula (XI) to formula (XII), s is 0, 1, or 2; t is 0, 1, or 2; p1 is 1; R ⁰ is hydrogen; R ^b1 is methyl, ethyl or halogen; R ^a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl; each ^Ra1 is independently selected from the group consisting of oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, _-SF5 , -S- _CH3 , _-CONH2 , -( _CH2 ) _iSO2R9 , -( _CH2 )iP ₍ O) ^{R9R10 ,} -(CH2) _iC (O) ^-OR11 , -( _CH2 ) _iOC (O ₎ ^R11 _, ^-CONR13R11 _, ^{-NR13CO - R11 ,} _-NR13R11 , -O( _CH2 ) ^iR12 , - ⁽ _CH2 ) ^{iR12 ;} i is 0, 1, 2, or 3; ^R9 and ^R10 are independently hydrogen or C1-C6 alkyl; R ¹³ is hydrogen or C1-C6 alkyl; R ¹¹ and R ¹² are unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl; the substitution in R ¹¹ and R ¹² refers to substitution by one or more substituents selected from Group B; the substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; Preferably, In formula (II), formula ( ^{III), formula (IV) and formula (V), at least one Ra is -O(CH2)iR12 ,} _{and i} is 0; In formula (VI), formula (VII), formula (XI) and formula (XII), at least one R ^a1 is -O(CH ₂ ) _i R ¹² , and i is 0. The compound of formula (I) as claimed in claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: the compound of formula (I) is selected from the following compounds:





A pharmaceutical composition comprising a compound as shown in formula (I) according to any one of claims 1 to 11, its isotope-labeled substance, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient. A use of a compound as shown in formula (I) according to any one of claims 1 to 11, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 12 in the preparation of an eIF4E inhibitor or a drug; the drug is a drug for treating and/or preventing a disease by inhibiting eIF4E. A use of a compound of formula (I) as described in any one of claims 1 to 11, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 12 in the preparation of a drug for treating and/or preventing cancer. A method for treating and/or preventing cancer, characterized in that a therapeutically effective amount of a compound as shown in formula (I) according to any one of claims 1 to 11, its isotope-labeled substance, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof is administered to a patient.