Carboxylic acid compound, and preparation method therefor and use thereof

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 class of carboxylic acid compounds and their preparation method and application

[0001] This application claims priority to 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. The entire text of the above-mentioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] The present invention relates to an eIF4E inhibitor, a preparation method and application thereof, and in particular to a class of carboxylic acid compounds, compositions thereof and applications thereof in treating and preventing cancer. Background Art

[0003] Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in the initial stage of eukaryotic protein synthesis. As the rate-limiting step of cap-dependent translation, the combination of eIF4E and the m7GTP cap (cap) structure at the end of mRNA 5' leads to the formation of 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 of eIF4E and eIF4G promotes the loading of 40S ribosomal small subunits onto mRNA molecules, thereby triggering the scanning of start codons. eIF4E binding protein (4E-BP) inhibits cap-dependent translation by competing with eIF4G for the binding of eIF4E, and therefore becomes an important regulatory factor of the process. The binding of 4E-BP to eIF4E is regulated by its phosphorylation state. After being phosphorylated by mTORC1, 4E-BP releases eIF4E, allowing it 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).

[0004] 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). The animal experimental results reported by Ruggero D et al. in 2004 that eIF4E overexpression in mice can promote tumorigenesis (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) revealed the important role of eIF4E in cancer occurrence. Overexpression of eIF4E has been found to be widespread in various cancer types, including 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. This type of mRNA has a relatively complex 5' untranslated region (5'-UTR) and 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 cells are more sensitive to eIF4E inhibition 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-eIF4Eaxis 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).

[0005] Although the above studies have shown that eIF4E is a very promising target for cancer therapy, the development of eIF4E inhibitors has been slow to date. Although the eIF4E antisense oligonucleotide LY-2275796 and the nucleoside (m7G) analog Ribavirin have undergone 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 pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced 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 cap-dependent translation initiation process, small molecule inhibitors targeting the eIF4E / eIF4G interaction are likely to be a new strategy for safe and effective cancer treatment.

[0006] Summary of the Invention

[0007] In order to overcome the defects in the prior art, the present invention provides a class of compounds and their preparation methods and applications. The compounds of the present invention have good inhibitory activity against eIF4E.

[0008] The present invention also provides a compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, wherein the compound of formula (I) is selected from the following structures:

[0009] in,

[0010] X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR5 , X 4 N or CR 6 ;

[0011] R 3 、R 4 、R 5 and R 6 Each is 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;

[0012] for

[0013] R 0 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0014] R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is 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 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 cycloalkoxy, -NR x1 R y1 , C3-C6 cycloalkyl, 3-8 membered heterocyclic group, -C(O)ORz ; R x1 and R y1 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R z is hydrogen or C1-C6 alkyl;

[0015] R 2 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;

[0016] Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0017] i is 0, 1, 2, or 3;

[0018] R 9 and R 10are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0019] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0020] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0021] 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0022] 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;

[0023] The compound of formula (I) is not any of the following compounds:

[0024] As a preferred technical solution, the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, the compound of formula (I) is selected from the following structures:

[0025] in,

[0026] X 1 N or CR 3 , X 2 N or CR4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0027] R 3 、R 4 、R 5 and R 6 Each is 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;

[0028] for

[0029] R 0 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0030] R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, carboxyl, cyano, -CONR 7 R 8 、-NR 8 CO-R 7 、-NR 7 R 8 、-SO2R 7 、-SO2NR 7 R 8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R 7 R 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; 8 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl;

[0031] R2 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;

[0032] Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0033] i is 0, 1, 2, or 3;

[0034] R 9 and R 10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0035] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0036] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0037] Group B substituents 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0038] 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.

[0039] 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, wherein the compound of formula (I) is selected from the following structures:

[0040] in,

[0041] X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0042] R 3 、R 4 、R 5 and R 6Each is 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;

[0043] for

[0044] R 0 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0045] R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is 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 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 cycloalkoxy, -NR x1 R y1 , C3-C6 cycloalkyl; R x1 and R y1 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0046] R 2C6-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;

[0047] Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0048] i is 0, 1, 2, or 3;

[0049] R 9 and R 10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0050] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0051] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0052] 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0053] 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.

[0054] 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, wherein the compound of formula (I) is selected from the following structures:

[0055] in,

[0056] X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0057] R 3 、R 4 、R 5 and R 6Each is 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;

[0058] for

[0059] R 0 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0060] R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is 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 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 cycloalkoxy, -NR x1 R y1 , C3-C6 cycloalkyl, 3-8 membered heterocyclic group, -C(O)OR z ; R x1 and R y1 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R z is hydrogen or C1-C6 alkyl;

[0061] R2 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;

[0062] Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0063] i is 0, 1, 2, or 3;

[0064] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0065] R 13 is hydrogen or C1-C6 alkyl;

[0066] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0067] 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0068] 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.

[0069] As the preferred technical solution, X 1 N or CR 3 , X 2 CR 4 , X 3 CR 5 , X 4 N or CR 6 ; Other substituents are defined as above.

[0070] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0071] Among them, R 0 、R 1 、R 2 and R 5 The definition of is the same as above;

[0072] Preferably, when formula (I) is formula (I-1) or (I-4), R 2 When R is selected from unsubstituted C1-C8 alkyl, 1 is selected from C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkyl which is unsubstituted or substituted, 0 and R 5 The definition of is the same as above.

[0073] As a preferred technical solution, R 0 、R 1 、R 2 、R 3 、R4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R z 、R x 、R y , among the substituents of Group C, the substituents of Group B and the substituents of 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 C1-C6 alkyl group which is unsubstituted or substituted by one or more substituents selected from Group A, 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 by a C1-C6 alkyl group are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0074] As a preferred technical solution, R 2 In the C1-C8 alkyl group, the C1-C8 alkyl group that is unsubstituted or substituted with 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 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0075] As a preferred technical solution, R 3 、R 4 、R 5 、R 6 , 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.

[0076] As a preferred technical solution, R 2 、R 3 、R 4 、R 5 、R 6 、R 11 、R 12In the substituents of 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.

[0077] As a preferred technical solution, R 2 、R 3 、R 4 、R 5 、R 6 、R 11 、R 12 , 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 benzo5-10 membered heteroaryl which is unsubstituted or substituted with one or more substituents selected from group A are independently 5-6 membered monocyclic heteroaryl, 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.

[0078] As a preferred technical solution, R 1 、R 11 、R 12 , 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.

[0079] As a preferred technical solution, R 2 wherein 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.

[0080] As a preferred technical solution, R 2 In the 3-8 membered heterocyclic group which is unsubstituted or substituted by one or more substituents selected from Group A, the 3-8 membered heterocyclic group 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.

[0081] As a preferred technical solution, in formula (I), formula (I-1) to formula (I-6),

[0082] 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 For hydrogen.

[0083] As a preferred technical solution, in formula (I) and (I-1) to (I-6),

[0084] R 1 is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; R 1 The substituted C1-C6 alkyl group refers to a substituent selected from the following: deuterium, halogen, amino, hydroxyl, cyano, C6-C10 aryl which is unsubstituted or substituted with one or more substituents selected from Group C, C3-C6 cycloalkyl, a 3-8 membered heterocyclyl which is unsubstituted or substituted with -C(O)O C1-C6 alkyl, and a 5-10 membered heteroaryl.

[0085] More preferably, R 1 is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; R 1 The substituted C1-C6 alkyl group refers to a group selected from the group consisting of deuterium, halogen, amino, hydroxy, cyano, phenyl, halophenyl, pyridine, halopyridyl, cyclopropyl, cyclohexyl, and piperidinyl substituted with -C(O)O C1-C6 alkyl.

[0086] More preferably, R 1 Selected from methyl, ethyl, n-propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl,

[0087] Most preferably, R 1 It is -CH2CH(CH3)2.

[0088] As a preferred technical solution, in formula (I) and (I-1) to (I-6), R 4 and R 6 Each is independently selected from hydrogen, hydroxy, carboxyl, cyano or amino, preferably hydrogen.

[0089] 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 -(CH2) i R 12 ; R 12 is a C1-C6 alkyl group;

[0090] Preferably, R 5 for

[0091] The most preferred 5 for

[0092] As a preferred technical solution, in formula (I) and (I-1) to (I-6),

[0093] R 2 Selected from C1-C6 alkyl or halogenated C1-C6 alkyl, For example, R 2 Selected from More preferably, R 2 Selected from

[0094] in,

[0095] n is 0, 1, 2, 3 or 4; preferably, n is 0, 1, 2 or 3; more preferably, n is 0, 1 or 2;

[0096] Each R a Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0097] i is 0, 1, 2 or 3; preferably, i is 0, 1 or 2;

[0098] R 9 and R 10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0099] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0100] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0101] Group B substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0102] 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;

[0103] R d Selected from hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl.

[0104] Preferably, R 2 Select from any of the following structures:

[0105] As a preferred technical solution, in formula (I),

[0106] 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;

[0107] R 1 is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; R 1 The substituted C1-C6 alkyl group is substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, phenyl, and C3-C6 cycloalkyl; more preferably, R 1 is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; R 1 The substituted C1-C6 alkyl group is substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, phenyl, and C3-C6 cycloalkyl; more preferably, R 1 is selected from cyclopentyl, cyclohexyl, unsubstituted or substituted C1-C6 alkyl; R 1 The substituted C1-C6 alkyl group is substituted by one or more selected from halogen, phenyl, and C3-C6 cycloalkyl; more preferably, R 1 Selected from 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 -CH2CH(CH3)2;

[0108] 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, R5 for Most preferably, R 5 for

[0109] As a preferred technical solution, the substituents in group A of the present invention include: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0110] i is 0, 1, 2, or 3;

[0111] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0112] R 13 is hydrogen or C1-C6 alkyl;

[0113] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0114] Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

[0115] 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.

[0116] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0117] n is 0, 1, 2, 3 or 4; preferably, n is 0, 1, 2 or 3; more preferably, n is 0, 1 or 2;

[0118] m is 0, 1, 2 or 3; preferably, m is 0 or 1; more preferably, m is 0;

[0119] p is 0, 1, 2 or 3; preferably, p is 0, 1 or 2; more preferably, p is 1 or 2;

[0120] r is 0, 1, 2 or 3; preferably, r is 0, 1 or 2; more preferably, r is 0 or 1;

[0121] q is 0, 1, 2 or 3; preferably, q is 0, 1 or 2; more preferably, q is 1 or 2;

[0122] R 0 Selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl;

[0123] Each R a 、R b Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0124] i is 0, 1, 2, or 3;

[0125] R 9 and R 10are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0126] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0127] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0128] 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0129] 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.

[0130] or R a Same definition as above R 5 Definition of the substituents in Group A, R b Same definition as above R 2 The definition of the substituents in Group A.

[0131] As a preferred technical solution, in formula (II), formula (III), formula (IV) and formula (V), at least one R a -O(CH2) i R 12 , i is 0.

[0132] As a preferred technical solution, in formula (II), formula (III), formula (IV) and formula (V),

[0133] n is 0, 1, or 2;

[0134] m is 0 or 1;

[0135] p is 1 or 2;

[0136] r is 0 or 1;

[0137] q is 1 or 2;

[0138] R 0 is hydrogen;

[0139] R b is methyl, ethyl or halogen;

[0140] Each R a Each independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0141] i is 0, 1, 2, or 3;

[0142] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0143] R 13 is hydrogen or C1-C6 alkyl;

[0144] R 11 and R 12is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0145] Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

[0146] 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.

[0147] As a preferred technical solution, in formula (II), formula (III), formula (IV) and formula (V),

[0148] n is 0 or 1;

[0149] m is 0 or 1;

[0150] p is 1 or 2;

[0151] r is 0 or 1;

[0152] q is 1 or 2;

[0153] R 0 is hydrogen;

[0154] R e is hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl or -OC(O)C(CH3)3;

[0155] R b is methyl, ethyl or halogen;

[0156] Each R a Each independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0157] i is 0, 1, 2, or 3;

[0158] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0159] R 13 is hydrogen or C1-C6 alkyl;

[0160] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C6 cycloalkyl group; R 11 and R 12 The substitution mentioned here 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, and C1-C6 alkoxy.

[0161] As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0162] s is 0, 1, 2, or 3;

[0163] t is 0, 1, 2, or 3;

[0164] p1 is 0, 1, or 2;

[0165] R 0 Selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl;

[0166] R e Selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OC(O)C(CH3)3;

[0167] R a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

[0168] Each R a1 、R b1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) iSO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R x R y 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0169] i is 0, 1, 2, or 3;

[0170] R 9 and R 10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0171] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0172] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0173] 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y, C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, or C3-C6 cycloalkyl;

[0174] 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.

[0175] or R b1 Same definition as above R 5 Definition of the substituents in Group A, R a1 、R a1 and R e The definition of R is the same as above 2 The definition of the substituents in Group A.

[0176] As a preferred technical solution, in formula (VI), formula (VII), formula (VIII), formula (VIIII) and formula (X),

[0177] s is 0, 1, or 2;

[0178] t is 0 or 1;

[0179] p1 is 1 or 2;

[0180] R 0 is hydrogen;

[0181] R e is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or -OC(O)C(CH3)3;

[0182] R b1 is methyl, ethyl or halogen;

[0183] R a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

[0184] Each R a1 Each independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R x R y、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0185] i is 0, 1, 2, or 3;

[0186] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0187] R 13 is hydrogen or C1-C6 alkyl;

[0188] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0189] Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

[0190] 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.

[0191] As a preferred technical solution, in formula (VI), formula (VII), formula (VIII), formula (VIIII) and formula (X),

[0192] s is 0 or 1;

[0193] t is 0 or 1;

[0194] p1 is 1;

[0195] R 0 is hydrogen;

[0196] R e is hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl or -OC(O)C(CH3)3;

[0197] R b1 is methyl, ethyl or halogen;

[0198] R a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl;

[0199] Each R a1 Each independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R x R y 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0200] i is 0, 1, 2, or 3;

[0201] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0202] R 13 is hydrogen or C1-C6 alkyl;

[0203] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C6 cycloalkyl group; R 11 and R 12 The substitution mentioned here 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, and C1-C6 alkoxy.

[0204] As a preferred technical solution, in formula (VI) and formula (VII), at least one R a1 -O(CH2) i R 12 , i is 0. As a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0205] s is 0, 1, 2, or 3;

[0206] t is 0, 1, 2, or 3;

[0207] R 0 Selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl;

[0208] Each R a1 、R b1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0209] i is 0, 1, 2, or 3;

[0210] R 9 and R 10 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0211] R 13 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0212] R 11 and R 12is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0213] 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0214] 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.

[0215] or R b1 Same definition as above R 5 Definition of the substituents in Group A, R a1 、R a1 and R e The definition of R is the same as above 2 The definition of the substituents in Group A.

[0216] As a preferred technical solution, in formula (XI) and formula (XII),

[0217] s is 0, 1, or 2;

[0218] t is 0, 1, or 2;

[0219] R 0 is hydrogen;

[0220] R b1 is methyl, ethyl or halogen;

[0221] R a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

[0222] Each R a1 Each independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0223] i is 0, 1, 2, or 3;

[0224] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0225] R 13 is hydrogen or C1-C6 alkyl;

[0226] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted 3-8 membered heterocyclyl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-C6 cycloalkyl group, or an unsubstituted or substituted C6-C10 aryl group; R 11 and R 12 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0227] Group B substituents include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

[0228] 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.

[0229] As a preferred technical solution, in formula (XI) and formula (XII),

[0230] s is 0, 1, or 2;

[0231] t is 0, 1, or 2;

[0232] p1 is 1;

[0233] R 0 is hydrogen;

[0234] R b1 is methyl, ethyl or halogen;

[0235] R a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl;

[0236] Each R a1 Each independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i SO2R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ;

[0237] i is 0, 1, 2, or 3;

[0238] R 9 and R 10 are independently hydrogen or C1-C6 alkyl;

[0239] R 13 is hydrogen or C1-C6 alkyl;

[0240] R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C6 cycloalkyl group; R 11 and R 12 The substitution mentioned here 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, and C1-C6 alkoxy.

[0241] As a preferred technical solution, in formula (XI) and formula (XII), at least one R a1 -O(CH2) i R 12 , i is 0.

[0242] As a preferred technical solution, the compound represented by formula (I) is selected from the following compounds:

[0243] The present invention also provides methods for preparing the compound represented by formula (I), its isotope-labeled products, enantiomers, diastereomers, solvates, or pharmaceutically acceptable salts thereof, including the following methods:

[0244] Method 1:

[0245] Step 1: Compound a-1 and compound R 1 -Z 2 Nucleophilic substitution or Mitsunobu reaction occurs to obtain compound a-2; wherein R 1 The definition of Z is the same as above; 1 Selected from Cl, Br, I; Z 2 Selected from Cl, Br, I, OTf, OH;

[0246] Step 2: Compound a-2 and compound a-3 undergo Suzuki coupling reaction to obtain compound a-4; wherein R 2 The definition of is the same as above;

[0247] Step 3: Compound a-4 undergoes electrophilic halogenation reaction with a halogenating agent to obtain compound a-5; wherein Z 3 Selected from Cl, Br, I;

[0248] Step 4: Compound a-5 is subjected to metal-catalyzed hydrogenation conditions or the action of a metal organic reagent to remove a halogen molecule to obtain compound a-6; the metal may be Pd; the metal organic reagent may be ethylmagnesium bromide;

[0249] 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 、X 4 The definition of Z is the same as above; 4 is a C1-C6 alkyl group; the metal reagent may be a reagent containing Pd or Cu, such as a palladium reagent;

[0250] Step 6: Compound a-8 is reacted under alkaline or acidic conditions to obtain compound a; the alkaline conditions can be carried out in the presence of an inorganic base (such as LiOH, NaOH); the acidic conditions can be carried out in the presence of trifluoroacetic acid or hydrochloric acid.

[0251] Method 2:

[0252] Step 1: Compound b-1 and compound R 1 -Z 2 Nucleophilic substitution or Mitsunobu reaction occurs to obtain compound b-2; R 1 The definition of Z is the same as above; 1 Selected from Cl, Br, I; Z 2 Selected from Cl, Br, I, OTf, OH;

[0253] Step 2: Compound b-2 and compound b-3 undergo Suzuki coupling reaction to obtain compound b-4; wherein R 2 The definition of is the same as above;

[0254] Step 3: Compound b-4 undergoes nitro reduction to obtain aminoimidazole compound b-5;

[0255] 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 、X 4 The definition of Z is the same as above; 5 Selected from Cl, Br, I, OTf; Z 4 is a C1-C6 alkyl group; the metal may be a metal reagent and may be a reagent containing Pd or Cu, such as a palladium reagent;

[0256] Step 5: Compound b-7 is reacted under alkaline or acidic conditions to obtain compound b; the alkaline conditions can be carried out in the presence of an inorganic base (such as LiOH, NaOH); the acidic conditions can be carried out in the presence of trifluoroacetic acid or hydrochloric acid.

[0257] Method 3:

[0258] Step 1: Compound c-1 and compound R 2 (OH)2 undergoes Chan-Lam reaction to obtain compound c-2, or c-1 and compound R 2 Z 2 Nucleophilic substitution or Mitsunobu reaction occurs to obtain compound c-2; R 0 、R2 The definition of Z is the same as above; 1 Selected from Cl, Br, I; Z 2 Selected from Cl, Br, I, OTf, OTs, OH;

[0259] Step 2: Compound c-2 and compound c-3 undergo metal-catalyzed coupling reaction to obtain compound c-4; R c and R c’ Each independently selected from H and C1-C4 alkyl;

[0260] Step 3: Compound c-4 is reduced to a carbon-carbon double bond under hydrogenation conditions to obtain compound c-5; R 1 CH2CH(R c )R c’ ; The hydrogenation conditions may be carried out in the presence of PtO2 / H2;

[0261] 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 、X 4 The definition of Z is the same as above; 4 is a C1-C6 alkyl group; the metal may be a metal reagent and may be a reagent containing Pd or Cu, such as a palladium reagent;

[0262] Step 5: Compound c-7 is reacted under alkaline or acidic conditions to obtain compound c; the alkaline conditions can be carried out in the presence of an inorganic base (such as LiOH, NaOH); the acidic conditions can be carried out in the presence of trifluoroacetic acid or hydrochloric acid.

[0263] The present invention also provides a pharmaceutical composition comprising the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0264] 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.

[0265] The present invention also provides a 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 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.

[0266] The present invention also provides the use of the compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, or the pharmaceutical composition thereof in the preparation of a drug for treating and / or preventing cancer.

[0267] The cancer is preferably breast cancer.

[0268] 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-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.

[0269] The cancer is preferably breast cancer.

[0270] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0271] 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, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0272] 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.

[0273] The term "pharmaceutically acceptable salt solvate" refers to a compound formed by combining with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of solvent may be stoichiometric or non-stoichiometric.

[0274] 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)- means an acetyl group.

[0275] When the group valence bond has a wavy line When, for example, In the example, the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0276] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0277] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, a carbonyl replacing a methylene group.

[0278] The term "alkyl" refers to a linear or branched, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). 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.

[0279] The term "alkoxy" refers to a group R X -O-, R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0280] The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., one, two, or three) carbon-carbon sp 2 Double bond. Alkenyl groups include but are not limited to: vinyl, wait.

[0281] 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, bridged, and spirocyclic rings. Cycloalkyl groups include, but are not limited to: wait.

[0282] 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 one, two, or three double bonds. Cycloalkyl groups include, but are not limited to: wait.

[0283] The term "cycloalkoxy" refers to a group R Y -O-, R Y The same definition as the term "cycloalkyl". Cycloalkoxy includes but is not limited to cyclopropyloxy and the like.

[0284] The term "aryl" refers to a group having the specified number of carbon atoms (e.g., C6-C 10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic rings, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0285] 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-, The group formed by partial replacement of 1-4 Alkyl, C 3-6 Cycloalkyl or nitrogen protecting group (for example, 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, and spirocyclic rings and may be partially or completely saturated, such as 4-10 membered saturated or unsaturated heterocyclic groups, 4-6 membered saturated or unsaturated heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, oxetanyl, azetidinyl, oxiranyl, aziridine, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxetanyl, etc. For example, the heterocyclic group of the present invention may be preferably selected from the following groups:

[0286] 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, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolinyl, isoquinolinyl, etc.

[0287] The term "isotopically labeled" refers to an isotopically labeled compound in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature, compared to the nitrogen-containing compound of 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. Compounds of the present invention, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or prodrugs thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0288] 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.

[0289] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0290] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0291] The term "prevent" refers to reducing the risk of developing a disease.

[0292] The term "patient" refers to any animal, typically 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, and the like.

[0293] The term "PG" represents a protecting group, such as a Boc protecting group and the like.

[0294] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0295] The reagents and raw materials used in the present invention are commercially available.

[0296] 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

[0297] Figure 1 shows the immunoblotting results of the m7GTP pull down experiment in ZR-75-1 cells.

[0298] Figure 2 shows the results of immunoblotting experiments on ZR-75-1 cells.

[0299] Figure 3 shows the tumor growth curve of the ZR-75-1 human breast cancer orthotopic xenograft model.

[0300] Figure 4 shows the relative body weight changes of mice in the ZR-75-1 human breast cancer orthotopic xenograft model. DETAILED DESCRIPTION

[0301] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0302] In each embodiment, 1 HNMR was recorded by a BRUKER AVANCE NEO 400 MHz, JNM-ECZ400s nuclear magnetic resonance instrument, and the chemical shift is expressed in δ (ppm); liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD, Agilent 1260 and Agilent 1200 mass spectrometers; preparative HPLC separations were performed using a WATERS Autop, Shimadzu LC20AR liquid chromatograph.

[0303] In the following experimental descriptions, the following abbreviations may be used:

[0304] Preparation of intermediate INT-1

[0305] Step 1: 2-amino-5-(thiophen-2-yl)nicotinate methyl ester

[0306] Under nitrogen, thiophene-2-boronic acid pinacol ester INT-1-1 (9.09 g, 43.3 mmol) and 2-amino-5-bromonicotinate 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 extracted with ethyl acetate (300 mL x 2). The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated to obtain the crude product. The product 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, 74.9% yield, yellow solid). LC-MS calculation for C 11 H 11 N2O2S[M+1] + :m / z=235.1;Found:235.1.

[0307] Preparation of intermediate INT-2

[0308] Step 1: 2-chloro-5-(thiophen-2-yl)nicotinate methyl ester

[0309] Under nitrogen, thiophene-2-boronic acid pinacol ester INT-1-1 (419 mg, 2.00 mmol) and 2-chloro-5-bromonicotinate 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 extraction was performed with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over 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, 45.3% yield), as a yellow solid. LC-MS calculation for C 11 H9ClNO2S[M+1] + :m / z=254.0;Found:254.0.

[0310] 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)

[0311] Step 1: 1-isobutyl-2-bromoimidazole

[0312] Under nitrogen, 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 a reaction flask. Sodium hydroxide (4.08 g, 102 mmol, 60%) was then added portionwise. After stirring at 50°C for 6 hours, the reaction mixture was poured into water and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated sodium chloride 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 give 1-isobutyl-2-bromoimidazole 1-2 (3.20 g, 46.3% yield, yellow liquid). LC-MS calc. for C7H 12 BrN2[M+1] + :m / z=203.0 / 205.0; Found:203.0 / 205.0.

[0313] Step 2: 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutylimidazole

[0314] Under nitrogen, tetrakis(triphenylphosphine)palladium (1.82 g, 1.58 mmol) and sodium carbonate (3.34 g, 31.5 mmol) were added to a mixed solution of 1-isobutyl-2-bromoimidazole 1-2 (3.19 g, 15.7 mmol) and [3-chloro-4-(2-methoxyethoxy)phenyl]boronic acid 1-3 (4.36 g, 18.9 mmol) in toluene (30 mL), methanol (15 mL), and water (15 mL). The mixture was stirred at 100°C for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride 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 give 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-1-isobutylimidazole 1-4 (4.45 g, 91.7% yield, yellow solid). LC-MS calculation for C 16 H 22 ClN2O2[M+1] + :m / z=309.1;Found:309.2.

[0315] Step 3: 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4,5-diiodo-1-isobutylimidazole

[0316] 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 sequentially to a reaction flask and stirred at 90°C for 18 h. The reaction mixture was cooled, water was added, and extraction was performed with ethyl acetate (50 mL x 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, 35.6% yield, yellow solid). LC-MS calculation for C 16 H 20 ClI2N2O2[M+1] + :m / z=560.9;Found:561.0.

[0317] Step 4: 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4-iodo-1-isobutylimidazole

[0318] Under nitrogen, 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4,5-diiodo-1-isobutylimidazole 1-5 (2.41 g, 4.30 mmol) and tetrahydrofuran (25 mL) were added to the reaction flask. The system was stirred at -15°C for 10 min, followed by the dropwise addition of ethylmagnesium bromide in tetrahydrofuran (6.40 mL, 6.40 mmol, 1 mol / mL). Stirring was continued for 1 hour after the addition was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EA = 10:1) to afford 2-[3-chloro-4-(2-methoxyethoxy)phenyl]-4-iodo-1-isobutylimidazole 1-6 (880 mg, 47.0% yield, white solid). LC-MS calculation for C 16 H 21 ClIN2O2[M+1] + :m / z=435.0;Found:435.1.

[0319] Step 5: 2-(2-(3-chloro-4-(2-methoxyethoxy)phenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0320] 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 in parallel 6 times. The reaction mixture was combined and adjusted to pH 2-3 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over sodium sulfate, concentrated, and purified using a 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, 8.25% yield, yellow solid). LC-MS calc. for C 26 H 28 ClN4O4S[M+H] + :m / z=527.1;Found:527.2; 1 H NMR (400MHz, DMSO-d6) 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).

[0321] Example 2: 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-2)

[0322] Step 1: 3,5-dibromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]pyrazole

[0323] To a solution of compound 2-1 (2.00 g, 8.85 mmol) and compound 1-3 (2.04 g, 8.85 mmol) in toluene (30 mL) were added pyridine (2.15 mL, 26.6 mmol) and copper acetate (2.42 g, 13.3 mmol). The mixture was stirred at 90°C for 16 hours. The mixture was filtered, concentrated, and purified by column chromatography (PE:EA = 3:17) to afford 3,5-dibromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]pyrazole 2-2 (3.17 g, 87.4% yield, white solid). LC-MS calculation for C 12 H 12 Br2ClN2O2[M+H] + :m / z=408.9 / 410.9 / 412.9; Found:408.9 / 410.9 / 412.9.

[0324] Step 2: 3-Bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-(2-methylprop-1-en-1-yl)pyrazole

[0325] Under nitrogen, compound 2-3 (814 mg, 4.47 mmol), Pd(dppf)Cl2 (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 stirred at 70°C for 16 hours. After cooling, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified 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, 91.6% yield, white solid). LC-MS calc. for C 16 H 19 BrClN2O2[M+H] + :m / z=385.0 / 387.0; Found:385.0 / 387.0.

[0326] Step 3: 3-Bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazole

[0327] To a solution of compound 2-4 (795 mg, 2.07 mmol) in methanol (3 mL) was added platinum dioxide (94.2 mg, 415 μmol) at 0°C. The mixture was stirred under a hydrogen atmosphere for half an hour. The filtrate was filtered, concentrated, and purified by column chromatography (PE:EA = 1:9) to afford 3-bromo-1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazole 2-5 (672 mg, 83.7% yield, colorless oil). LC-MS calculation for C 16 H 21 BrClN2O2[M+H] + :m / z=387.0 / 389.0; Found:387.0 / 389.0.

[0328] Step 4: 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0329] Under nitrogen, 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). The mixture was stirred at 100°C for 10 hours. The reaction mixture was filtered, the filtrate was concentrated, and then purified by column chromatography (PE:EA = 1:3) to give methyl 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate 2-6 (190 mg, 68.1% yield, yellow solid). LC-MS calculation for C 27 H 30 ClN4O4S[M+H] + :m / z=541.2;Found:541.2.

[0330] Step 5: 2-[[1-[3-chloro-4-(2-methoxyethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0331] To a mixed solution of compound 2-6 (170 mg, 314 μmol) in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL) was added lithium hydroxide (45.2 mg, 1.89 mmol), and the mixture was stirred at 75°C for 1 hour. The mixture was concentrated, and the pH was adjusted to 5-6 by adding hydrochloric acid (1.5 N). The mixture was then extracted with dichloromethane / methanol (10 / 1) (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase preparative chromatography to afford 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, 57.5% yield, yellow solid). LC-MS calculation for C 26 H 28 ClN4O4S[M+H] + :m / z=527.1;Found:527.4; 1 H NMR (400MHz, DMSO-d6) 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),3.3 6(s,3H),2.56(d,J=7.0Hz,2H),1.79(dp,J=13.6,6.8Hz,1H),0.85(d,J=6.6Hz,6H).

[0332] Example 3: 2-((2-(3-ethoxyphenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-3)

[0333] Step 1: 1-isobutyl-2-bromo-4-nitroimidazole

[0334] Under nitrogen, compound 3-1 (2.00 g, 10.4 mmol), isobutane bromide (2.88 g, 15.6 mmol), potassium carbonate (4.32 g, 31.3 mmol), and acetonitrile (20 mL) were added sequentially to a reaction flask and stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature, filtered, concentrated, and then added with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (30 mL x 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 = 3:1) to obtain compound 1-isobutyl-2-bromo-4-nitroimidazole 3-2 (2.10 g, 81.4% yield, yellow solid). LC-MS calculation for C7H 11 BrN3O2[M+H] + :m / z=248.0 / 250.0; Found:248.0 / 250.0.

[0335] Step 2: 1-isobutyl-2-(3-ethoxyphenyl)-4-nitroimidazole

[0336] Under nitrogen, 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 mixture of dioxane and water (35 mL, 6:1) and stirred at 100°C for 20 hours. After cooling to room temperature, the reaction solution was filtered and concentrated. The residue was added with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were 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, 86.5% yield, white solid). LC-MS calculation for C 15 H 20 N3O3[M+H] + :m / z=290.1;Found:290.2.

[0337] Step 3: 1-isobutyl-2-(3-ethoxyphenyl)-4-aminoimidazole

[0338] Compound 3-4 (1.50 g, 5.18 mmol), palladium hydroxide (873 mg, 6.22 mmol), and methanol (10 mL) were added to a 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, 4 N) was added and stirred for 10 minutes. The reaction solution was filtered and concentrated to obtain crude product 3-5 (1.20 g, 89.3% yield, yellow liquid), which was used directly in the next reaction. LC-MS calculation for C 15 H 22 N3O[M+H] + :m / z=260.2;Found:260.3.

[0339] Step 4: 2-((2-(3-ethoxyphenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinate

[0340] 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. After cooling to room temperature, saturated aqueous ammonium chloride solution (30 mL) was added and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed twice with saturated aqueous sodium chloride solution 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 3-6 (700 mg, yield 38.0%, yellow solid). LC-MS calc. for C 26 H 29 N4O3S[M+H] + :m / z=477.2;Found:477.3.

[0341] Step 5: 2-((2-(3-ethoxyphenyl)-1-isobutyl-1H-imidazol-4-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0342] Compound 3-6 (650 mg, 1.36 mmol) and lithium hydroxide (163 mg, 6.82 mmol) were dissolved in a mixture 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 and collected by filtration. The solid was then dissolved and directly purified by reverse phase reaction to obtain compound Cpd-3 (250 mg, yield 39.7%, yellow solid). LC-MS calc. for C 25 H27 N4O3S[M+H] + :m / z=463.2;Found:463.4; 1 H NMR (400MHz, DMSO-d6) 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=8.6Hz,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).

[0343] Example 4: 2-[[1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-4)

[0344] Step 1: 3,5-dibromo-1-[3-(2,2-difluoroethoxy)phenyl]pyrazole

[0345] Compounds 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. The system was stirred at 90°C under an oxygen atmosphere for 12 hours. TLC indicated the reaction was complete. The crude compound was filtered and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 5:1) afforded compound 4-2 (2.90 g, 71.6% yield, colorless liquid). LCMS calc. for C 11 H9Br2F2N2O[M+H] + :m / z=380.9 / 382.9 / 384.9; Found:380.9 / 383.0 / 384.9.

[0346] Step 2: 3-Bromo-1-[3-(2,2-difluoroethoxy)phenyl]-5-(22-methylprop-1-en-1-yl)pyrazole

[0347] Compounds 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). Pd(dppf)Cl2 (555 mg, 759 μmol) and potassium phosphate (3.22 g, 15.2 mmol) were added at room temperature. The atmosphere was purged with nitrogen 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. Column chromatography (PE:EA = 20:1) afforded compound 4-3 (2.50 g, 92.5% yield, colorless liquid). LCMS calculation for C 15 H 16 BrF2N2O[M+H] + :m / z=357.0 / 359.0; Found:357.0 / 359.1.

[0348] Step 3: 3-Bromo-1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutylpyrazole

[0349] 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 with hydrogen three times, and the system was stirred at 0°C for 0.5 hours. The mixture was filtered, and the solid was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (PE:EA = 4:1) to obtain compound 4-4 (750 mg, 74.8% yield, colorless liquid). LCMS calculation for C 15 H 18 BrF2N2O[M+H] + :m / z=359.1 / 361.1; Found:359.0 / 361.1.

[0350] Step 4: 2-[[1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0351] 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. The system was stirred at 120°C under a nitrogen atmosphere for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (PE:EA = 5:1) to afford compound 4-5 (250 mg, 97.4% yield, yellow solid). LCMS calculation for C 26 H27 F2N4O3S[M+H] + :m / z=513.2;Found:513.3.

[0352] Step 5: 2-[[1-[3-(2,2-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0353] Compound 4-5 (270 mg, 527 μmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and water (1 mL). Lithium hydroxide (100 mg, 4.21 mmol) was added at room temperature, and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 4 with 2N hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered and concentrated to obtain a crude product that was purified by reverse phase preparative reaction to obtain compound Cpd-4 (112 mg, 42.6% yield, yellow solid). LCMS calculation for C 25 H 25 F2N4O3S[M+H] + :m / z=499.2;Found:499.2; 1 H NMR (400MHz, DMSO-d6) 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).

[0354] Example 5: 2-((5-isobutyl-1-(3-methylphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-5)

[0355] Step 1: 3,5-dibromo-1-(3-methylphenyl)-1H-pyrazole

[0356] 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by column chromatography (PE:EA = 10:1) to obtain compound 5-2 (583 mg, 83.6% yield, yellow liquid). LCMS calculation for C 10 H9Br2N2[M+H] + :m / z=314.9 / 316.9 / 318.9; Found:315.2 / 317.2 / 319.2.

[0357] Step 2: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(3-methylphenyl)-1H-pyrazole

[0358] Compounds 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)Cl2 (459 mg, 633 μmol) were added, and the system was stirred at 70°C under nitrogen for 2 hours. After the reaction, 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, 60.2% yield, colorless liquid). LCMS calculation for C 14 H 16 BrN2[M+H] + :m / z=291.0 / 293.0; Found:291.3 / 293.3.

[0359] Step 3: 3-Bromo-5-isobutyl-1-(3-methylphenyl)-1H-pyrazole

[0360] 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 under a hydrogen atmosphere for 30 minutes. After the reaction was complete, the product was filtered, concentrated, and purified by column chromatography (PE:EA = 9:1) to obtain compound 5-4 (600 mg, 92.1% yield, colorless liquid). LCMS calculation for C 14 H 18 BrN2[M+H] +:m / z=293.1 / 295.1; Found:293.3 / 295.3.

[0361] Step 4: 2-(5-isobutyl-1-(3-methylphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0362] Compound 5-4 (420 mg, 1.43 mmol) and INT-1 (403 mg, 1.72 mmol) were dissolved in toluene (2 mL), and t-BuBrettphos Pd G3 (122 mg, 143 μmol) and cesium carbonate (933 mg, 2.86 mmol) were added. The system was stirred at 120°C under nitrogen for 16 hours. After completion of the reaction, the mixture 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, 15.6% yield, yellow solid). LCMS calculation for C 25 H 27 N4O2S[M+H] + :m / z=447.2;Found:447.4.

[0363] Step 5: 2-((5-isobutyl-1-(3-methylphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0364] Compound 5-5 (100 mg, 224 μmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (1 mL). Lithium hydroxide (32.2 mg, 1.34 mmol) was added, and the system was stirred at 50°C for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 4. The mixture was extracted with dichloromethane (10 mL), and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by preparative column chromatography to obtain compound Cpd-5 (70.0 mg, 72.3% yield, yellow solid). LCMS calculation for C 24 H 25 N4O2S[M+H] + :m / z=433.2;Found:433.4; 1H NMR (400MHz, DMSO-d6) 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).

[0365] Example 6: 2-((5-isobutyl-1-(3-ethoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-6)

[0366] Step 1: 3,5-dibromo-1-(3-ethoxyphenyl)-1H-pyrazole

[0367] Under an 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 stirred at 90°C for 16 hours. The reaction mixture was 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 6-2 (5.01 g, 65.3% yield, colorless liquid). LCMS calculation for C 11 H 11 Br2N2O[M+H] + :m / z=344.9 / 346.9 / 348.9; Found:345.2 / 347.2 / 349.2.

[0368] Step 2: 3-Bromo-1-(3-ethoxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0369] Under nitrogen, compound 6-2 (4.00 g, 11.6 mmol), compound 2-3 (2.32 g, 12.7 mmol), Pd(dppf)Cl2 (1.68 g, 2.31 mmol), potassium phosphate (4.91 g, 23.1 mmol), and a tetrahydrofuran / water mixture (35 mL, 6:1) were added to a reaction flask. 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 phases were washed with 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, 59.2% yield, white solid). LCMS calculation for C 15 H 18 BrN2O[M+H] + :m / z=321.1 / 323.1; Found:321.1 / 323.1.

[0370] Step 3: 3-Bromo-1-(3-ethoxyphenyl)-5-isobutyl-1H-pyrazole

[0371] Under nitrogen, 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 atmosphere was replaced with hydrogen three times, and the system was stirred at 0°C for 0.5 hours. The filtrate was filtered, and the crude product obtained after concentration was subjected to column chromatography (PE:EA = 10:1) to obtain compound 6-4 (1.50 g, 74.7% yield, colorless liquid). LCMS calculation for C 15 H 20 BrN2O[M+H] + :m / z=323.1 / 325.1; Found:323.3 / 325.3.

[0372] Step 4: 2-((1-(3-ethoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0373] Under nitrogen, 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) were added to a reaction flask and stirred at 120°C for 1 hour. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was then subjected to column chromatography (PE:EA = 5:1) to afford compound 6-5 (300 mg, 20.4% yield, yellow solid). LCMS calculation for C 26 H 29 N4O3S[M+H] + :m / z=477.2;Found:477.3.

[0374] Step 5: 2-((1-(3-ethoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0375] Compound 6-5 (300 mg, 629 μmol) and lithium hydroxide (75.4 mg, 3.15 mmol) were dissolved in a mixture 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). The pH of the aqueous phase was then adjusted to 5 with 1N hydrochloric acid, and then extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then purified by preparative purification to obtain compound Cpd-6 (125 mg, 42.9% yield, yellow solid). LCMS calc. for C 25 H 27 N4O3S[M+H] + :m / z=463.2;Found:463.2; 1 H NMR (400MHz, DMSO-d6) 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).

[0376] Example 7: 2-((5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-7)

[0377] Step 1: 3,5-dibromo-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazole

[0378] Under an 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 a reaction flask and stirred at 90°C for 16 hours. The mixture was 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, 67.9% yield, white solid). LCMS calculation for C 12 H 13 Br2N2O2[M+H] + :m / z=374.9 / 376.9 / 378.9; Found:375.2 / 377.2 / 379.2.

[0379] Step 2: 3-Bromo-1-(3-(2-methoxyethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0380] Under nitrogen, compound 7-2 (1.00 g, 2.66 mmol), compound 2-3 (611 mg, 3.35 mmol), Pd(dppf)Cl2 (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 a reaction flask. The system was stirred and reacted at 120°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2) and 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 7-3 (680 mg, 73.0% yield, white solid). LCMS calc. for C 16 H 20 BrN2O2[M+H] + :m / z=351.1 / 353.1; Found:351.1 / 353.1.

[0381] Step 3: 3-Bromo-5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazole

[0382] Compound 7-3 (520 mg, 1.48 mmol) was dissolved in methanol (10 mL). Platinum dioxide (200 mg, 0.890 mmol) was added at 0°C and the system was stirred under a hydrogen atmosphere for 4 hours. 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 calculation for C 16 H 22 BrN2O[M+H] + :m / z=353.1 / 355.1; Found:353.1 / 355.1.

[0383] Step 4: 2-((5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0384] Under nitrogen, 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 a reaction flask and stirred at 100°C for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 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 7-5 (250 mg, 48.4% yield, white solid). LCMS calc. for C 27 H 31 N4O4S[M+H] + :m / z=507.6;Found:507.5.

[0385] Step 5: 2-((5-isobutyl-1-(3-(2-methoxyethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0386] Compound 7-5 (240 mg, 0.474 mmol) and lithium hydroxide (56.7 mg, 2.37 mmol) were dissolved in a mixture of tetrahydrofuran / methanol / water (2 mL, 2:1:1). The system was stirred at 70°C for 10 minutes. The reaction solution was concentrated, and 1N hydrochloric acid was added to adjust the pH to 5. The solution was then extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The crude product obtained after concentration was purified to obtain Cpd-7 (113 mg, 48.4% yield, yellow solid). LCMS calculation for C 26 H 29 N4O4S[M+H] + :m / z=493.2;Found:493.2; 1 H NMR (400MHz, DMSO-d6) 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).

[0387] Example 8: 2-((5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-8)

[0388] Step 1: 3,5-dibromo-1-(3-isopropoxyphenyl)-1H-pyrazole

[0389] Under an 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 a reaction flask and stirred at 90°C for 16 hours. The mixture was 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, 79.9% yield, yellow liquid). LCMS calculation for C 12 H 13 Br2N2O[M+H] +:m / z=358.9 / 360.9 / 362.9; Found:359.1 / 361.1 / 363.1.

[0390] Step 2: 3-Bromo-1-(3-isopropoxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0391] Under nitrogen, compound 8-2 (2.00 g, 5.55 mmol), compound 2-3 (1.21 g, 6.67 mmol), Pd(dppf)Cl2 (813 mg, 1.11 mmol), potassium phosphate (2.59 g, 12.2 mmol), and a dioxane / water mixture (24 mL, 5:1) were added to a reaction flask and stirred at 80°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (40 mL x 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 8-3 (1.01 g, 54.4% yield, colorless liquid). LCMS calculation for C 16 H 20 BrN2O[M+H] + :m / z=335.1 / 337.2; Found:335.2 / 337.2.

[0392] Step 3: 3-Bromo-5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazole

[0393] Under nitrogen, 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 atmosphere was replaced with hydrogen three times, and the system was stirred at 0°C for 1 hour. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 10:1) to obtain compound 8-4 (600 mg, 85.4% yield, colorless liquid). LCMS calculation for C 16 H 22 BrN2O[M+H] + :m / z=337.1 / 339.1; Found:337.2 / 339.2.

[0394] Step 4: 2-((5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0395] Under nitrogen, 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 flask. The system was stirred and reacted at 120°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (20 mL × 3). The organic phase was 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 8-5 (320 mg, 66.7% yield, yellow solid). LCMS calculation for C 27 H 31 N4O3S[M+H] + :m / z=491.2;Found:491.2.

[0396] Step 5: 2-((5-isobutyl-1-(3-isopropoxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0397] Compound 8-5 (350 mg, 713 μmol) and lithium hydroxide (103 mg, 4.28 mmol) were dissolved in a mixture 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), then adjusted to pH 5 with 1N hydrochloric acid, and 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 N4O3S[M+H] + :m / z=477.2;Found:477.3; 1 H NMR (400MHz, DMSO-d6) 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).

[0398] Example 9: 2-((5-isobutyl-1-(3-cyclopropyloxyphenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-9)

[0399] Step 1: 3,5-dibromo-1-(3-cyclopropyloxyphenyl)-1H-pyrazole

[0400] Under an oxygen atmosphere, compound 2-1 (2.54 g, 11.2 mmol), compound 9-1 (2.00 g, 11.2 mmol), copper acetate (3.06 g, 16.9 mmol), pyridine (2.72 mL, 33.7 mmol), and toluene (30 mL) were added to a reaction flask and stirred at 90°C for 3 hours. The reaction mixture was 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 9-2 (2.60 g, 64.8% yield, white solid). LCMS calculation for C 12 H 11 Br2N2O[M+H] + :m / z=356.9 / 358.9 / 360.9; Found:357.1 / 359.1 / 361.1.

[0401] Step 2: 3-Bromo-1-(3-cyclopropyloxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0402] Under nitrogen, compound 9-2 (1.00 g, 2.79 mmol), compound 2-3 (610 mg, 3.35 mmol), Pd(dppf)Cl2 (410 mg, 560 μmol), potassium phosphate (1.30 g, 6.14 mmol), and a dioxane / water mixture (20 mL, 5:1) were added to a reaction flask. The system was stirred and reacted at 80°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with 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, 88.5% yield, colorless liquid). LCMS calculation for C 16 H 18 BrN2O[M+H] + :m / z=333.1 / 335.1; Found:333.1 / 335.1.

[0403] Step 3: 3-Bromo-1-(3-cyclopropyloxyphenyl)-5-isobutyl-1H-pyrazole

[0404] Compound 9-3 (680 mg, 2.04 mmol) was dissolved in methanol (2 mL). Platinum dioxide (140 mg, 610 μmol) was added at 0°C. The system was stirred under a hydrogen atmosphere for 0.5 hours. 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, 80.8% yield, colorless liquid). LCMS calculation for C 16 H 20 BrN2O[M+H] + :m / z=335.1 / 337.1; Found:335.2 / 337.2.

[0405] Step 4: 2-((1-(3-cyclopropyloxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0406] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 5:1) to afford compound 9-5 (161 mg, 61.1% yield, yellow liquid). LCMS calc. for C 27 H 29 N4O3S[M+H] + :m / z=489.2;Found:489.2.

[0407] Step 5: 2-((1-(3-cyclopropyloxyphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0408] Compound 9-5 (150 mg, 310 μmol) and lithium hydroxide (73.5 mg, 3.07 mmol) were dissolved in a tetrahydrofuran / methanol / water mixture (2 mL; 2:1:1). The system was stirred and reacted at 50°C for 0.5 hours. The reaction solution was concentrated and adjusted to pH 5 by adding 1N dilute hydrochloric acid. The solution was then extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The crude product obtained after concentration was purified to obtain Cpd-9 (38.4 mg, 26.1% yield, yellow solid). LCMS calculation for C 26 H 27 N4O3S[M+H] + :m / z=475.2;Found:475.2; 1 H NMR(400MHz,DMSO-d6)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,4 H),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).

[0409] Example 10: 2-((5-isobutyl-1-(3-(cyclopropylmethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-10)

[0410] Step 1: 3,5-dibromo-1-(3-(cyclopropylmethoxy)phenyl)-1H-pyrazole

[0411] To a solution of compound 2-1 (2.00 g, 8.85 mmol) and compound 10-1 (1.70 g, 8.85 mmol) in toluene (20 mL) were added pyridine (2.15 mL, 26.6 mmol) and copper acetate (2.41 g, 13.3 mmol). The system was stirred at 90°C under an oxygen atmosphere for 3 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 9:1) to obtain compound 10-2 (1.97 g, 59.8% yield, yellow liquid). LCMS calculation for C 13 H 13 Br2N2O[M+H] + :m / z=370.9 / 372.9 / 374.9; Found:371.0 / 373.0 / 375.0.

[0412] Step 2: 3-Bromo-1-(3-(cyclopropylmethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0413] To a mixed solution of compound 10-2 (1.00 g, 2.69 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added compound 2-3 (587 mg, 3.23 mmol), potassium phosphate (1.26 g, 5.91 mmol), and Pd(dppf)Cl2 (393 mg, 538 μmol). The system was stirred at 80°C under a nitrogen atmosphere for 1.5 hours. After cooling, the reaction solution was extracted with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 19:1) to obtain compound 10-3 (787 mg, 84.5% yield, yellow liquid). LCMS calculation for C 17 H 20 BrN2O[M+H] + :m / z=347.1 / 349.1; Found:347.1 / 349.1.

[0414] Step 3: 3-Bromo-1-(3-(cyclopropylmethoxy)phenyl)-5-isobutyl-1H-pyrazole

[0415] Platinum dioxide (151 mg, 665 μmol) was added to a solution of compound 10-3 (770 mg, 2.22 mmol) in methanol (2 mL). The system was stirred at 0°C under a hydrogen atmosphere for 1 hour. The reaction solution was filtered, concentrated, and purified by column chromatography (PE:EA = 9:1) to obtain compound 10-4 (580 mg, 75.1% yield, yellow liquid). LCMS calculation for C 17 H 22 BrN2O[M+H] + :m / z=349.1 / 351.1; Found:349.1 / 351.1.

[0416] Step 4: 2-((1-(3-(cyclopropylmethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0417] To a solution of compound 10-4 (200 mg, 573 μmol) and INT-1 (134 mg, 572 μmol) in toluene (5 mL) were added t-BuBrettphos Pd G3 (147 mg, 172 μmol) and cesium carbonate (466 mg, 1.43 mmol). The reaction was stirred at 120°C under nitrogen for 1 hour. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 9:1) to afford compound 10-5 (210 mg, 73.0% yield, yellow solid). LCMS calculation for C 28 H 31 N4O3S[M+H] + :m / z=503.2;Found:503.2.

[0418] Step 5: 2-((1-(3-(cyclopropylmethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0419] To a solution of compound 10-5 (160 mg, 318 μmol) in tetrahydrofuran (10 mL) and water (2 mL) was added lithium hydroxide (45.7 mg, 1.91 mmol) at room temperature, and the reaction mixture was stirred at 50°C for 1 hour. 1.5N 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 preparatively purified to afford Cpd-10 (70.2 mg, 45.2% yield, yellow solid). LCMS calc. for C 27 H 29 N4O3S[M+H] + :m / z=489.2;Found:489.3; 1 H NMR (400MHz, DMSO-d6) 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).

[0420] 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)

[0421] Step 1: 1-Bromo-3-(1,1,2,2,2-pentadeuterioethoxy)benzene

[0422] 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 with 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. Water (50 mL) was added, and the product was extracted with dichloromethane (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11-2 (2.98 g, crude product, colorless liquid). 1 H NMR (400MHz, DMSO-d6) δ7.27-7.16(m,1H),7.10-7.01(m,2H),6.95-6.81(m,1H).

[0423] Step 2: 3-(1,1,2,2,2-pentadeuterioethoxy)phenylboronic acid

[0424] Compound 11-2 (1.60 g, 7.76 mmol) was dissolved in tetrahydrofuran (15 mL). The air was replaced with nitrogen three times. n-Butyl lithium (7.28 mL, 11.6 mmol, 1.6 M n-hexane solution) was added dropwise at -78°C and stirred for 0.5 hours. Trimethyl borate (2.42 g, 23.3 mmol) was then added dropwise and stirred for 12 hours. The mixture was slowly warmed to room temperature and the pH was adjusted to 4 with 2N hydrochloric acid. Ethyl acetate (10 mL x 3) was then added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried (PE:EA = 10:1) to obtain compound 11-3 (532 mg, 40.1% yield, white solid). LCMS calc. for C8H7D5BO3[M+H] + :m / z=172.1;Found:172.2.

[0425] Step 3: 3,5-dibromo-1-[3-(1,1,2,2,2-pentadeuterioethoxy)phenyl]pyrazole

[0426] Compounds 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. The air was replaced with oxygen three times, and the system was stirred at 90°C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:1) to obtain compound 11-4 (446 mg, 58.5% yield, light yellow liquid). LCMS calculation for C 11 H6D5Br2N2O[M+H] + :m / z=350.0 / 352.0 / 354.0; Found:350.0 / 352.1 / 354.1.

[0427] Step 4: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-[3-(1,1,2,2,2-pentadeuterioethoxy)phenyl]pyrazole

[0428] Compounds 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). Pd(dppf)Cl2 (98.0 mg, 134 μmol) and potassium phosphate (568 mg, 2.68 mmol) were added at room temperature. The air was replaced with 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. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 11-5 (320 mg, 73.4% yield, colorless liquid). LCMS calculation for C 15 H 13 D5BrN2O[M+H] + :m / z=326.1 / 328.1; Found:326.1 / 328.1.

[0429] Step 5: 3-Bromo-5-isobutyl-1-[3-(1,1,2,2,2-pentadeuterioethoxy)phenyl]pyrazole

[0430] Compound 11-5 (400 mg, 1.23 mmol) was dissolved in methanol (6 mL). Platinum dioxide (55.7 mg, 245 μmol) was added at 0°C. The air was replaced with hydrogen three times, and the system was stirred at 0°C for 1 hour. The mixture was filtered, the solid was washed with methanol (10 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 25:1) to obtain compound 11-6 (216 mg, 53.7% yield, colorless liquid). LCMS calculation for C 15 H15 D5BrN2O[M+H] + :m / z=328.1 / 330.1; Found:328.1 / 330.2. 1 H NMR (400MHz, DMSO-d6) 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).

[0431] Step 6: 2-[[5-isobutyl-1-[3-(1,1,2,2,2-pentadeuterioethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0432] 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. The system was stirred at 125°C under a nitrogen atmosphere 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 x 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-11 (82.7 mg, 29.1% yield, yellow solid). LCMS calculation for C 25 H 22 D5N4O3S[M+H] + :m / z=468.2;Found:468.3; 1 H NMR (400MHz, DMSO-d6) 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).

[0433] Example 12: 2-[[5-Isobutyl-1-[3-(methoxymethyl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-12)

[0434] Step 1: 3,5-dibromo-1-[3-(methoxymethyl)phenyl]pyrazole

[0435] Compounds 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. The air was replaced with oxygen three times, and the system was stirred at 90°C for 12 hours. The product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 12-2 (701 mg, 35.1% yield, yellow liquid). LCMS calculation for C 11 H 11 Br2N2O[M+H] + :m / z=344.9 / 346.9 / 348.9; Found:344.9 / 346.9 / 349.0.

[0436] Step 2: 3-Bromo-1-[3-(methoxymethyl)phenyl]-5-(2-methylprop-1-en-1-yl)pyrazole

[0437] Compounds 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). Pd(dppf)Cl2 (211 mg, 289 μmol) and potassium phosphate (1.23 g, 5.78 mmol) were added at room temperature. The air was replaced with 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. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 12-3 (640 mg, 69.2% yield, yellow liquid). LCMS calculation for C 15 H 18 BrN2O[M+H] + :m / z=321.1 / 323.1; Found:321.0 / 323.0.

[0438] Step 3: 3-Bromo-5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazole

[0439] Compound 12-3 (800 mg, 2.49 mmol) was dissolved in methanol (10 mL). Platinum dioxide (113 mg, 498 μmol) was added at 0°C. The air was replaced with hydrogen three times, and the system was stirred at 0°C for 0.5 hours. The mixture was filtered, and the solid was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 25:1) to obtain compound 12-4 (420 mg, 52.3% yield, colorless liquid). LCMS calculation for C 15 H 20 BrN2O[M+H] + :m / z=323.1 / 325.1; Found:323.1 / 325.1.

[0440] Step 4: 2-[[5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0441] 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. The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. The mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 5:1) to obtain compound 12-5 (117 mg, 13.2% yield, yellow liquid). LCMS calculation for C 26 H 29 N4O3S[M+H] + :m / z=477.2;Found:477.3.

[0442] Step 5: 2-[[5-isobutyl-1-[3-(methoxymethyl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0443] Compound 12-5 (130 mg, 273 μmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and water (1 mL). Lithium hydroxide (39.2 mg, 1.64 mmol) was added at room temperature, and the mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 4 with 2N hydrochloric acid and extracted with ethyl acetate (10 mL x 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-12 (50.0 mg, 39.6% yield, yellow solid). LCMS calculation for C 25 H 27 N4O3S[M+H] +:m / z=463.2;Found:463.3; 1 H NMR (400MHz, DMSO-d6) 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).

[0444] Example 13: 2-[[1-(3-ethoxy-4-methoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-13)

[0445] Step 1: 4-Bromo-2-ethoxy-1-methoxybenzene

[0446] 5-Bromo-2-methoxyphenol 13-1 (2.00 g, 9.85 mmol) was dissolved in DMF (15 mL), and ethyl bromide (2.15 g, 19.7 mmol) and potassium carbonate (2.72 g, 19.7 mmol) were added. The system was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was washed with water (40 mL) and extracted with ethyl acetate (40 mL × 3). 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, 88.7% yield, as a white solid).

[0447] Step 2: 3-Ethoxy-4-methoxyphenylboronic acid

[0448] Under nitrogen, compound 13-2 (3.00 g, 13.0 mmol) was dissolved in tetrahydrofuran (30 mL) and 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 continued for 0.5 hour. Trimethyl borate (4.05 g, 39.0 mmol) was added and stirred for 0.5 hour. The pH was adjusted to 4 with 2N hydrochloric acid and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phase was dried and concentrated to afford crude product 13-3 (2.00 g, 78.5% yield, as a yellow solid).

[0449] Step 3: 3,5-dibromo-1-(3-ethoxy-4-methoxyphenyl)pyrazole

[0450] 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. The mixture was cooled and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE:EA = 9:1) to obtain compound 13-4 (1.08 g, 61.9% yield, white solid). LCMS calculation for C 12 H 13 Br2N2O2[M+H] + :m / z=374.9 / 376.9 / 378.9; Found:375.1 / 377.1 / 379.1.

[0451] Step 4: 3-Bromo-1-(3-ethoxy-4-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

[0452] Compounds 13-4 (1.20 g, 3.19 mmol) and 2-3 (697 mg, 3.83 mmol) were dissolved in a mixture of tetrahydrofuran (12 mL) and water (3 mL). Pd(dppf)Cl2 (233 mg, 319 μmol) and potassium phosphate (1.35 g, 6.38 mmol) were added, and the system was stirred at 70°C under nitrogen for 16 hours. After cooling, water (15 mL) was added, and the mixture was extracted with ethyl acetate (35 mL x 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, 17.0% yield, colorless liquid). LCMS calculation for C 16 H 20 BrN2O2[M+H] + :m / z=351.1 / 353.1; Found:351.2 / 353.2.

[0453] Step 5: 3-Bromo-1-(3-ethoxy-4-methoxyphenyl)-5-isobutylpyrazole

[0454] 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 under a hydrogen atmosphere for 1 hour. After the reaction was completed, the product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 9:1) to obtain compound 13-6 (136 mg, 67.9% yield, colorless liquid). LCMS calculation for C 16 H 22 BrN2O2[M+H]+ :m / z=353.1 / 355.1; Found: 353.2 / 355.2.

[0455] Step 6: 2-[[1-(3-ethoxy-4-methoxyphenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0456] Compound 13-6 (160 mg, 454 μmol) and INT-1 (106 mg, 453 μmol) were dissolved in DMF (3 mL) and 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. After completion of the reaction, 1N hydrochloric acid was added to adjust the pH to 5. The mixture was extracted with dichloromethane (30 mL x 3). The organic phase was dried and concentrated to obtain the crude product, which was then purified by preparative purification to afford Cpd-13 (76.8 mg, 34.3% yield, yellow solid). LCMS calculated for C 26 H 29 N4O4S[M+H] + :m / z=493.2;Found:493.2; 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.80(d,J=2.6Hz,1H),8.38(d,J=2.6Hz,1H),7.5 6-7.52(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 =7.2Hz, 2H), 1.79 (dt, J = 13.7, 7.0Hz, 1H), 1.33 (t, J = 6.9Hz, 3H), 0.85 (d, J = 6.6Hz, 6H).

[0457] Example 14: 2-[[1-(3-ethoxy-5-methoxyphenyl)-5-isobutyl-1H-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-14)

[0458] Step 1: 1-Bromo-3-ethoxy-5-methoxybenzene

[0459] Potassium carbonate (5.44 g, 39.4 mmol) was added to a solution of 3-bromo-5-methoxyphenol 14-1 (4.00 g, 19.7 mmol) and bromoethane (4.29 g, 39.4 mmol) in DMF (20 mL). The system was reacted at 50°C for 2 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (150 mL), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (PE:EA = 19:1) to afford 14-2 (3.60 g, 79.4% yield, colorless liquid).

[0460] Step 2: 3-Ethoxy-5-methoxyphenylboronic acid

[0461] Under nitrogen, compound 14-2 (2.80 g, 12.1 mmol) was dissolved in tetrahydrofuran (30 mL). The system was cooled to -60°C, and n-butyllithium (7.27 mL, 18.2 mmol, 2.5 M solution in n-hexane) was slowly added dropwise. The mixture was 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 to a pH of 2-3, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic layer was washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then slurried with PE:EA (10:1) to afford 14-3 (1.08 g, 45.5% yield, as a white solid).

[0462] Step 3: 3,5-dibromo-1-(3-ethoxy-5-methoxyphenyl)pyrazole

[0463] Compound 2-1 (800 mg, 3.54 mmol) was dissolved in toluene (16 mL), and pyridine (0.857 mL, 10.6 mmol), copper acetate (965 mg, 5.31 mmol), and 14-3 (764 mg, 3.90 mmol) were added. The system was stirred at 45°C under an oxygen atmosphere for 16 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was collected and concentrated, and the crude product was purified by column chromatography (PE:EA = 10:1) to obtain 14-4 (810 mg, 60.8% yield, colorless liquid). LC-MS calculation for C 12 H 13 Br2N2O2[M+H] + :m / z=374.9 / 376.9 / 378.9; Found:375.0 / 377.0 / 379.0.

[0464] Step 4: 3-Bromo-1-(3-ethoxy-5-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

[0465] Compounds 14-4 (900 mg, 2.39 mmol) and 2-3 (435 mg, 2.39 mmol) were dissolved in tetrahydrofuran (10 mL), and Pd(dppf)Cl2 (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. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 14-5 (585 mg, 69.9% yield, colorless liquid). LC-MS calculation for C 16 H 20 BrN2O2[M+H] + :m / z=351.1 / 353.1; Found:351.2 / 353.2.

[0466] Step 5: 3-Bromo-1-(3-ethoxy-5-methoxyphenyl)-5-isobutylpyrazole

[0467] 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. The mixture was filtered, and the filter cake was washed with methanol (20 mL). The filtrate was collected and concentrated, and the residue was subjected to column chromatography (PE:EA = 10:1) to obtain compound 14-6 (360 mg, 59.8% yield, colorless liquid). LC-MS calculation for C 16 H 22 BrN2O2[M+H] + :m / z=353.1 / 355.1; Found:353.1 / 355.1.

[0468] Step 6: 2-[[1-(3-ethoxy-5-methoxyphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0469] Compound 14-6 (300 mg, 849 μmol) and INT-1 (298 mg, 1.27 mmol) were dissolved in toluene (5 mL), followed by the addition of t-BuBrettphos Pd G3 (109 mg, 127 μmol) and cesium carbonate (552 mg, 1.70 mmol). The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EA = 9:1) to afford compound 14-7 (180 mg, 41.9% yield, yellow solid). LC-MS calculation for C 27 H 31 N4O4S[M+H] + :m / z=507.2;Found:507.3.

[0470] Step 7: 2-[[1-(3-ethoxy-5-methoxyphenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0471] Compound 14-7 (250 mg, 493 μmol) was dissolved in a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL). Lithium hydroxide (118 mg, 4.93 mmol) was added, and the mixture was heated to 50°C and stirred for 1 hour. 1N hydrochloric acid was added to adjust the pH to 2-3, and the reaction mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative purification to obtain compound Cpd-14 (95.0 mg, 39.1% yield, yellow solid). LC-MS calculation for C 26 H 29 N4O4S[M+H] + :m / z=493.2;Found:493.3. 1 H NMR (400MHz, DMSO-d6) 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).

[0472] Example 15: 2-[[1-[4-Fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-15)

[0473] Step 1: 4-Fluoro-3-(trifluoromethoxy)phenylboronic acid

[0474] 4-Bromo-1-fluoro-2-(trifluoromethoxy)benzene 15-1 (4.50 g, 17.4 mmol) was dissolved in tetrahydrofuran (50 mL). n-Butyl lithium (16.3 mL, 26.1 mmol, 1.6 M solution in n-hexane) was slowly added dropwise at -78°C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at -78°C for 0.5 hour. Trimethyl borate (5.42 g, 52.1 mmol) was then added dropwise. The mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with 1N hydrochloric acid (50 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product 15-2 (3.00 g, 77.0% yield, colorless liquid).

[0475] Step 2: 3,5-dibromo-1-[4-fluoro-3-(trifluoromethoxy)phenyl]pyrazole

[0476] 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. The system was stirred at 90°C under an oxygen atmosphere for 2 hours. After completion of the reaction, the mixture 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, 13.7% yield, colorless liquid). LCMS calculation for C 10 H5Br2F4N2O[M+H] + :m / z=402.9 / 404.9 / 406.9; Found:402.9 / 404.9 / 406.9.

[0477] Step 3: 3-Bromo-1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-(2-methylprop-1-en-1-yl)pyrazole

[0478] Compounds 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)Cl2 (326 mg, 446 μmol) were added at room temperature. The system was stirred at 75°C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the reaction solution was filtered and partitioned with ethyl acetate (40 mL) and water (10 mL). 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, 48.0% yield, colorless liquid). LCMS calc. for C 14 H 12 BrF4N2O[M+H] + :m / z=379.0 / 381.0; Found:379.0 / 381.0.

[0479] Step 4: 3-Bromo-1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazole

[0480] Compound 15-4 (300 mg, 793 μmol) was dissolved in methanol (5 mL). Platinum dioxide (53.9 mg, 238 μmol) was added at room temperature. The air was replaced with hydrogen three times, and the system was stirred at 0°C for 0.5 hours. After completion of the reaction, the mixture was filtered with methanol (40 mL) and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain compound 15-5 (120 mg, 39.8% yield, colorless liquid). LCMS calculation for C 14 H 14 BrF4N2O[M+H] + :m / z=381.0 / 383.0; Found:381.1 / 383.1.

[0481] Step 5: 2-[[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0482] 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. The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. The mixture was cooled and filtered, and the filtrate was partitioned between ethyl acetate (70 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to afford compound 15-6 (212 mg, 75.6% yield, yellow solid). LCMS calculation for C 25 H 23 F4N4O3S[M+H] + :m / z=535.1;Found:535.2.

[0483] Step 6: 2-[[1-[4-fluoro-3-(trifluoromethoxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0484] Compound 15-6 (250 mg, 468 mol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (56.0 mg, 2.34 mmol) was added at room temperature, and 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 was adjusted to 5-6 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3) and dried under vacuum to obtain the crude product. Preparative purification was then performed to obtain compound Cpd-15 (118 mg, 48.5% yield, yellow solid). LCMS calculation for C 24 H 21 F4N4O3S[M+H] + :m / z=521.1;Found:521.1; 1 H NMR (400MHz, DMSO-d6) 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).

[0485] Example 16: 2-[[1-(5-Ethoxy-2-fluorophenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-16)

[0486] Step 1: 3,5-dibromo-1-(5-ethoxy-2-fluorophenyl)pyrazole

[0487] Compounds 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. The air was replaced with oxygen three times, and the system was stirred at 90°C for 12 hours. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (PE:EA = 4:1) to obtain compound 16-2 (510 mg, 15.8% yield, colorless liquid). LCMS calculation for C 11 H 10 Br2FN2O[M+H] + :m / z=362.9 / 364.9 / 366.9; Found:363.0 / 365.0 / 367.0.

[0488] Step 2: 3-Bromo-1-(5-ethoxy-2-fluorophenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

[0489] Compounds 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). Pd(dppf)Cl2 (128 mg, 175 μmol) and potassium phosphate (746 mg, 3.52 mmol) were added at room temperature. The air was replaced with 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. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 16-3 (560 mg, 94.1% yield, yellow liquid). LCMS calculation for C 15 H 17 BrFN2O[M+H] + :m / z=339.0 / 341.0; Found:339.2 / 341.2.

[0490] Step 3: 3-Bromo-1-(5-ethoxy-2-fluorophenyl)-5-isobutyl-pyrazole

[0491] Compound 16-3 (560 mg, 1.65 mmol) was dissolved in methanol (10 mL). Platinum dioxide (75.0 mg, 330 μmol) was added at 0°C. The air was replaced with hydrogen three times, and the system was stirred at 0°C for 1 hour. The mixture was filtered, and the solid was washed with methanol (10 mL). The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 15:1) to obtain compound 16-4 (203 mg, 36.1% yield, colorless liquid). LCMS calculation for C 15 H 19 BrFN2O[M+H] + :m / z=341.1 / 343.1; Found:341.1 / 343.1; 1 H NMR(400MHz,DMSO-d6)δ7.38-7.32(m,1H),7.11-7.02(m,2H),6.43(s,1H),4.03-3.98(m,2 H), 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).

[0492] Step 4: 2-[[1-(5-ethoxy-2-fluorophenyl)-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0493] 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. The system was stirred at 125°C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, adjusted to pH 5 with 2N hydrochloric acid, and extracted with ethyl acetate (10 mL x 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-16 (86.2 mg, 30.6% yield, yellow solid). LCMS calculation for C 25 H 26 FN4O3S[M+H] + :m / z=481.2;Found:481.2; 1H NMR (400MHz, DMSO-d6) 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),7.1 5-6.98(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).

[0494] Example 17: 2-[[1-(3-ethoxy-2-fluorophenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thien-2-yl)nicotinic acid (Cpd-17)

[0495] Step 1: 3,5-dibromo-1-(3-ethoxy-2-fluorophenyl)-1H-pyrazole

[0496] Compound 2-1 (2.00 g, 8.85 mmol) was dissolved in toluene (20 mL), and 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. After cooling, the reaction solution was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 17-2 (560 mg, 17.4% yield, yellow liquid). LCMS calculation for C 11 H 10 Br2FN2O[M+H] + :m / z=362.9 / 364.9 / 366.9; Found:363.0 / 365.0 / 367.0.

[0497] Step 2: 3-Bromo-1-(3-ethoxy-2-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0498] Compound 17-2 (700 mg, 1.92 mmol) was dissolved in tetrahydrofuran (10 mL), and 2-3 (385 mg, 2.12 mmol), Pd(dppf)Cl2 (141 mg, 192 μmol), and potassium phosphate (816 mg, 3.85 mmol) were added. The system was stirred at 70°C under nitrogen for 2 hours. After the reaction, 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) to obtain compound 17-3 (315 mg, 48.5% yield, colorless liquid). LCMS calculation for C 15 H 17 BrFN2O[M+H] + :m / z=339.0 / 341.0; Found:339.1 / 341.1.

[0499] Step 3: 3-Bromo-1-(3-ethoxy-2-fluorophenyl)-5-isobutyl-1H-pyrazole

[0500] 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 under hydrogen for 1 hour. The product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 17-4 (270 mg, 77.1% yield, colorless liquid). LCMS calculation for C 15 H 19 BrFN2O[M+H] + :m / z=341.1 / 343.1; Found:341.2 / 343.2.

[0501] Step 4: 2-[[1-(3-ethoxy-2-fluorophenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thien-2-yl)nicotinic acid

[0502] 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 under nitrogen for 3 hours. The mixture was cooled and filtered, and the filtrate was concentrated to obtain a crude product which was then preparatively purified to yield compound Cpd-17 (174 mg, 41.2% yield, yellow solid). LCMS calculation for C 25 H 26 FN4O3S[M+H] +:m / z=481.2;Found:481.2; 1 H NMR(400MHz, DMSO-d6)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(dd d,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).

[0503] Example 18: 2-[[1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-18)

[0504] Step 1: 3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)phenol

[0505] Compound 6-4 (1.00 g, 3.09 mmol) was dissolved in hydrobromic acid (8 mL) and water (4 mL) and 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. The residue was purified by column chromatography (PE:EA = 5:1) to obtain compound 18-1 (900 mg, 99.1% yield, yellow liquid). LCMS calculation for C 13 H 16 BrN2O[M+H] + :m / z=295.0 / 297.0; Found:295.2 / 297.2.

[0506] Step 2: 3-Bromo-1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazole

[0507] 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 between 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, 47.4% yield, colorless liquid). LCMS calculation for C 17 H 22 BrN2O[M+H] + :m / z=349.1 / 351.1; Found:349.2 / 351.1.

[0508] Step 3: 2-[[1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0509] 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. The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. The mixture was cooled and filtered, and the filtrate was partitioned between ethyl acetate (70 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (PE:EA = 10:1) to obtain compound 18-3 (73.4 mg, 51.1% yield, yellow solid). LCMS calculation for C 28 H 31 N4O3S[M+H] + :m / z=503.2;Found:503.3.

[0510] Step 4: 2-[[1-[3-(cyclobutyloxy)phenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0511] Compound 18-3 (110 mg, 219 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (26.2 mg, 1.09 mmol) was added at room temperature, and the mixture was stirred at 65°C for 0.5 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 5-6 with 1N hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The organic phase was dried and concentrated, and the crude product was purified to afford compound Cpd-18 (65.0 mg, 60.8% yield, yellow solid). LCMS calculation for C 27 H 29 N4O3S[M+H] + :m / z=489.2;Found:489.3; 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.80(d,J=2.3Hz,1H),8.38(d,J=2.5Hz,1H), 7.54(t,J=4.3Hz,2H),7.39(t,J=8.4Hz,1H),7.18-7.12(m,1H),7.02(d,J=8.2Hz,1 H),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,2 H),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).

[0512] Example 19: 2-[[5-Isobutyl-1-[3-(2,2,2-trifluoroethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-19)

[0513] Step 1: 3-Bromo-5-isobutyl-1-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazole

[0514] 3-(3-Bromo-5-isobutylpyrazol-1-yl)phenol 18-1 (200 mg, 678 μmol) was dissolved in DMF (3 mL), and 2,2,2-trifluoroethyl p-toluenesulfonate 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. After cooling, water (15 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 19-2 (210 mg, 82.3% yield, colorless liquid). LCMS calc. for C 15 H 17 BrF3N2O[M+H] + :m / z=377.0 / 379.0; Found:377.1 / 379.1.

[0515] Step 2: 2-[[5-isobutyl-1-[3-(2,2,2-trifluoroethoxy)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0516] Compound 19-2 (300 mg, 795 μmol) was dissolved in DMF (3 mL), and t-BuBrettphos Pd G3 (67.9 mg, 79.5 μmol) and cesium carbonate (777 mg, 2.39 mmol) were added. The system was stirred at 120°C under nitrogen for 16 hours. The mixture was cooled, and the pH was adjusted to 5 with 1N hydrochloric acid. The mixture was extracted with dichloromethane (30 mL), and the organic phase was concentrated to obtain the crude product. Compound Cpd-19 (95.1 mg, 23.1% yield, yellow solid) was obtained by preparative purification. LCMS calculation for C 25 H 24 F3N4O3S[M+H] + :m / z=517.1;Found:517.2; 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.81(d,J=2.6Hz,1H),8.39(d,J=2.6Hz,1H),7.61-7.41(m,3H),7.23-7.0 8(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).

[0517] Example 20: 2-[[1-[3-(1,1-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-20)

[0518] Step 1: 3-Bromo-1-[3-(2-bromo-1,1-difluoro-ethoxy)phenyl]-5-isobutyl-pyrazole

[0519] 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 and stirred for 10 minutes. The mixture was then heated to 65°C and stirred for 3 hours. The reaction was complete. After cooling to room temperature, the reaction solution was added with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 20-2 (220 mg, 74.0% yield, yellow liquid). LCMS calc. for C 15 H 17 Br2F2N2O[M+H] + :m / z=437.0 / 439.0 / 441.0; Found:437.0 / 439.0 / 441.0.

[0520] Step 2: 2-[[1-[3-(1,1-difluoroethoxy)phenyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0521] 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. The system was stirred at 120°C under a nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction solution was adjusted to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product, which was purified to obtain compound Cpd-20 (14.6 mg, 8.03% yield, yellow solid). LCMS calculation for C 25 H 25 F2N4O3S[M+H] + :m / z=499.2;Found:499.3; 1H NMR(400MHz,DMSO-d6)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).

[0522] Example 21: 2-[[5-Isobutyl-1-(3-methoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-21)

[0523] Step 1: 3,5-dibromo-1-(3-methoxyphenyl)pyrazole

[0524] 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. The air was replaced with oxygen three times, and the system was stirred at 90°C for 2 hours. After completion of the reaction, the mixture 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 compound 21-2 (1.00 g, 67.9% yield, colorless liquid). LCMS calculation for C 10 H9Br2N2O[M+H] + :m / z=330.9 / 332.9 / 334.9; Found:330.9 / 333.0 / 334.9.

[0525] Step 2: 3-Bromo-1-(3-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

[0526] Compounds 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). Pd(dppf)Cl2 (437 mg, 603 μmol) and potassium phosphate (1.28 g, 6.02 mmol) were added at room temperature. The air was replaced with nitrogen three times, and the system was stirred at 70°C for 2 hours. The mixture was cooled to room temperature and filtered. 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, 58.6% yield, colorless liquid). LCMS calculation for C 14 H 16 BrN2O[M+H] + :m / z=307.0 / 309.0; Found:307.3 / 309.3.

[0527] Step 3: 3-Bromo-5-isobutyl-1-(3-methoxyphenyl)pyrazole

[0528] Compound 21-3 (540 mg, 1.76 mmol) was dissolved in methanol (6 mL). Platinum dioxide (86.2 mg, 352 μmol) was added at room temperature. The air was replaced with hydrogen three times, and the system was stirred at 0°C for 2 hours. The mixture was filtered, and the solid was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE:EA = 10:1) to afford compound 21-4 (440 mg, 81.1% yield, colorless liquid). LCMS calculation for C 14 H 18 BrN2O[M+H] + :m / z=309.1 / 311.1; Found:309.0 / 311.0.

[0529] Step 4: 2-[[5-isobutyl-1-(3-methoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)pyridine-3-carboxylic acid methyl ester

[0530] 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. The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. The mixture was cooled and filtered. The filtrate was added with water (30 mL) and extracted with ethyl acetate (30 mL x 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 = 4:1) to obtain compound 21-5 (300 mg, 57.4% yield, yellow liquid). LCMS calculation for C 25 H 27 N4O3S[M+H] + :m / z=463.2;Found:463.3.

[0531] Step 5: 2-[[5-isobutyl-1-(3-methoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0532] Compound 21-5 (300 mg, 646 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (77.7 mg, 3.24 mmol) was added at room temperature, and the system was stirred at 50°C for 0.5 hours. The mixture was cooled to room temperature, and the pH was adjusted to 5-6 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product, which was purified to afford compound Cpd-21 (56.4 mg, 19.4% yield, yellow solid). LCMS calculation for C 24 H 25 N4O3S[M+H] + :m / z=449.2;Found:449.4; 1 H NMR (400MHz, DMSO-d6) 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).

[0533] Example 22: 2-((1-(3-ethoxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-22)

[0534] Step 1: 3,5-dibromo-1-(3-ethoxy-4-fluorophenyl)-1H-pyrazole

[0535] 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 a reaction flask and stirred at 90°C in an oxygen atmosphere for 2 hours. The mixture was cooled and filtered, and the filtrate was added with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). 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 = 19:1) to obtain compound 22-2 (1.28 g, 52.9% yield, white solid). LCMS calculation for C 11 H 10 Br2FN2O[M+H] + :m / z=362.9 / 364.9 / 366.9; Found:363.1 / 365.1 / 367.1.

[0536] Step 2: 3-Bromo-1-(3-ethoxy-4-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0537] Under nitrogen, compound 22-2 (1.00 g, 2.75 mmol), compound 2-3 (450 mg, 2.47 mmol), Pd(dppf)Cl2 (402 mg, 550 μmol), potassium phosphate (1.17 g, 5.49 mmol), and a dioxane / water mixture (10 mL, 4:1) were added to a reaction flask and stirred at 120°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2). The organic phases were concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 19:1) to afford compound 22-3 (532 mg, 57.2% yield, white solid). LCMS calculation for C 15 H 17 BrFN2O[M+H] + :m / z=339.0 / 341.0; Found:339.0 / 341.0.

[0538] Step 3: 3-Bromo-1-(3-ethoxy-4-fluorophenyl)-5-isobutyl-1H-pyrazole

[0539] 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 under a hydrogen atmosphere for 2 hours. The mixture was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 19:1) to obtain compound 22-4 (442 mg, 82.8% yield, white solid). LCMS calculation for C 15 H 19 BrFN2O[M+H] + :m / z=341.1 / 343.1; Found:341.3 / 343.3.

[0540] Step 4: 2-((1-(3-ethoxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0541] Under nitrogen, 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 a reaction flask and stirred at 125° for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with 1N hydrochloric acid (10 mL) and then with saturated aqueous sodium chloride (10 mL × 2). The organic phase was concentrated to obtain a crude product which was subjected to column chromatography (DCM:MeOH = 19:1) to afford compound Cpd-22 (55.0 mg, 19.4% yield, yellow solid). LCMS calc. for C 25 H 26 FN4O3S[M+H] + :m / z=481.2;Found:480.8; 1H NMR (400MHz, DMSO-d6) 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).

[0542] Example 23: 2-((1-(3-ethoxy-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-23)

[0543] Step 1: 3,5-dibromo-1-(3-ethoxy-5-fluorophenyl)-1H-pyrazole

[0544] 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 a reaction flask and stirred at 90°C in an oxygen atmosphere for 2 hours. The mixture was cooled and filtered, and the filtrate was added with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 19:1) to obtain compound 23-2 (1.41 g, 58.3% yield, white solid). LCMS calculation for C 11 H 10 Br2FN2O[M+H] + :m / z=362.9 / 364.9 / 366.9; Found:363.1 / 365.1 / 367.1.

[0545] Step 2: 3-Bromo-1-(3-ethoxy-5-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0546] Under nitrogen, compound 23-2 (1.40 g, 3.87 mmol), compound 2-3 (633 mg, 3.48 mmol), Pd(dppf)Cl2 (566 mg, 773 μmol), potassium phosphate (1.64 g, 7.73 mmol), and a dioxane / water mixture (20 mL, 4:1) were added to a reaction flask and stirred at 120°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2). The organic phases were concentrated, and the residue was purified by column chromatography (PE:EA = 19:1) to afford compound 23-3 (1.10 g, 84.1% yield, white solid). LCMS calculation for C 15 H 17 BrFN2O[M+H] + :m / z=339.0 / 341.0; Found:339.1 / 341.1.

[0547] Step 3: 3-Bromo-1-(3-ethoxy-5-fluorophenyl)-5-isobutyl-1H-pyrazole

[0548] 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 under a hydrogen atmosphere for 2 hours. 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, 76.7% yield, white solid). LCMS calculation for C 15 H 19 BrFN2O[M+H] + :m / z=341.1 / 343.1; Found:341.2 / 343.2.

[0549] Step 4: 2-((1-(3-ethoxy-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0550] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL × 2). The organic phases were concentrated, and the residue was purified by column chromatography (DCM:MeOH = 19: 1) to obtain compound Cpd-23 (266 mg, 22.3% yield, white solid). LCMS calculation for C 25 H 26 FN4O3S[M+H] + :m / z=481.2;Found:481.2; 1 H NMR (400MHz, DMSO-d6) 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,2H),6.88(dd,J=10.0,2.0Hz,2H),4.11(q,J=6.8Hz,2H),2.66(d,J=7.2H z,2H),1.82(dt,J=13.6,6.8Hz,1H),1.34(t,J=7.2Hz,3H),0.87(d,J=6.8Hz,6H).

[0551] Example 24: 2-(1-(3-ethoxyphenyl)-5-neopentyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-24)

[0552] Step 1: 1-[5-bromo-2-(3-ethoxyphenyl)pyrazol-3-yl]-2,2-dimethylpropan-1-ol

[0553] Under nitrogen, 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, 2 M 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 stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography (PE:EA = 5:1) to obtain compound 24-1 (2.61 g, 85.5% yield, light yellow liquid). LC-MS calc. for C 16 H 22 BrN2O2[M+H] + :m / z=353.1 / 355.1; Found:353.3 / 355.3.

[0554] Step 2: 3-Bromo-5-neopentyl-1-(3-ethoxyphenyl)pyrazole

[0555] 24-1 (1.00 g, 2.83 mmol) was dissolved in trifluoroacetic acid (15 mL), and triethylsilane (15 mL) was added. The system was stirred at 80°C for 48 hours. The reaction solution was concentrated, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate. The solution was then extracted with dichloromethane (100 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography (PE:EA = 10:1) to obtain compound 24-2 (315 mg, 33.1% yield, light yellow solid). LC-MS calculation for C 16 H 22 BrN2O[M+H] + :m / z=337.1 / 339.1; Found:337.3 / 339.3.

[0556] Step 3: 2-[[5-neopentyl-1-(3-ethoxyphenyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0557] Under nitrogen, 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, 61.9% yield, yellow solid). LC-MS calculation for C 27 H 31 N4O3S[M+H] + :m / z=491.2;Found:491.4.

[0558] Step 4: 2-(1-(3-ethoxyphenyl)-5-neopentyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0559] Compound 24-3 (250 mg, 509 μmol) was dissolved in a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL). Lithium hydroxide (122 mg, 5.10 mmol) was added, and the system was stirred at 75°C for 0.5 hours. 1N hydrochloric acid was added to adjust the pH to 3, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative method to yield compound Cpd-24 (105 mg, 43.3% yield, yellow solid). LC-MS calculation for C 26 H 29 N4O3S[M+H] + :m / z=477.2;Found:477.5; 1 H NMR (400MHz, DMSO-d6) 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).

[0560] 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)

[0561] Step 1: 2-[[1-(3-ethoxyphenyl)-5-(1-hydroxy-2,2-dimethylpropyl)pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0562] 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. The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. 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, 69.9% yield, yellow solid). LC-MS calculation for C 27 H 31 N4O4S[M+H] + :m / z=507.2;Found:507.5.

[0563] Step 2: 2-((1-(3-ethoxyphenyl)-5-(1-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0564] Compound 25-1 (200 mg, 394 μmol) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL), and water (1 mL). Lithium hydroxide (94.5 mg, 3.95 mmol) was added, and the mixture was stirred at 75°C for 30 minutes. After cooling, the reaction mixture was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL x 2). 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, 36.1% yield, yellow solid). LC-MS calculation for C 26 H 29 N4O4S[M+H] + :m / z=493.2;Found:493.3; 1H NMR (400MHz, DMSO-d6) 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,1 H),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).

[0565] Example 26: 2-((1-(3-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-26)

[0566] Step 1: 3,5-dibromo-1-(3-(difluoromethoxy)phenyl)-1H-pyrazole

[0567] Compound 2-1 (1.00 g, 4.43 mmol), compound 26-1 (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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 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 = 20:1) to obtain compound 26-2 (1.53 g, 93.8% yield, colorless liquid). LCMS calculation for C 10 H7Br2F2N2O[M+H] + :m / z=366.9 / 368.9 / 370.9; Found:367.0 / 369.0 / 371.0.

[0568] Step 2: 3-Bromo-1-(3-(difluoromethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0569] Under nitrogen, compound 26-2 (1.49 g, 4.05 mmol), compound 2-3 (664 mg, 3.64 mmol), Pd(dppf)Cl2 (296 mg, 410 μmol), potassium phosphate (1.72 g, 8.10 mmol), and a 1,4-dioxane / water mixture (20 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The crude product obtained after concentration of the organic phases was subjected to column chromatography (PE:EA = 20:1) to obtain compound 26-3 (862 mg, 62.2% yield, colorless liquid). LCMS calculation for C 14 H 14 BrF2N2O[M+H] + :m / z=343.0 / 345.0; Found:343.0 / 345.0.

[0570] Step 3: 3-Bromo-1-(3-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazole

[0571] 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 under 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, 91.1% yield, colorless liquid). LCMS calculation for C 14 H 16 BrF2N2O[M+H] + :m / z=345.0 / 347.0; Found:344.9 / 346.9.

[0572] Step 4: 2-((1-(3-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0573] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL × 2). The crude product obtained after concentration of the organic phase was subjected to column chromatography (DCM:MeOH = 93:7) and then purified by preparative purification to obtain compound Cpd-26 (356 mg, 32.2% yield, yellow solid). LCMS calc. for C 24 H 23 F2N4O3S[M+H] + :m / z=485.1;Found:485.3; 1 H NMR (400MHz, DMSO-d6) 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) ,7.45-7.31(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).

[0574] Example 27: 2-((1-cyclohexyl-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-27)

[0575] Step 1: 3,5-dibromo-1-cyclohexyl-pyrazole

[0576] 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), and cesium carbonate (2.53 g, 7.75 mmol) was added. The system was reacted at 100°C for 16 hours. The mixture was cooled and filtered, and the filtrate was added with water (20 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 20:1) to obtain the product 27-2 (400 mg, 41.8% yield, yellow liquid). LCMS calculation for C9H 13 N2Br2[M+H] +:m / z=306.9 / 308.9 / 310.9; Found:306.9 / 309.0 / 311.0.

[0577] Step 2: 3-Bromo-1-cyclohexyl-5-(2-methylprop-1-en-1-yl)pyrazole

[0578] Compound 27-2 (350 mg, 1.14 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL). 2-3 (207 mg, 1.14 mmol), potassium phosphate (481 mg, 2.27 mmol), and Pd(dppf)Cl2 (83.1 mg, 114 mmol) were added. The system was stirred at 70°C under 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. The crude product was purified by column chromatography (PE:EA = 30:1) to obtain compound 27-3 (150 mg, 46.6% yield, yellow liquid). LCMS calculation for C 13 H 20 N2Br[M+H] + :m / z=283.1 / 285.1; Found:283.3 / 285.3.

[0579] Step 3: 3-Bromo-1-cyclohexyl-5-isobutyl-pyrazole

[0580] 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 under a hydrogen atmosphere for 0.5 hours. The product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 27-4 (650 mg, 81.1% yield, yellow liquid). LCMS calculation for C 13 H 22 N2Br[M+H] + :m / z=285.1 / 287.1; Found:285.1 / 287.1.

[0581] Step 4: 2-[(1-cyclohexyl-5-isobutyl-pyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid

[0582] 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 under a nitrogen atmosphere for 2 hours. After cooling, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). 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, 11.2% yield, yellow solid). LCMS calculation for C 23 H 29 N4O2S[M+H] + :m / z=425.2;Found:425.2; 1 H NMR (400MHz, DMSO-d6) 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,1 H),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).

[0583] Example 28: 2-[(1-cycloheptyl-5-isobutyl-pyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-28)

[0584] Step 1: 3,5-dibromo-1-cycloheptyl-1H-pyrazole

[0585] 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) and cesium carbonate (4.60 g, 14.1 mmol) was added. The system was stirred at 90°C for 2 hours under nitrogen. After the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (60 mL). The organic phase was washed with saturated aqueous sodium chloride solution (30 mL), dried and concentrated, and purified by column chromatography (PE:EA = 10:1) to obtain compound 28-2 (1.62 g, 89.0% yield, colorless liquid). LCMS calculation for C 10 H 15 Br2N2[M+H]+ :m / z=321.0 / 323.0 / 325.0; Found:321.1 / 323.1 / 325.1.

[0586] Step 2: 3-Bromo-1-cycloheptyl-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0587] Compound 28-2 (1.00 g, 3.11 mmol) was dissolved in tetrahydrofuran (15 mL) and water (3 mL). Compound 28-3 (678 mg, 3.73 mmol), Pd(dppf)Cl2 (227 mg, 311 μmol), and potassium phosphate (1.32 g, 6.21 mmol) were added. The system was stirred at 70°C under nitrogen for 2 hours. After the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated, and purified by column chromatography (PE 100%) to obtain compound 28-3 (693 mg, 75.3% yield, colorless liquid). LCMS calculation for C 14 H 22 BrN2[M+H] + :m / z=297.1 / 299.1; Found:297.3 / 299.3.

[0588] Step 3: 3-Bromo-1-cycloheptyl-5-isobutyl-1H-pyrazole

[0589] 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 column chromatography (PE 100%) to obtain compound 28-4 (475 mg, 61.5% yield, colorless liquid). LCMS calculation for C 14 H 24 BrN2[M+H] + :m / z=299.1 / 231.1; Found:299.2 / 231.2.

[0590] Step 4: 2-((1-cycloheptyl-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0591] Under nitrogen, 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 solution of 28-4 (250 mg, 835 μmol) in DMF (3 mL). 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 column chromatography (PE:EA = 5:1) to obtain compound 28-5 (200 mg, 53.0% yield, yellow liquid). LCMS calculation for C 25 H 33 N4O2S[M+H] + :m / z=453.2;Found:453.3.

[0592] Step 5: 2-[(1-cycloheptyl-5-isobutyl-pyrazol-3-yl)amino]-5-(thiophen-2-yl)nicotinic acid

[0593] 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. The mixture was stirred at 45°C for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 5. The mixture was extracted with dichloromethane (20 mL). The organic phase was dried and concentrated to obtain a crude product. Preparative purification was then performed to obtain compound Cpd-28 (147 mg, 75.9% yield, yellow solid). LCMS calculation for C 24 H 31 N4O2S[M+H] + :m / z=439.2;Found:439.3; 1 H NMR (400MHz, DMSO-d6) 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),4.20(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).

[0594] Example 29: 2-((1-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-29)

[0595] Step 1: tert-Butyl 3-(3,5-dibromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0596] Under nitrogen, 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 an ice bath. The system was stirred and reacted at room temperature for 1 hour. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic phase was concentrated to obtain a crude product, which was then purified by column chromatography (PE:EA = 19:1) to afford compound 29-2 (4.41 g, 81.1% yield, colorless liquid). LCMS calculation for C 13 H 20 Br2N3O2[M+H] + :m / z=408.0 / 410.0 / 412.0; Found:408.1 / 410.1 / 412.1.

[0597] Step 2: tert-Butyl 3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0598] Under nitrogen, compound 29-2 (2.00 g, 4.89 mmol), compound 2-3 (890 mg, 4.89 mmol), Pd(dppf)Cl2 (257 mg, 490 μmol), potassium phosphate (2.08 g, 9.78 mmol), and a dioxane / water mixture (25 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with 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, 72.1% yield, colorless liquid). LCMS calculation for C 17 H 27 BrN3O2[M+H] + :m / z=384.1 / 386.1; Found:384.1 / 386.1.

[0599] Step 3: tert-Butyl 3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0600] Compound 29-3 (1.00 g, 2.60 mmol) was dissolved in methanol (10 mL). Platinum dioxide (118 mg, 520 μmol) was added at 0°C and stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA = 19:1) to obtain compound 29-4 (847 mg, 84.6% yield, colorless liquid). LCMS calculation for C 17 H 29 BrN3O2[M+H] + :m / z=386.1 / 388.1; Found:386.3 / 388.3.

[0601] Step 4: 2-((1-(1-(tert-Butoxycarbonyl)piperidin-3-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0602] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL). The organic phases were concentrated, and the resulting crude product was subjected to column chromatography (DCM:MeOH = 19:1) to obtain compound Cpd-29 (55.0 mg, 5.06% yield, yellow solid). LCMS calculation for C 27 H 36 N5O4S[M+H] + :m / z=526.2;Found:525.9; 1H NMR (400MHz, DMSO-d6) δ13.84(s,1H),10.68(s,1H),8.72(s,1H),8.35(d,J=2.4Hz,1 H),7.51(dd,J=10.8,4.4Hz,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).

[0603] 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)

[0604] Step 1: 3-(3-Bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)piperidine

[0605] Compound 29-3 (500 mg, 1.30 mmol) and dichloromethane (4 mL) were added to a 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 crude product 30-1 (277 mg, 74.8% yield, white solid). LCMS calculation for C 12 H 19 BrN3[M+H] + :m / z=284.1 / 286.1; Found:284.2 / 286.2.

[0606] Step 2: 3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine

[0607] Compound 30-1 (277 mg, 975 μmol), potassium carbonate (404 mg, 2.92 mmol), and DMF (5 mL) were added to a reaction flask, followed by the dropwise addition of compound 30-2 (452 ​​mg, 1.95 mmol). The reaction mixture was stirred at 50°C for 1 hour. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL). The organic phases were concentrated, and the resulting crude product was subjected to column chromatography (PE:EA = 19:1) to afford compound 30-3 (117 mg, 32.9% yield, white solid). LCMS calculation for C 14 H 20 BrF3N3[M+H] + :m / z=366.1 / 368.1; Found:366.3 / 368.3.

[0608] Step 3: 3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine

[0609] Compound 30-3 (117 mg, 321 μmol) was dissolved in methanol (4 mL). Platinum dioxide (14.5 mg, 63.8 μmol) was added at 0°C and stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and concentrated, and the crude product was subjected to column chromatography (PE:EA = 19:1) to obtain compound 30-4 (100 mg, 84.9% yield, white solid). LCMS calculation for C 14 H 22 BrF3N3[M+H] + :m / z=368.1 / 370.1; Found:368.2 / 370.2.

[0610] 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

[0611] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL). The organic phases were concentrated, and the resulting crude product was subjected to column chromatography (DCM:MeOH = 19:1) to obtain compound Cpd-30 (35.1 mg, 25.5% yield, yellow solid). LCMS calculation for C 24 H 29 F3N5O2S[M+H] + :m / z=508.2;Found:508.0; 1 H NMR (400MHz, DMSO-d6) δ13.84(s,1H),10.71(s,1H),8.72(d,J=2.4Hz,1H),8.34(d,J=2.4Hz,1 H),7.51(dd,J=11.2,4.4Hz,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,2H),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).

[0612] 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)

[0613] Step 1: 3-Hydroxycyclohexyl p-toluenesulfonate

[0614] Under nitrogen, 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 stirred at room temperature for 1 hour. The reaction solution was quenched with water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 4:1) to afford compound 31-2 (2.40 g, 19.1% yield, colorless liquid). LCMS calculated for C 13 H 18 O4SNa[M+Na] + :m / z=293.1;Found:293.1.

[0615] Step 2: 3-(3,5-dibromo-1H-pyrazol-1-yl)cyclohexanol

[0616] Under nitrogen, 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 stirred at 100°C for 1.5 hours. After cooling, the reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then purified by column chromatography (PE:EA = 4:1) to afford compound 31-3 (1.40 g, 48.7% yield, colorless liquid). LCMS calc. for C9H 13 Br2N2O[M+H] + :m / z=322.9 / 324.9 / 326.9; Found:323.1 / 325.1 / 327.1.

[0617] Step 3: 3,5-dibromo-1-(3-methoxycyclohexyl)-1H-pyrazole

[0618] Under nitrogen, sodium hydride (320 mg, 8.02 mmol, 60% content) was added to a solution of compound 31-3 (1.30 g, 4.01 mmol) in DMF (10 mL) at 0°C. After stirring at this temperature for 0.5 hour, iodomethane (0.50 mL, 8.02 mmol) was added and stirring continued for 1 hour. The reaction was quenched by adding water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 10:1) to afford compound 31-4 (1.10 g, 81.2% yield, colorless liquid). LCMS calculation for C 10 H 15 Br2N2O[M+H] + :m / z=337.0 / 339.0 / 341.0; Found:337.0 / 339.1 / 340.9.

[0619] Step 4: 3-Bromo-1-(3-methoxycyclohexyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0620] Under nitrogen, compound 31-4 (801 mg, 2.37 mmol), compound 2-3 (474 ​​mg, 2.60 mmol), Pd(dppf)Cl2 (346 mg, 473 μmol), and potassium phosphate (1.11 g, 5.21 mmol) were dissolved in a mixture of dioxane and water (12 mL, 5:1) and stirred at 80°C for 1 hour. The mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 10:1) to afford compound 31-5 (450 mg, 60.9% yield, yellow liquid). LCMS calculation for C 14 H 22 BrN2O[M+H] + :m / z=313.1 / 315.1; Found:313.3 / 315.3.

[0621] Step 5: 3-Bromo-5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazole

[0622] 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 under hydrogen for 1 hour. 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, 60.8% yield, yellow liquid). LCMS calculation for C 14 H 24 BrN2O[M+H] + :m / z=315.1 / 317.1; Found:315.2 / 317.2.

[0623] Step 6: 2-((5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0624] Under nitrogen, 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 a reaction flask and stirred at 120°C for 2 hours. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 5:1) to afford compound 31-7 (210 mg, 54.2% yield, yellow solid). LCMS calculation for C 25 H 33 N4O3S[M+H] + :m / z=469.2;Found:469.3.

[0625] Step 7: 2-((5-isobutyl-1-(3-methoxycyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0626] Compound 31-7 (210 mg, 449 μmol) and lithium hydroxide (76.7 mg, 3.20 mmol) were dissolved in a mixture of water (3 mL) and tetrahydrofuran (3 mL). The mixture 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 H31 N4O3S[M+H] + :m / z=455.2;Found:455.3; 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.76 (d, J = 2.6 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.14 (dd, J = 5.1, 3.6 Hz, 1H), 6.59 (s, 1H), 4.20 (d, J = 4.6 Hz, 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 = 13.8 Hz, 1H), 0.94 (s, 6H); compound Cpd-31-B was obtained (26.2 mg, yield 12.9%), as a yellow solid. LCMS calc.for C 24 H 26 N5O3S[M+H] + :m / z=455.2;Found:455.3; 1 H NMR (400MHz, DMSO-d6) 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).

[0627] Example 32: 2-[[1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-32)

[0628] Step 1: 3,5-dibromo-1-(3-fluoro-5-methoxyphenyl)pyrazole

[0629] 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. The atmosphere was purged with oxygen three times, and the system was stirred at 90°C for 2 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and extracted with ethyl acetate (200 mL) and water (70 mL). The combined organic phases were dried over anhydrous sodium sulfate, and 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, 63.9% yield, white solid). LCMS calc. for C 10 H8Br2FN2O[M+H] + :m / z=348.9 / 350.9 / 352.9; Found:348.7 / 350.8 / 352.8.

[0630] Step 2: 3-Bromo-1-(3-fluoro-5-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

[0631] 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)Cl2 (1.63 g, 2.23 mmol) were added at room temperature. The atmosphere was purged with nitrogen three times, and the system was stirred at 70°C for 5 hours. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, filtered, and extracted with ethyl acetate (100 mL) and water (30 mL). The combined organic phases were 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, 51.8% yield, yellow liquid). LCMS calc. for C 14 H 15 BrFN2O[M+H] + :m / z=325.0 / 327.0; Found:324.9 / 326.9.

[0632] Step 3: 3-Bromo-1-(3-fluoro-5-methoxyphenyl)-5-isobutylpyrazole

[0633] Compound 32-3 (4.00 g, 12.3 mmol) was dissolved in methanol (40 mL). Platinum dioxide (559 mg, 2.46 mmol) was added at room temperature. The atmosphere was replaced with hydrogen five times, and the system was stirred at 0°C for 1.5 hours. LCMS indicated the reaction was complete. The mixture was filtered with methanol (40 mL), and the resulting crude product was collected under reduced pressure and purified by column chromatography (PE:EA = 8:1) to yield compound 32-4 (2.97 g, 74.1% yield, colorless liquid). LCMS calculation for C 14 H 17 BrFN2O[M+H] + :m / z=327.0 / 329.0; Found:326.8 / 328.9.

[0634] Step 4: 3-(3-bromo-5-isobutylpyrazol-1-yl)-5-fluorophenol

[0635] Compound 32-4 (3.50 g, 10.7 mmol) was dissolved in a hydrobromic acid / acetic acid solution (15 mL, 33% content) and an aqueous hydrobromic acid solution (15 mL, 48% content). The system was stirred at 120°C for 4 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature and made alkaline with saturated sodium bicarbonate (100 mL). Ethyl acetate (100 mL) was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was purified by column chromatography (PE:EA = 4:1) to obtain compound 32-5 (2.25 g, 67.4% yield, yellow liquid). LCMS calc. for C 13 H 15 BrFN2O[M+H] + :m / z=313.0 / 315.0; Found:312.9 / 314.9.

[0636] Step 5: 3-Bromo-1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazole

[0637] 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 indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and extracted with ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate, and the crude product was filtered and concentrated. It was purified by column chromatography (PE:EA = 8:1) to obtain compound 32-6 (720 mg, 41.1% yield, colorless liquid). LCMS calc. for C 17 H 21 BrFN2O[M+H]+ :m / z=367.1 / 369.1; Found:366.8 / 368.9.

[0638] Step 6: 2-[[1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0639] 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. The system was stirred at 120°C under a nitrogen atmosphere for 1 hour. After cooling to room temperature, ethyl acetate (70 mL) and water (50 mL) were added. The mixture was separated and the organic phase was dried over anhydrous sodium sulfate. The filtered and concentrated crude product was purified by column chromatography (PE:EA = 8:1) to obtain compound 32-7 (198 mg, 46.6% yield, yellow liquid). LCMS calculation for C 28 H 30 FN4O3S[M+H] + :m / z=521.2;Found:521.0.

[0640] Step 7: 2-[[1-[3-(cyclobutyl)-5-fluorophenyl]-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0641] Compound 32-7 (198 mg, 381 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (55.2 mg, 2.30 mmol) was added at room temperature, and the system was stirred at 60°C for 0.5 hours. LCMS indicated the reaction was complete. After cooling to room temperature, the pH was adjusted to 5-6 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL). The organic phase was concentrated and purified using preparative methods to obtain compound Cpd-32 (71.5 mg, 37.1% yield, yellow solid). LCMS calculation for C 27 H 28 FN4O3S[M+H] + :m / z=507.2;Found:507.2; 1H NMR (400MHz, DMSO-d6) 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) ,2.08-2.03(m,2H),1.86-1.70(m,2H),1.68-1.56(m,1H),0.83(d,J=6.6Hz,6H).

[0642] Example 33: 2-((1-(3-cyclobutyloxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-33)

[0643] Step 1: 3,5-dibromo-1-(4-fluoro-3-methoxyphenyl)-1H-pyrazole

[0644] 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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtered and concentrated crude product was purified by column chromatography (PE:EA = 19:1) to obtain compound 33-2 (2.22 g, 53.8% yield, white solid). LCMS calculation for C 10 H8Br2FN2O[M+H] + :m / z=348.9 / 350.9 / 352.9; Found:349.3 / 351.3 / 353.3.

[0645] Step 2: 3-Bromo-1-(4-fluoro-3-methoxyphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0646] Under nitrogen, compound 33-2 (2.22 g, 6.35 mmol), compound 2-3 (1.04 g, 5.72 mmol), Pd(dppf)Cl2 (465 mg, 640 μmol), potassium phosphate (2.70 g, 12.7 mmol), and a 1,4-dioxane / water mixture (20 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 19:1) to obtain compound 33-3 (1.73 g, 93.3% yield, white solid). LCMS calc. for C 14 H 15 BrFN2O[M+H] + :m / z=325.0 / 327.0; Found:325.3 / 327.3.

[0647] Step 3: 3-Bromo-1-(4-fluoro-3-methoxyphenyl)-5-isobutyl-1H-pyrazole

[0648] 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 under a hydrogen atmosphere for 2 hours. The reaction mixture 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, 65.6% yield, white solid). LCMS calculation for C 14 H 17 BrFN2O[M+H] + :m / z=327.0 / 329.0; Found:327.2 / 329.2.

[0649] Step 4: 5-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-fluorophenol

[0650] 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, 55.0% yield, white solid). LCMS calculation for C 13 H 15 BrFN2O[M+H] +:m / z=313.0 / 315.0; Found:313.2 / 315.2.

[0651] Step 5: 3-Bromo-1-(3-cyclobutyloxy-4-fluorophenyl)-5-isobutyl-1H-pyrazole

[0652] 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 stirred at 120°C for 1 hour. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated aqueous sodium chloride (20 mL × 2) and concentrated. The crude product was purified by column chromatography (PE:EA = 19:1) to obtain compound 33-6 (699 mg, 100% yield, white solid). LCMS calculation for C 17 H 21 BrFN2O[M+H] + :m / z=367.1 / 369.1; Found:367.2 / 369.2.

[0653] Step 6: 2-((1-(3-cyclobutyloxy-4-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0654] Under nitrogen, 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 a reaction flask and stirred at 120°C for 2 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2). The organic phases were concentrated to obtain a crude product which was purified by preparative purification to yield compound Cpd-33 (72.2 mg, 7.51% yield, pale yellow solid). LCMS calc. for C 27 H 28 FN4O3S[M+H] + :m / z=507.2;Found:506.8; 1H NMR (400MHz, DMSO-d6) 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).

[0655] Example 34: 2-((5-isobutyl-1-(3-morpholinophenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-34)

[0656] Step 1: 4-(3-(3,5-dibromo-1H-pyrazol-1-yl)phenyl)morpholine

[0657] 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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtered and concentrated crude product was purified by column chromatography (PE:EA = 19:1) to obtain compound 34-2 (1.40 g, 74.9% yield, colorless liquid). LCMS calculation for C 13 H 14 Br2N3O[M+H] + :m / z=385.9 / 387.9 / 389.9; Found:386.1 / 388.1 / 390.1.

[0658] Step 2: 4-(3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)phenyl)morpholine

[0659] Under nitrogen, compound 34-2 (1.40 g, 3.40 mmol), compound 2-3 (594 mg, 3.26 mmol), Pd(dppf)Cl2 (265 mg, 360 μmol), potassium phosphate (1.54 g, 7.25 mmol), and a 1,4-dioxane / water mixture (20 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 19:1) to obtain compound 34-3 (821 mg, 69.8% yield, white solid). LCMS calculation for C 17 H 21 BrN3O[M+H] + :m / z=362.1 / 364.1; Found:362.2 / 364.2.

[0660] Step 3: 4-(3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)phenyl)morpholine

[0661] 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 mixture was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA = 19:1) to obtain compound 34-4 (413 mg, 50.1% yield, white solid). LCMS calculation for C 17 H 23 BrN3O[M+H] + :m / z=364.1 / 366.1; Found:364.3 / 366.3.

[0662] Step 4: 2-((5-isobutyl-1-(3-morpholinophenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0663] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2). The organic phases were concentrated and purified to obtain compound Cpd-34 (27.1 mg, 4.77% yield, pale yellow solid). LCMS calculation for C 27 H 30 N5O3S[M+H] + :m / z=504.2;Found:504.1; 1 H NMR(400MHz, DMSO-d6)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=5.2,3.6H z,1H),7.02-6.94(m,2H),6.93-6.83(m,2H),3.80-3.68(m,4H),3.21-3.1 2(m,4H),2.59(d,J=7.2Hz,2H),1.87-1.74(m,1H),0.85(d,J=6.4Hz,7H).

[0664] Example 35: 2-((5-isobutyl-1-(3-(piperidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-35)

[0665] Step 1: 1-(3-(3,5-dibromo-1H-pyrazol-1-yl)phenyl)piperidine

[0666] 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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtered and concentrated crude product was purified by column chromatography (PE:EA = 19:1) to obtain compound 35-2 (1.31 g, 69.7% yield, white solid). LCMS calculation for C 14 H 16 Br2N3[M+H] + :m / z=384.0 / 386.0 / 388.0; Found:384.1 / 386.1 / 388.0.

[0667] Step 2: 1-(3-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)phenyl)piperidine

[0668] Under nitrogen, compound 35-2 (1.31 g, 3.40 mmol), compound 2-3 (557 mg, 3.06 mmol), Pd(dppf)Cl2 (249 mg, 341 μmol), potassium phosphate (1.44 g, 6.80 mmol), and a 1,4-dioxane / water mixture (20 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (15 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 19:1) to obtain compound 35-3 (866 mg, 78.8% yield, white solid). LCMS calc. for C 18 H 23 BrN3[M+H] + :m / z=360.1 / 362.1; Found:360.0 / 362.0.

[0669] Step 3: 1-(3-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)phenyl)piperidine

[0670] 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 under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA = 19:1) to obtain compound 35-4 (578 mg, 66.7% yield, white solid). LCMS calculation for C 18 H 25 BrN3[M+H] + :m / z=362.1 / 364.1; Found:362.0 / 364.0.

[0671] Step 4: 2-((5-isobutyl-1-(3-(piperidin-1-yl)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0672] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2). The organic phases were concentrated and purified to obtain compound Cpd-35 (264 mg, 32.9% yield, white solid). LCMS calculation for C 28 H 32 N5O2S[M+H] + :m / z=502.2;Found:502.0; 1 H NMR (400MHz, DMSO-d6) 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).

[0673] Example 36: 2-((5-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-36)

[0674] Step 1: 3,5-dibromo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

[0675] 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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtered and concentrated crude product was purified by column chromatography (PE:EA = 20:1) to obtain compound 36-2 (764 mg, 44.7% yield, colorless liquid). LCMS calculation for C 10 H6Br2F3N2O[M+H] + :m / z=384.9 / 386.9 / 388.9; Found:385.1 / 387.1 / 389.1.

[0676] Step 2: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

[0677] Under nitrogen, compound 36-2 (764 mg, 1.98 mmol), compound 2-3 (360 mg, 1.98 mmol), Pd(dppf)Cl2 (145 mg, 200 μmol), potassium phosphate (821 mg, 5.94 mmol), and a 1,4-dioxane / water mixture (15 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 20:1) to obtain compound 36-3 (469 mg, 65.8% yield, colorless liquid). LCMS calc. for C 14 H 13 BrF3N2O[M+H] + :m / z=361.0 / 363.0; Found:361.0 / 363.0.

[0678] Step 3: 3-Bromo-5-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole

[0679] 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 under a hydrogen atmosphere for 2 hours. 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, 72.2% yield, colorless liquid). LCMS calculation for C 14 H 15 BrF3N2O[M+H] + :m / z=363.0 / 365.0; Found:363.0 / 365.0.

[0680] Step 4: 2-((5-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0681] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 2). The organic phases were concentrated and purified by preparative purification to obtain Cpd-36 (40.0 mg, 14.5% yield, yellow solid). LCMS calculation for C 24 H 22 F3N4O3S[M+H] + :m / z=503.1;Found:503.0; 1 H NMR (400MHz, DMSO-d6) 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),7.5 7-7.48(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).

[0682] Example 37: 2-((1-(4-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-37)

[0683] Step 1: 3,5-dibromo-1-(4-(difluoromethoxy)phenyl)-1H-pyrazole

[0684] 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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtered and concentrated crude product was purified by column chromatography (PE:EA = 20:1) to obtain compound 37-2 (1.63 g, 100% yield, colorless liquid). LCMS calculation for C 10 H7Br2F2N2O[M+H] + :m / z=366.9 / 368.9 / 370.9; Found:367.0 / 369.0 / 371.0.

[0685] Step 2: 3-Bromo-1-(4-(difluoromethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0686] Under nitrogen, compound 37-2 (784 mg, 2.13 mmol), compound 2-3 (388 mg, 2.13 mmol), Pd(dppf)Cl2 (156 mg, 210 μmol), potassium phosphate (885 mg, 6.40 mmol), and a dioxane / water mixture (15 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 20:1) to obtain compound 37-3 (606 mg, 83.2% yield, colorless liquid). LCMS calc. for C 14 H 14 BrF2N2O[M+H] + :m / z=343.0 / 345.0; Found:343.1 / 345.1.

[0687] Step 3: 3-Bromo-1-(4-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazole

[0688] 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 under a hydrogen atmosphere for 2 hours. 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, 55.8% yield, colorless liquid). LCMS calculation for C 14 H 16 BrF2N2O[M+H] + :m / z=345.0 / 347.0; Found:344.8 / 346.8.

[0689] Step 4: 2-((1-(4-(difluoromethoxy)phenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0690] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 2). The organic phases were concentrated and purified to obtain Cpd-37 (67.1 mg, 23.9% yield, yellow solid). LCMS calculation for C 24 H 23 F2N4O3S[M+H] + :m / z=485.1;Found:484.8; 1 H NMR (400MHz, DMSO-d6) 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) ,7.36-7.26(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).

[0691] 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)

[0692] Step 1: tert-Butyl 4-(3,5-dibromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0693] Under nitrogen 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. The reaction was quenched by adding water (20 mL) and 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, 49.3% yield, off-white solid). LCMS calc. for C9H 12 Br2N3O2[M+2H-tBu] + :m / z=351.9 / 353.9 / 355.9; Found:351.8 / 353.8 / 355.8.

[0694] Step 2: tert-Butyl 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0695] 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) were added potassium phosphate (3.54 g, 16.7 mmol) and Pd(dppf)Cl2 (1.11 g, 1.52 mmol) at room temperature. The system was stirred at 80°C under nitrogen for 1 hour. 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, 80.4% yield, yellow liquid). LCMS calculation for C 13 H 19 BrN3O2[M+2H-tBu] + :m / z=328.1 / 330.1; Found:328.0 / 329.9.

[0696] Step 3: tert-Butyl 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0697] To a solution of compound 38-3 (2.34 g, 6.09 mmol) in methanol (25 mL) was added platinum dioxide (415 mg, 1.83 mmol) at 0°C. The system was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 9:1) to obtain compound 38-4 (2.20 g, 93.8% yield, yellow liquid). LCMS calculation for C 13 H 21 BrN3O2[M+2H-tBu] + :m / z=330.1 / 332.1; Found:329.9 / 331.9.

[0698] Step 4: 2-((1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0699] To a toluene (8 mL) solution of compound 38-4 (500 mg, 1.29 mmol) and compound INT-1 (303 mg, 1.29 mmol) were added t-BuBrettphos Pd G3 (221 mg, 259 μmol) and cesium carbonate (1.05 g, 3.24 mmol) at room temperature. The reaction was stirred at 120°C under nitrogen for 1 hour. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 9:1) to afford compound 38-5 (495 mg, 71.2% yield, yellow solid). LCMS calculation for C 28 H 38 N5O4S[M+H] + :m / z=540.3;Found:540.0.

[0700] Step 5: 2-((5-isobutyl-1-(piperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0701] To a solution of compound 38-5 (470 mg, 871 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and saturated aqueous sodium carbonate was added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate (10 mL), and 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, 77.4% yield, yellow solid). LCMS calculation for C23 H 30 N5O2S[M+H] + :m / z=440.2;Found:440.0.

[0702] Step 6: 2-((5-isobutyl-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0703] To a solution of compound 38-6 (125 mg, 284 μmol) in acetonitrile (2 mL) was added diisopropylethylamine (495 μL, 2.84 mmol) and then (2,2,2-trifluoroethyl) trifluoromethanesulfonate (99.0 mg, 427 μmol) at room temperature. 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 yield compound 38-7 (135 mg, crude product, yellow solid). LCMS calc. for C 25 H 31 F3N5O2S[M+H] + :m / z=522.2;Found:522.0.

[0704] 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

[0705] To a solution of compound 38-7 (100 mg, 192 μmol) in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL) was added lithium hydroxide (27.6 mg, 1.15 mmol) at room temperature. The system was stirred at 50°C for 1 hour. The mixture was cooled, and the pH was adjusted to 5-6 with 1.5N hydrochloric acid. 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, 54.2% yield, yellow solid). LCMS calculation for C 24 H 29 F3N5O2S[M+H] + :m / z=508.2;Found:508.2; 1H NMR (400MHz, DMSO-d6) 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) ,4.25-3.92(m,1H),3.59-3.36(m,2H),3.14-2.96(m,2H),2.18-2.02(m,2 H),1.91-1.81(m,1H),1.73(dd,J=14.4,4.2Hz,2H),0.96(d,J=6.5Hz,6H).

[0706] 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)

[0707] Compound 38-5 (297 mg, 550 μmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide (79.1 mg, 3.30 mmol) was added, and the system was stirred at 50°C for 1 hour. 1.5N hydrochloric acid was added to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated and purified to obtain compound Cpd-39 (108 mg, 37.5% yield, white solid). LCMS calculation for C 27 H 36 N5O4S[M+H] + :m / z=526.2;Found:526.3; 1 H NMR (400MHz, DMSO-d6) 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(d d,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).

[0708] Example 40: 2-[1-[2-(difluoromethoxy)-5-pyridinyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-40)

[0709] Step 1: [2-(difluoromethoxy)-5-pyridyl]boronic acid

[0710] Compound 40-1 (2.50 g, 11.2 mmol) and pinacol diboronate (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)Cl2 (815 mg, 1.12 mmol) were added and stirred at 90°C under nitrogen for 3 hours. The mixture was cooled, ethyl acetate (50 mL) was added, and the mixture was filtered. The filtrate was concentrated to obtain compound 40-2 (2.61 g, crude product, black oil). LCMS calc. for C6H7BF2NO3[M+3H-Pinacol] + :m / z=190.0;Found:190.3.

[0711] Step 2: 5-(3,5-dibromopyrazol-1-yl)-2-(difluoromethoxy)pyridine

[0712] 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. 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, 40.5% yield, yellow oil). LCMS calculated for C9H6Br2F2N3O[M+H] + :m / z=367.9 / 369.9 / 371.9; Found:368.0 / 370.0 / 372.0.

[0713] Step 3: 5-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]-2-(difluoromethoxy)pyridine

[0714] 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)Cl2 (464 mg, 630 μmol) were added, and the system was stirred at 70°C under nitrogen for 2 hours. After the reaction, the mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and purified by column chromatography (PE:EA = 10:1) to obtain compound 40-4 (250 mg, 14.8% yield, colorless liquid). LCMS calculation for C 13 H 13 BrF2N3O[M+H] + :m / z=344.0 / 346.0; Found:344.0 / 346.0.

[0715] Step 4: 5-(3-bromo-5-isobutylpyrazol-1-yl)-2-(difluoromethoxy)pyridine

[0716] 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 under a hydrogen atmosphere for 30 minutes. The product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 40-5 (250 mg, 99.4% yield, colorless oil). LCMS calculation for C 13 H 15 BrF2N3O[M+H] + :m / z=346.0 / 348.0; Found:346.2 / 348.2.

[0717] Step 5: 2-[[1-[2-(difluoromethoxy)-5-pyridinyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0718] 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. The system was stirred at 120°C under nitrogen for 2 hours. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 85:15) to obtain compound 40-6 (220 mg, 66.2% yield, yellow solid). LCMS calculation for C 24 H 24F2N5O3S[M+H] + :m / z=500.2;Found:500.2.

[0719] Step 6: 2-[1-[2-(difluoromethoxy)-5-pyridinyl]-5-isobutyl-pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0720] Compound 40-6 (210 mg, 420 μmol) was dissolved in a mixture of tetrahydrofuran (5 mL), methanol (5 mL), and water (1 mL). 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, adjusted to pH 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (50 mL x 2). The organic phase was dried, concentrated, and preparatively purified to obtain Cpd-40 (130 mg, 63.7% yield, yellow solid). LCMS calculation for C 23 H 22 F2N5O3S[M+H] + :m / z=486.1;Found:486.1; 1 H NMR (400MHz, DMSO-d6) 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).

[0721] Example 41: 2-((1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-41)

[0722] Step 1: 3,5-dibromo-1-(3-methylphenyl)-1H-pyrazole

[0723] Under nitrogen at -60°C, isopropylmagnesium chloride (8.06 mL, 8.06 mmol, 1 M tetrahydrofuran solution) was added dropwise to a solution of compound 40-4 (2.00 g, 5.38 mmol) in tetrahydrofuran (20 mL). The system was stirred at -60°C for 1 hour. A solution of p-fluorobenzaldehyde (801 mg, 6.45 mmol) in tetrahydrofuran (4 mL) was then added dropwise to the reaction solution. The dry ice bath was removed, the mixture was allowed to warm to room temperature, and stirring continued for 1 hour. After completion, the reaction was quenched by the addition of saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL x 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 afford compound 41-1 (1.29 g, 57.5% yield, yellow oil). LCMS calculated for C 20 H 19 BrFN2O2[M+H] + :m / z=417.1 / 419.1; Found:416.8 / 418.8.

[0724] Step 2: 3-Bromo-1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazole

[0725] 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, saturated sodium carbonate solution was added to adjust the pH to 8-9, and the mixture was extracted with ethyl acetate (15 mL x 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, 96.4% yield, yellow oil). LCMS calculation for C 20 H 19 BrFN2O[M+H] + :m / z=401.1 / 403.1; Found:401.2 / 403.2.

[0726] Step 3: 2-((1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0727] 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. The system was stirred at 120°C under nitrogen for 16 hours. After completion of the reaction, the mixture was filtered and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 41-3 (101 mg, 48.7% yield, yellow solid). LCMS calculation for C 31 H 28 FN4O3S[M+H] + :m / z=555.2;Found:555.4.

[0728] Step 5: 2-((1-(3-cyclobutyloxyphenyl)-5-(4-fluorobenzyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0729] Compound 41-3 (90.0 mg, 162 μmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide (23.3 mg, 971 μmol) was added, and the system was stirred at 50°C for 1 hour. After the reaction, 1.5N hydrochloric acid was added to adjust the pH to 6. The mixture was extracted with ethyl acetate (10 mL x 3). 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, 72.3% yield, yellow solid). LCMS calculation for C 30 H 26 FN4O3S[M+H] + :m / z=541.2;Found:541.1; 1H NMR (400MHz, DMSO-d6) 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) ,7.06-7.02(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).

[0730] 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)

[0731] Step 1: 3,5-dibromo-1-(4-(trifluoromethyl)cyclohexyl)-1H-pyrazole

[0732] Under ice-cooling, diisopropyl azodicarboxylate (13.9 mL, 70.6 mmol) was added dropwise to a 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) in tetrahydrofuran (50 mL). The reaction solution was slowly warmed to room temperature and stirred under nitrogen for 16 hours. After the reaction was complete, water (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product 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 Br2F3N2[M+H] + :m / z=374.9 / 376.9 / 378.9; Found:375.0 / 377.0 / 379.0.

[0733] Step 2: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(4-(trifluoromethyl)cyclohexyl))-1H-pyrazole

[0734] 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)Cl2 (584 mg, 798 μmol) were added, and the system was stirred at 80°C under nitrogen for 1 hour. After the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phase was dried and concentrated, and purified by column chromatography (PE:EA = 10:1) to obtain compound 42-3 (900 mg, 64.2% yield, white solid). LCMS calculation for C 14 H 19 BrF3N2[M+H] + :m / z=351.1 / 353.1; Found:351.1 / 353.1.

[0735] Step 3: 3-Bromo-5-isobutyl-1-(4-(trifluoromethyl)cyclohexyl))-1H-pyrazole

[0736] 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 under a hydrogen atmosphere for 1 hour. After the reaction was complete, the mixture was filtered and concentrated to give compound 42-4 (700 mg, crude product, colorless liquid). LCMS calculation for C 14 H 21 BrF3N2[M+H] + :m / z=353.1 / 355.1; Found:353.2 / 355.2.

[0737] Step 4: 2-((5-isobutyl-1-(4-(trifluoromethyl)cyclohexyl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0738] 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. The system was stirred at 120°C under nitrogen for 1 hour. After completion of the reaction, the mixture was filtered and concentrated. The residue was purified by column chromatography (PE:EA = 1:1) to obtain compound 42-5 (560 mg, 65.1% yield, yellow solid). LCMS calculation for C 25 H 30 F3N4O2S[M+H] +:m / z=507.2;Found:507.3.

[0739] 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

[0740] Compound 42-5 (560 mg, 1.11 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (159 mg, 6.63 mmol) was added, and the system was stirred at 50°C for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 4. The mixture was extracted with dichloromethane (10 mL × 3). The organic phase was dried, concentrated, preparatively purified, and separated by SFC to obtain compound Cpd-42 (64.9 mg, 11.9% yield, yellow solid). LCMS calculation for C 24 H 28 F3N4O2S[M+H] + :m / z=493.2;Found:493.3; 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.30 (s, 1H), 7.30 (s, 2H), 7.07 (d, J = 4.2 Hz, 1H), 6.48 (s, 1H), 4.11 (s, 1H), 2.49 (d, J = 7.2 Hz, 2H), 2.26 (d, J = 12.0 Hz, 5H), 2.02-1.73 (m, 5H), 0.98 (s, 6H); Compound Cpd-43 (61.2 mg, yield 11.2%, yellow solid), LCMS calc. for C 24 H 28 F3N4O2S[M+H] + :m / z=493.2;Found:493.3; 1 H NMR (400MHz, CDCl3) 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).

[0741] Example 44: 2-((1-(3-(difluoromethoxy)-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-44)

[0742] Step 1: 3,5-dibromo-1-(3-(difluoromethoxy)-5-fluorophenyl)-1H-pyrazole

[0743] 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 a reaction flask and stirred at 90°C for 2 hours. The mixture was cooled to room temperature, filtered, and the concentrated crude product was purified by column chromatography (PE:EA = 20:1) to obtain compound 44-2 (1.09 g, 58.0% yield, colorless liquid). LCMS calculation for C 10 H6Br2F3N2O[M+H] + :m / z=384.9 / 386.9 / 388.9; Found:385.0 / 387.0 / 389.0.

[0744] Step 2: 3-Bromo-1-(3-(difluoromethoxy)-5-fluorophenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0745] Under nitrogen, compound 44-2 (1.09 g, 2.82 mmol), compound 2-3 (461 mg, 2.53 mmol), Pd(dppf)Cl2 (206 mg, 280 μmol), potassium phosphate (1.20 g, 5.63 mmol), and a 1,4-dioxane / water mixture (15 mL, 4:1) were added to a reaction flask and stirred at 100°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 20:1) to obtain compound 44-3 (751 mg, 73.8% yield, colorless liquid). LCMS calculation for C 14 H 13 BrF3N2O[M+H] + :m / z=361.0 / 363.0; Found:361.1 / 363.1.

[0746] Step 3: 3-Bromo-1-(3-(difluoromethoxy)-5-fluorophenyl)-5-isobutyl-1H-pyrazole

[0747] 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 under 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 44-4 (511 mg, 67.7% yield, colorless liquid). LCMS calculation for C 14 H 15 BrF3N2O[M+H] + :m / z=363.0 / 365.0; Found:363.3 / 365.3.

[0748] Step 4: 2-((1-(3-(difluoromethoxy)-5-fluorophenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0749] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 2). The organic phases were concentrated and preparatively purified to obtain compound Cpd-44 (23.8 mg, 3.69% yield, yellow solid). LCMS calc. for C 24 H 22 F3N4O3S[M+H] + :m / z=503.1;Found:503.2; 1 H NMR (400MHz, DMSO-d6) 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).

[0750] Example 45: 2-((5-isobutyl-1'-(2,2,2-trifluoroethyl)-1'H-[1,3'-bipyrazol]-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-45)

[0751] Step 1: 3-Bromo-1-(2,2,2-trifluoroethyl)pyrazole

[0752] Compound 45-1 (5.00 g, 34.0 mmol) was dissolved in DMF (60 mL). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (15.8 g, 68.1 mmol) and cesium carbonate (22.2 g, 68.1 mmol) were added at room temperature. The reaction mixture was stirred at 35°C for 2 hours. The reaction mixture was filtered, and the filtrate was added with water (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 2:1) to obtain compound 45-2 (2.43 g, 31.2% yield, yellow oil). LCMS calc. for C5H5BrF3N2 [M+H] + :m / z=229.0 / 231.0; Found:228.9 / 231.0.

[0753] Step 2: [1-(2,2,2-trifluoroethyl)pyrazol-3-yl]boronic acid

[0754] Compound 45-2 (2.20 g, 9.61 mmol) and pinacol diboronate (2.93 g, 11.5 mmol) were dissolved in 1,4-dioxane (30 mL). Pd(dppf)Cl2 (702 mg, 960 μmol) and potassium acetate (2.83 g, 28.8 mmol) were added at room temperature. The system was stirred at 90°C under a nitrogen atmosphere for 16 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 2:1) to afford compound 45-3 (1.28 g, 68.7% yield, brown oil). LCMS calc. for C5H7BF3N2O2 [M+3H-Pinacol] + :m / z=195.1;Found:195.2.

[0755] Step 3: 3,5-dibromo-1-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyrazole

[0756] 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. The system was stirred at 80°C under an oxygen atmosphere for 3 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 4:1) to afford compound 45-4 (990 mg, 50.0% yield, colorless oil). LCMS calc. for C8H6Br2F3N4[M+H] + :m / z=372.9 / 374.9 / 376.9; Found:372.9 / 374.9 / 377.0.

[0757] Step 4: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyrazole

[0758] 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). Pd(dppf)Cl2 (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 under nitrogen and stirred for 2 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 4:1) to afford compound 45-5 (595 mg, 70.8% yield, yellow oil). LCMS calculated for C 12 H 13 BrF3N4[M+H] + :m / z=349.0 / 351.0; Found:349.1 / 351.0.

[0759] Step 5: 3-Bromo-5-isobutyl-1-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyrazole

[0760] 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 under a hydrogen atmosphere for 1 hour. LCMS showed that the reaction was complete. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 4:1) to obtain compound 45-6 (440 mg, 63.6% yield, colorless oil). LCMS calc. C12 H 15 BrF3N4[M+H] + :m / z=351.0 / 353.0; Found:351.1 / 353.0.

[0761] Step 6: 2-((5-isobutyl-1'-(2,2,2-trifluoroethyl)-1'H-[1,3'-bipyrazol]-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0762] 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. The system was stirred at 120°C under a nitrogen atmosphere for 4 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, water (50 mL) was added, and extraction with ethyl acetate (70 mL) was performed. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 4:1) to obtain compound 45-7 (135 mg, 31.3% yield, yellow solid). LCMS calc. C 23 H 24 F3N6O2S[M+H] + :m / z=505.2;Found:505.2.

[0763] Step 7: 2-((5-isobutyl-1'-(2,2,2-trifluoroethyl)-1'H-[1,3'-bipyrazol]-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0764] Compound 45-7 (135 mg, 268 μmol) was dissolved in a mixture of methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Lithium hydroxide (68.8 mg, 2.87 mmol) was added, and the system was stirred at 75°C for 0.5 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, and the pH was adjusted to 5-6 with 1.5N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated and purified by preparative purification to obtain compound Cpd-45 (41.5 mg, 31.6% yield, white solid). LCMS calculation for C 22 H 22 F3N6O2S[M+H] + :m / z=491.1;Found:491.2; 1H NMR(400MHz,DMSO-d6)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).

[0765] 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)

[0766] 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

[0767] In an ice-water bath, diisopropyl azodicarboxylate (8.90 g, 43.9 mmol) was added dropwise to a 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) in tetrahydrofuran (80 mL). The reaction solution was slowly warmed to room temperature and stirred under nitrogen for 16 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 1:5) to obtain compound 46-2 (5.40 g, 70.5% yield, yellow solid). LCMS calculation for C 11 H 14 Br2N3O2[M+2H-tBu] + :m / z=377.9 / 379.9 / 381.9; Found:377.8 / 379.8 / 381.8.

[0768] 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

[0769] 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)Cl2 (1.01 g, 1.38 mmol) were added. The reaction system was stirred at 100°C under nitrogen for 2 hours. LCMS showed that the reaction was complete. 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. The residue was purified by column chromatography (PE:EA = 1:5) to obtain compound 46-3 (720 mg, 25.5% yield, yellow oil). LCMS calculation for C 15 H 21 BrN3O2[M+2H-tBu] + :m / z=354.1 / 356.1; Found:353.9 / 355.9.

[0770] 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

[0771] 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. The catalyst was removed by filtration, and the mixture was concentrated under reduced pressure to obtain compound 46-4 (544 mg, crude product, colorless oil). LCMS calculation for C 15 H 23 BrN3O2[M+2H-tBu] + :m / z=356.1 / 358.1; Found: 355.9 / 357.9; 1 H NMR (400MHz, DMSO-d6) 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,2H),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).

[0772] 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

[0773] Under nitrogen, 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. The reaction solution was heated to 120°C and stirred for 1 hour. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature and diluted with water (50 mL). The solution was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 3:1) to afford compound 46-5 (450 mg, 48.2% yield, yellow solid). LCMS calculation for C 30 H 40 N5O4S[M+H] + :m / z=566.3;Found:566.3.

[0774] 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

[0775] Compound 46-5 (260 mg, 460 μmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL). Lithium hydroxide (88.1 mg, 3.68 mmol) was added at room temperature, and the system was stirred at 70°C for 2 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, the pH was adjusted to 5-6 with 1N hydrochloric acid, and extraction was performed with ethyl acetate (20 mL x 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-46 (121 mg, 47.9% yield, yellow solid). LCMS calculation for C 29 H 38 N5O4S[M+H] + :m / z=552.3;Found:552.0; 1H NMR (400MHz, DMSO-d6) 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).

[0776] 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)

[0777] 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

[0778] Trifluoroacetic acid (1 mL) was added to a solution of compound 46-5 (120 mg, 218 μmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 47-1 (95.0 mg, crude product, yellow oil). LCMS calculated for C 25 H 32 N5O2S[M+H] + :m / z=466.2;Found:466.3.

[0779] 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

[0780] At room temperature, N,N-diisopropylethylamine (264 mg, 2.04 mmol) and (2,2,2-trifluoroethyl) trifluoromethanesulfonate (142 mg, 610 μmol) were added to a solution of compound 47-1 (95.0 mg, 204 μmol) in acetonitrile (4 mL). The reaction was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete, and the reaction solution was concentrated under reduced pressure and purified by column chromatography (PE:EA = 15:1) to afford compound 47-2 (70.0 mg, 62.6% yield, yellow solid). LCMS calculation for C 27 H 33 F3N5O2S[M+H] + :m / z=548.2;Found:548.2.

[0781] 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

[0782] Compound 47-2 (70.0 mg, 128 μmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL). Lithium hydroxide (3.06 mg, 128 μmol) was added at room temperature, and the reaction mixture was stirred at 70°C for 1 hour. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, adjusted to pH 5-6 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated and purified using preparative purification to obtain compound Cpd-47 (26.6 mg, 39.0% yield, yellow solid). LCMS calculated for C 26 H 31 F3N5O2S[M+H] + :m / z=534.2;Found:534.1; 1H NMR (400MHz, DMSO-d6) δ13.83(s,1H),10.56(s,1H),8.71(d,J=2.4Hz,1H),8.31(d,J=2.4H z,1H),7.51-7.45(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,2H),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).

[0783] Example 48: 2-((1-(2-(difluoromethoxy)pyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-48)

[0784] Step 1: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-methoxypyridine

[0785] At room temperature, (2-methoxypyridin-4-yl)boronic 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 solution of 3,5-dibromopyrazole (5.00 g, 22.1 mmol) in toluene (100 mL). The system was stirred at 90°C under an oxygen atmosphere for 3 hours. 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, 65.1% yield, white solid). LCMS calculation for C9H8Br2N3O [M+H] + :m / z=331.9 / 333.9 / 335.9; found:331.9 / 333.9 / 335.9.

[0786] Step 2: 4-(3,5-dibromo-1H-pyrazol-1-yl)pyridin-2-ol

[0787] Compound 48-1 (2.50 g, 7.51 mmol) and hydrobromic acid / acetic acid solution (10 mL, 33% content) were added to a reaction flask and 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, 50.2% yield, white solid). LCMS calculation for C8H6Br2N3O[M+H] + :m / z=317.9 / 319.9 / 321.9; Found:317.9 / 319.9 / 321.8.

[0788] Step 3: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-(difluoromethoxy)pyridine

[0789] Compound 48-2 (720 mg, 2.26 mmol) was dissolved in acetonitrile (15 mL), and sodium difluorochloroacetate (418 mg, 2.71 mmol) was added. The mixture 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 = 5:1) to obtain compound 48-3 (450 mg, 54.0% yield, white solid). LCMS calculation for C9H6Br2F2N3O[M+H] + :m / z=367.9 / 369.9 / 371.9; Found:367.9 / 370.0 / 371.9.

[0790] Step 4: 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-2-(difluoromethoxy)pyridine

[0791] Under argon, a mixture of compound 48-3 (450 mg, 1.22 mmol), compound 2-3 (211 mg, 1.16 mmol), Pd(dppf)Cl2 (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. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 2). The organic phase was concentrated and purified by column chromatography (PE:EA = 5:1) to obtain compound 48-4 (330 mg, 78.6% yield, colorless liquid). LCMS calculation for C 13 H 13 BrF2N3O[M+H] +:m / z=344.0 / 346.0; Found:344.0 / 346.1.

[0792] Step 5: 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-(difluoromethoxy)pyridine

[0793] 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 under a hydrogen atmosphere for 2 hours. LCMS analysis showed complete consumption of the starting material and the detection of the desired compound. The reaction solution was filtered and concentrated to obtain compound 48-4 (200 mg, crude product, colorless liquid). The crude product was used directly in the next reaction. LCMS calculation for C 13 H 15 BrF2N3O[M+H] + :m / z=346.0 / 348.0; Found:346.0 / 348.0.

[0794] Step 6: 2-((1-(2-(difluoromethoxy)pyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0795] Under argon, 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 a reaction flask and stirred at 120°C for 2 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 2). The organic phases were concentrated and purified to obtain Cpd-48 (49.0 mg, 17.4% yield, yellow solid). LCMS calculation for C 23 H 22 F2N5O3S[M+H] + :m / z=486.1;Found:486.2; 1H NMR (400MHz, DMSO-d6) 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),7.5 6-7.52(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).

[0796] Example 49: 2-((1-(2-ethoxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-49)

[0797] Step 1: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-ethoxypyridine

[0798] At room temperature, (2-ethoxypyridin-4-yl)boronic 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 under an oxygen atmosphere for 3 hours. 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, 84.6% yield, white solid). LCMS calculated value: C 10 H 10 Br2N3O[M+H] + :m / z=345.9 / 347.9 / 349.9; Detected values: 346.0 / 348.0 / 350.0.

[0799] Step 2: 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-2-ethoxypyridine

[0800] Under argon, a mixture of compound 49-1 (1.00 g, 2.88 mmol), compound 2-3 (500 mg, 2.74 mmol), Pd(dppf)Cl2 (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. The mixture was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (30 mL × 2). The organic phase was concentrated and purified by column chromatography (PE:EA = 5:1) to obtain compound 49-2 (760 mg, crude, colorless liquid). LCMS calc. for C 14 H 17 BrN3O[M+H] + :m / z=322.1 / 324.1; Found:322.0 / 324.0.

[0801] Step 3: 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-ethoxypyridine

[0802] 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 under a hydrogen atmosphere for 2 hours. Filtered and concentrated to obtain compound 49-3 (480 mg, crude product, colorless liquid). LCMS calculation for C 14 H 19 BrN3O[M+H] + :m / z=324.1 / 326.1; Found:324.1 / 326.1.

[0803] Step 4: 2-((1-(2-ethoxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0804] Under argon, 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 a reaction flask and stirred at 120°C for 2 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (15 mL × 2). The organic phase was concentrated and purified by preparative purification to obtain Cpd-49 (96.0 mg, 33.4% yield, yellow solid). LCMS calculation for C 24 H26 N5O3S[M+H] + :m / z=464.2;Found:464.5; 1 H NMR (400MHz, DMSO-d6) 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).

[0805] Example 50: 2-((1-(4-trifluoromethylphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-50)

[0806] Step 1: 3,5-dibromo-1-(4-trifluoromethylphenyl)-1H-pyrazole

[0807] 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). The system was stirred at 90°C under an oxygen atmosphere for 2 hours. The mixture was cooled and filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain compound 50-1 (1.36 g, 34.9% yield, colorless liquid). LCMS calculated value: C 10 H6Br2F3N2[M+H] + :m / z=368.9 / 370.9 / 372.9; Detected values: 369.0 / 371.0 / 373.0.

[0808] Step 2: 3-Bromo-1-(4-trifluoromethylphenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrazole

[0809] Under nitrogen, a mixture of compound 50-1 (1.36 g, 3.68 mmol), compound 2-3 (669 mg, 3.68 mmol), Pd(dppf)Cl2 (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. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 20:1) to obtain compound 50-2 (792 mg, 62.4% yield, colorless liquid). LCMS calculation for C 14 H 13 BrF3N2[M+H] + :m / z=345.0 / 347.0; Found:345.1 / 347.1.

[0810] Step 3: 3-Bromo-1-(4-trifluoromethylphenyl)-5-isobutyl-1H-pyrazole

[0811] 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 under a hydrogen atmosphere for 2 hours. The mixture was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA = 20:1) to obtain compound 50-3 (735 mg, 92.4% yield, colorless liquid). LCMS calculation for C 14 H 15 BrF3N2[M+H] + :m / z=347.0 / 349.0; Found:347.0 / 349.0.

[0812] Step 4: 2-((1-(4-trifluoromethylphenyl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0813] Under nitrogen, 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 a reaction flask and stirred at 120°C for 1.5 hours. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 2). The organic phases were concentrated and purified to obtain compound Cpd-50 (85.8 mg, 15.8% yield, yellow solid). LCMS calculation for C 24 H 22 F3N4O2S[M+H] + :m / z=487.1;Found:487.3; 1 H NMR (400MHz, DMSO-d6) 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=8.4H z,2H),7.54(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).

[0814] 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)

[0815] Step 1: Iodo-mesitylene di[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate]

[0816] Under nitrogen atmosphere, compound 51-2 (910 mg, 2.50 mmol) and compound 51-1 (900 mg, 5.00 mmol) were dissolved in toluene (10 mL) and stirred at 55°C for 0.5 h. After concentration, compound 51-3 (1.70 g, crude product, white solid) was obtained.

[0817] Step 2: 3,5-dibromo-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole

[0818] Under nitrogen, 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) illumination. The system was then exposed to air for five minutes and quenched with saturated aqueous sodium carbonate (20 mL). The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the crude product was filtered and concentrated, and then purified by column chromatography (PE:EA = 5:1) to obtain compound 51-4 (431 mg, 42.4% yield, yellow solid). LCMS calc. for C9H8Br2F3N2 [M+H] + :m / z=358.9 / 360.9 / 362.9; Found:359.0 / 361.0 / 363.0.

[0819] Step 3: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole

[0820] Under nitrogen, compound 51-4 (431 mg, 1.20 mmol), compound 2-3 (220 mg, 1.20 mmol), Pd(dppf)Cl2 (171 mg, 240 μmol), and potassium phosphate (631 mg, 2.98 mmol) were dissolved in a mixture of 1,4-dioxane and water (6 mL, 5:1). The reaction was stirred at 70°C for 2 hours. The mixture was cooled and filtered, and the filtrate was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2). The organic phases were concentrated and purified by column chromatography (PE:EA = 5:1) to obtain compound 51-5 (191 mg, 47.7% yield, colorless oil). LCMS calculation for C 13 H 15 BrF3N2[M+H] + :m / z=335.0 / 337.0; Found:335.1 / 337.1.

[0821] Step 4: 3-Bromo-5-isobutyl-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1H-pyrazole

[0822] Compound 51-5 (191 mg, 572 μmol) was dissolved in methanol (2 mL). Platinum dioxide (25.9 mg, 110 μmol) was added at 0°C, and the system was stirred under a hydrogen atmosphere for 0.5 hours. 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, 90.0% yield, colorless oil). LCMS calculation for C 13 H 17 BrF3N2[M+H] + :m / z=337.0 / 339.0; Found:337.2 / 339.2.

[0823] 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

[0824] Under nitrogen, 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 stirred at 120°C for 1.5 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 3:1) to obtain compound 51-7 (182 mg, 73.4% yield, yellow solid). LCMS calculation for C 24 H 26 F3N4O2S[M+H] + :m / z=491.2;Found:491.2.

[0825] 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

[0826] Compound 51-7 (182 mg, 371 μmol) and lithium hydroxide (87.9 mg, 3.67 mmol) were dissolved in a mixture of tetrahydrofuran and water (3 mL, 2:1) and stirred at 50°C for 0.5 hours. The mixture was cooled to room temperature, adjusted to pH 3 with 1N hydrochloric acid, and extracted with dichloromethane (10 mL x 3). The organic phase was concentrated and purified using preparative methods to obtain Cpd-51 (41.1 mg, 23.5% yield, yellow solid). LCMS calculation for C 23 H 24 F3N4O2S[M+H] +:m / z=447.2;Found:477.2; 1 H NMR (400MHz, DMSO-d6) 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).

[0827] Example 52: 2-[[5-Isobutyl-1-[2-(trifluoromethoxy)-5-pyridyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-52)

[0828] Step 1: [2-(trifluoromethoxy)-5-pyridyl]boronic acid

[0829] Under nitrogen at -60°C, n-butyllithium (3.10 mL, 4.96 mmol, 1.6 M tetrahydrofuran solution) was slowly added dropwise to a solution of compound 52-1 (800 mg, 3.31 mmol) in THF (8 mL). After the addition was complete, the system was stirred for 30 minutes, then trimethyl borate (1.03 g, 9.92 mmol) was added. The reaction solution was warmed to room temperature and stirred 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 the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 52-2 (650 mg, crude, white solid). LCMS calc. for C6H6BF3NO3[M+H] + :m / z=208.0;Found:208.1.

[0830] Step 2: 5-(3,5-dibromopyrazol-1-yl)-2-(trifluoromethoxy)pyridine

[0831] 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. The reaction mixture was filtered, and 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, 33.4% yield, yellow oil). LCMS calculation for C9H5Br2F3N3O[M+H] + :m / z=385.9 / 387.9 / 389.9; Found:386.0 / 388.0 / 390.0.

[0832] Step 3: 5-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]-2-(trifluoromethoxy)pyridine

[0833] 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)Cl2 (86.0 mg, 118 μmol) were added, and the system was stirred at 70°C under nitrogen for 2 hours. After the reaction, 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, 91.5% yield, yellow liquid). LCMS calculation for C 13 H 12 BrF3N3O[M+H] + :m / z=362.0 / 364.0; Found:362.0 / 364.0.

[0834] Step 4: 5-(3-bromo-5-isobutylpyrazol-1-yl)-2-(trifluoromethoxy)pyridine

[0835] 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 under a hydrogen atmosphere for 30 minutes. After the reaction, the product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 8:1) to obtain compound 52-5 (140 mg, 49.7% yield, colorless oil). LCMS calculation for C 13 H 14 BrF3N3O[M+H]+ :m / z=364.0 / 366.0; Found:364.1 / 366.1.

[0836] Step 5: 2-[5-isobutyl-1-[2-(trifluoromethoxy)-5-pyridinyl]amino]-5-(thiophen-2-yl)nicotinate

[0837] 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. The system was stirred at 110°C under nitrogen for 1 hour. After the reaction, the product was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 8:1) to obtain compound 52-6 (55.0 mg, 29.7% yield, yellow solid). LCMS calculation for C 24 H 23 F3N5O3S[M+H] + :m / z=518.1;Found:518.1.

[0838] Step 6: 2-[[5-isobutyl-1-[2-(trifluoromethoxy)-5-pyridyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0839] Compound 52-6 (50.0 mg, 96.7 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (23.1 mg, 970 μmol) was added, and the system was stirred at 50°C for 1 hour. After the reaction, the pH was adjusted to 4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried and concentrated to obtain the crude product. Preparative purification was then performed to obtain compound Cpd-52 (22.0 mg, 45.2% yield, yellow solid). LCMS calculation for C 23 H 21 F3N5O3S[M+H] + :m / z=504.1;Found:504.1; 1H NMR (400MHz, DMSO-d6) 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).

[0840] Example 53: 2-((5-isobutyl-1-(2-isopropylpyridin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid (Cpd-53)

[0841] Step 1: (2-Isopropyl-4-pyridyl)boronic acid

[0842] Compound 53-1 (1.80 g, 11.5 mmol) and pinacol diboronate (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)Cl2 (845 mg, 1.16 mmol) were added. The system was stirred at 90°C under nitrogen 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 calculation for C8H 13 BNO2[M+3H-Pinacol] + :m / z=166.1;Found:166.3.

[0843] Step 2: 4-(3,5-dibromo-1H-pyrazol-1-yl)-2-isopropylpyridine

[0844] 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. 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, 29.2% yield, colorless oil). LCMS calculation for C 11 H 12 Br2N3[M+H] +:m / z=343.9 / 345.9 / 347.9; Found:344.1 / 346.1 / 348.1.

[0845] Step 3: 4-[3-bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]-2-isopropylpyridine

[0846] 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)Cl2 (424 mg, 580 μmol) were added, and the system was stirred at 70°C under nitrogen for 2 hours. After cooling, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated, and purified by column chromatography (PE:EA = 10:1) to obtain compound 53-4 (500 mg, 53.8% yield, colorless oil). LCMS calculation for C 15 H 19 BrN3[M+H] + :m / z=320.1 / 322.1; Found:320.1 / 322.1.

[0847] Step 4: 4-(3-bromo-5-isobutylpyrazol-1-yl)-2-isopropylpyridine

[0848] 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 under a hydrogen atmosphere for 1.5 hours. 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, 59.6% yield, colorless oil). LCMS calculation for C 15 H 21 BrN3[M+H] + :m / z=322.1 / 324.1; Found:322.2 / 324.2.

[0849] Step 5: 2-((5-isobutyl-1-(2-isopropylpyridin-4-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0850] 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. The system was stirred at 120°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was diluted with water (50 mL) and the pH was adjusted to 5-6 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by preparative method to obtain compound Cpd-53 (100 mg, 26.8% yield, yellow solid). LCMS calculation for C 25 H 28 N5O2S[M+H] + :m / z=462.2;Found:462.4. 1 H NMR (400MHz, DMSO-d6) 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 =7.1Hz, 2H), 1.86 (m, J = 13.4, 6.7Hz, 1H), 1.28 (d, J = 6.9Hz, 6H), 0.90 (d, J = 6.6Hz, 6H).

[0851] Example 54: 2-[[1-(4-cyclopropylphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-54)

[0852] Step 1: 3,5-dibromo-1-(4-cyclopropylphenyl)pyrazole

[0853] 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. The mixture was stirred at 90°C in an oxygen atmosphere for 12 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, filtered, concentrated, and purified by column chromatography (PE:EA = 1:4) to obtain compound 54-1 (1.92 g, 55.1% yield, yellow solid). LCMS calculation for C 12 H 11 Br2N2[M+H] + :m / z=340.9 / 342.9 / 344.9; Found:340.9 / 342.9 / 344.9.

[0854] Step 2: 3-Bromo-1-(4-cyclopropylphenyl)-5-(2-methylprop-1-en-1-yl)pyrazole

[0855] Under nitrogen, 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). Pd(dppf)Cl2 (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 indicated the reaction was complete. The mixture was cooled to room temperature and extracted with ethyl acetate (100 mL) and water (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 4:1) to afford compound 54-2 (850 mg, 53.9% yield, yellow oil). LCMS calc. for C 16 H 18 BrN2[M+H] + :m / z=317.0 / 319.0; Found:317.1 / 319.0.

[0856] Step 3: 3-Bromo-1-(4-cyclopropylphenyl)-5-isobutylpyrazole

[0857] 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 indicated the reaction was complete. Methanol (40 mL) was added, the mixture was filtered and concentrated, and the crude product was purified by column chromatography (PE:EA = 4:1) to obtain compound 54-3 (810 mg, 67.1% yield, colorless oil). LCMS calc. C16 H 20 BrN2[M+H] + :m / z=319.1 / 321.1; Found:319.1 / 321.1.

[0858] Step 4: 2-[[1-(4-cyclopropylphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinate

[0859] 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. The system was stirred at 120°C under a nitrogen atmosphere for 4 hours. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, water (50 mL) was added, and extraction was performed with ethyl acetate (70 mL). The combined organic phases were dried over anhydrous sodium sulfate, and the crude product after filtration and concentration was purified by column chromatography (PE:EA = 4:1) to obtain compound 54-4 (127 mg, 28.7% yield, yellow oil). LCMS calc. C 27 H 29 N4O2S[M+H] + :m / z=473.2;Found:473.3.

[0860] Step 5: 2-[[1-(4-cyclopropylphenyl)-5-isobutylpyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0861] Compound 54-4 (150 mg, 318 μmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL). Lithium hydroxide (45.6 mg, 1.90 mmol) was added at room temperature, and the system was stirred at 60°C for 0.5 hours. LCMS indicated the reaction was complete. After cooling the reaction solution to room temperature, the pH was adjusted to 5-6 with 1.5N hydrochloric acid. The solution was extracted with ethyl acetate (20 mL x 2), and the organic phase was dried and concentrated. The crude product was purified by preparative purification to yield Cpd-54 (61.1 mg, 41.2% yield, yellow solid). LCMS calculation for C 26 H 27 N4O2S[M+H] + :m / z=459.2;Found:459.3; 1H NMR (400MHz, DMSO-d6) 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).

[0862] Example 55: 2-[1-Isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-55)

[0863] Step 1: 2-Bromo-1-isobutyl-4-nitroimidazole

[0864] Compound 55-1 (10.0 g, 52.1 mmol) and isobutane 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 indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 1:4) to afford compound 55-2 (8.19 g, 63.4% yield, yellow solid). LCMS calculation for C7H 11 BrN3O2[M+H] + :m / z=248.0 / 250.0; Found:248.0 / 250.0.

[0865] Step 2: 1-isobutyl-4-nitro-2-[4-(trifluoromethyl)phenyl]imidazole

[0866] 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). Cesium carbonate (16.4 g, 50.4 mmol) and Pd(PPh3)4 (2.33 g, 2.02 mmol) were added at room temperature. The system was stirred at 100°C under nitrogen for 2 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 4:1) to obtain compound 55-3 (4.05 g, yield 64.1%), as a yellow solid. LCMS calculation for C 14 H 15 F3N3O2[M+H] + :m / z=314.1;Found:314.2.

[0867] Step 3: 1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-amine

[0868] Compound 55-3 (500 mg, 1.60 mmol) was dissolved in methanol (20 mL). Hydrochloric acid (0.50 mL, 3.00 mmol, 6N aqueous solution) was added at room temperature, followed by palladium hydroxide (224 mg, 10% content) and palladium carbon (194 mg, 10% content). The system was stirred at 30°C under hydrogen for 2 hours. LCMS indicated the reaction was complete. Methanol (40 mL) was added and filtered. The filtrate was decompressed to obtain compound 55-4 (400 mg, crude product, yellow oil). LCMS calc. C 14 H 17 F3N3[M+H] + :m / z=284.1;Found:284.2.

[0869] Step 4: 2-[1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]amino]-5-(thiophen-2-yl)nicotinate

[0870] Compound 55-4 (310 mg, 1.09 mmol) and compound INT-2 (278 mg, 1.09 mmol) were dissolved in toluene (5 mL). 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 under nitrogen for 1 hour. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 4:1) to obtain compound 55-5 (144 mg, 26.3% yield, yellow oil). LCMS calc. C 25 H 24 F3N4O2S[M+H] + :m / z=501.2;Found:501.1.

[0871] Step 5: 2-[1-isobutyl-2-[4-(trifluoromethyl)phenyl]imidazol-4-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0872] Compound 55-5 (130 mg, 260 μmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). 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 indicated the reaction was complete. The mixture was cooled to room temperature, the pH was adjusted to 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL). The organic phase was concentrated and purified by preparative purification to afford Cpd-55 (59.6 mg, 47.1% yield, yellow solid). LCMS calculated for C 24 H 22 F3N4O2S[M+H] + :m / z=487.1;Found:487.3; 1 H NMR (400MHz, DMSO-d6) 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,1 H),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).

[0873] Example 56: 2-[[5-Isobutyl-1-[4-(pentafluorosulfuryl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid (Cpd-56)

[0874] Step 1: (4-pentafluorosulfuryl)phenylboronic acid

[0875] Under ice-cooling conditions, a solution of tetrafluoroboric acid (4.32 mL, 25.6 mmol, 48% aqueous solution) in acetonitrile (10 mL) was added to a solution of compound 56-1 (2.25 g, 10.2 mmol) in acetonitrile (10 mL). After stirring for 5 minutes, a solution of tert-butyl nitrite (1.11 g, 10.7 mmol) in acetonitrile (10 mL) was added, and the reaction was stirred for another 15 minutes. A solution of bis(pinacol)boronate (2.61 g, 10.2 mmol) in acetonitrile (10 mL) was added, and the mixture was cooled to -20°C. A solution of pyridine (3.25 g, 41.1 mmol) in acetonitrile (10 mL) was slowly added, and the mixture was slowly warmed to room temperature and stirred for 1.5 hours. The pH was adjusted to 2-3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL x 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).

[0876] Step 2: [4-(3,5-dibromopyrazol-1-yl)phenyl]-sulfur pentafluoride

[0877] 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. The system was stirred at 90°C under an oxygen atmosphere for 16 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 10:1) to obtain compound 56-3 (1.50 g, 35.1% yield, yellow oil). LCMS calc. for C9H6Br2F5N2S[M+H] + :m / z=426.9 / 428.8 / 430.8; Found:426.9 / 428.9 / 430.9.

[0878] Step 3: [4-[3-Bromo-5-(2-methylprop-1-en-1-yl)pyrazol-1-yl]phenyl]-sulfur pentafluoride

[0879] 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)Cl2 (491 mg, 680 μmol) were added, and the system was stirred at 70°C under nitrogen 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, 98.0% yield, yellow oil). LCMS calculation for C 13 H 13 BrF5N2S[M+H] + :m / z=403.0 / 405.0; Found:403.0 / 405.0.

[0880] Step 4: [4-(3-bromo-5-isobutylpyrazol-1-yl)phenyl]-sulfur pentafluoride

[0881] 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. The system was stirred at 0°C under a hydrogen atmosphere for 30 minutes. The mixture was filtered and concentrated, and the crude product was purified by reverse phase column chromatography (H2O:CH3CN = 0-80%) to obtain compound 56-5 (650 mg, 43.1% yield, white solid). LCMS calculation for C 13 H 15 BrF5N2S[M+H] + :m / z=405.0 / 407.0; Found:405.1 / 407.1.

[0882] Step 5: 2-[[5-isobutyl-1-[4-(pentafluorosulfuryl)phenyl]pyrazol-3-yl]amino]-5-(thiophen-2-yl)nicotinic acid

[0883] Compound 56-4 (350 mg, 866 μmol) and compound INT-1 (303 mg, 1.30 mmol) were dissolved in DMF (7 mL), and t-BuBrettphos Pd G3 (110 mg, 129 μmol) and cesium carbonate (561 mg, 1.73 mmol) were added. The system was stirred at 120°C under nitrogen for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 5-6. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated to obtain the crude product, which was then purified to obtain compound Cpd-56 (58.0 mg, 12.3% yield, yellow solid). LCMS calculation for C23 H 22 F5N4O2S2[M+H] + :m / z=545.1;Found:545.1; 1 H NMR (400MHz, DMSO-d6) 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,2H),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).

[0884] 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)

[0885] Step 1: Spiro[2.5]octan-6-ol

[0886] Under an ice-water bath, sodium borohydride (1.22 g, 32.2 mmol) was added to a solution of compound 57-1 (2.00 g, 16.1 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 57-2 (1.87 g, crude product, yellow oil).

[0887] Step 2: 3,5-dibromo-1-(spiro[2.5]octan-6-yl)-1H-pyrazole

[0888] Under nitrogen, 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 at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated, and then purified by column chromatography (PE:EA = 20:1) to obtain compound 57-3 (1.20 g, 45.3% yield, yellow solid). LCMS calculation for C11 H 15 Br2N2[M+H] + :m / z=333.0 / 335.0 / 337.0; Found:333.1 / 335.0 / 337.1.

[0889] Step 3: 3-Bromo-5-(2-methylprop-1-en-1-yl)-1-(spiro[2.5]octan-6-yl)-1H-pyrazole

[0890] Under nitrogen, compound 57-3 (1.20 g, 3.59 mmol), compound 2-3 (780 mg, 4.31 mmol), Pd(dppf)Cl2 (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 reaction system was stirred at 80°C for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated, and then purified by column chromatography (PE:EA = 5:1) to obtain compound 57-4 (430 mg, 38.7% yield, colorless oil). LCMS calc. for C 15 H 22 BrN2[M+H] + :m / z=309.1 / 311.1; Found:309.2 / 311.2.

[0891] Step 4: 3-Bromo-5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazole

[0892] Compound 57-4 (400 mg, 1.30 mmol) was dissolved in methanol (2 mL). Platinum dioxide (56.8 mg, 250 μmol) was added at 0°C. The system was stirred under a hydrogen atmosphere for 0.5 hours. The mixture was filtered and concentrated to obtain compound 57-5 (361 mg, crude product, colorless oil). LCMS calculation for C 15 H 24 BrN2[M+H] + :m / z=311.1 / 313.1; Found:311.2 / 313.2.

[0893] Step 5: 2-((5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0894] Under nitrogen, 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 stirred at 120°C for 1.5 hours. The mixture was cooled and filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (PE:EA = 5:1) to afford compound 57-6 (171 mg, 37.9% yield, yellow solid). LCMS calculation for C 26 H 33 N4O2S[M+H] + :m / z=465.2;Found:465.3.

[0895] Step 6: 2-((5-isobutyl-1-(spiro[2.5]octan-6-yl)-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0896] Compound 57-6 (160 mg, 345 μmol) and lithium hydroxide (49.5 mg, 2.07 mmol) were dissolved in a mixture of tetrahydrofuran and water (3 mL, 2:1) and stirred at 50°C for 0.5 hours. After cooling to room temperature, the pH was adjusted to 3 by adding 1N hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 3). The organic phase was concentrated and purified by preparative purification to afford Cpd-57 (110 mg, 71.1% yield, yellow solid). LCMS calculation for C 25 H 31 N4O2S[M+H] + :m / z=451.2;Found:451.3; 1 H NMR (400MHz, DMSO-d6) 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),2.06-1.8 1(m,5H),1.77-1.68(m,2H),0.95(d,J=6.6Hz,8H),0.36-0.26(m,4H).

[0897] Example 58: 2-[[5-Isobutyl-1-[2-(trifluoromethoxy)-4-pyridinyl]amino]-5-(2-thienyl)pyridine-3-carboxylic acid

[0898] Step 1: 4-(3,5-dibromopyrazol-1-yl)-2-(trifluoromethoxy)pyridine

[0899] Compound 48-2 (4.20 g, 13.1 mmol) and 1-(trifluoromethyl)-1,2-benzidoxyl-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, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 58-1 (2.10 g, 41.2% yield, light yellow solid). LCMS calc. for C9H5Br2F3N3O[M+H] + :m / z=385.9 / 387.9 / 389.9; Found:385.9 / 387.9 / 389.9.

[0900] Step 2: 4-[3-bromo-5-(2-methylpropyl-1-enyl)pyrazol-1-yl]-2-(trifluoromethoxy)pyridine

[0901] 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)Cl2 (516 mg, 710 μmol) were added, and the system was stirred at 70°C under nitrogen for 2 hours. The mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 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, 81.4% yield, colorless liquid). LCMS calculation for C 13 H 12 BrF3N3O[M+H] + :m / z=362.0 / 364.0; Found:362.0 / 364.0.

[0902] Step 3: 4-(3-bromo-5-isobutylpyrazol-1-yl)-2-(trifluoromethoxy)pyridine

[0903] 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 under a hydrogen atmosphere for 30 minutes. After the reaction was complete, the mixture was filtered and concentrated. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain compound 58-3 (900 mg, 55.9% yield, colorless oil). LCMS calculation for C 13 H 14 BrF3N3O[M+H] + :m / z=364.0 / 366.0; Found:364.1 / 366.1.

[0904] Step 4: 2-[5-isobutyl-1-[2-(trifluoromethoxy)-4-pyridinyl]pyrazol-3-yl]amino]-5-(2-thienyl)pyridine-3-carboxylic acid methyl ester

[0905] 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. The system was stirred at 120°C under nitrogen for 2 hours. The mixture was cooled, filtered, and concentrated. 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, 31.6% yield, yellow solid). LCMS calculation for C 24 H 23 F3N5O3S[M+H] + :m / z=518.1;Found:518.2.

[0906] Step 5: 2-[[5-isobutyl-1-[2-(trifluoromethoxy)-4-pyridinyl]amino]-5-(2-thienyl)pyridine-3-carboxylic acid

[0907] Compound 58-4 (200 mg, 387 μmol) was dissolved in a mixture of tetrahydrofuran (15 mL), methanol (15 mL), and water (5 mL). Lithium hydroxide (92.5 mg, 3.86 mmol) was added, and 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. The solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried and concentrated to obtain the crude product, which was then purified by preparative purification to obtain compound Cpd-58 (105 mg, 53.9% yield, white solid). LCMS calculation for C 23 H 21 F3N5O3S[M+H]+ :m / z=504.1;Found:504.3; 1 H NMR (400MHz, DMSO-d6) 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).

[0908] Example 59: 2-((1-(2-cyclobutyloxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0909] Step 1: 4-Bromo-2-cyclobutoxypyridine

[0910] 59-1 (5.00 g, 28.4 mmol) was dissolved in tetrahydrofuran (50 mL), and cyclobutanol (2.67 mL, 34.1 mmol) and potassium tert-butoxide (9.56 g, 85.2 mmol) were added. The reaction mixture was stirred at 80°C for 3 hours. After cooling, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 59-2 (3.20 g, 49.4% yield, white solid). LCMS calculation for C9H 11 BrNO[M+H] + :m / z=228.0 / 230.0; Found:228.2 / 230.2.

[0911] Step 2: (2-cyclobutoxypyridin-4-yl)boronic acid

[0912] Under nitrogen at -78°C, n-butyllithium (14.0 mL, 22.4 mmol, 1.6 M THF solution) was slowly added dropwise to a solution of compound 59-2 (3.00 g, 13.2 mmol) in tetrahydrofuran (30 mL). Stirring was continued for 30 minutes after the addition was complete. Trimethyl borate (4.40 mL, 39.5 mmol) was then slowly added dropwise to the above system, which was then warmed to room temperature and stirred for 1 hour. LCMS analysis confirmed the complete reaction of the starting material, and the system was concentrated to obtain crude product 59-3 (2.50 g, colorless oil). This was used directly in the next reaction without further treatment. LCMS calculation for C9H 13 BNO3[M+H] + :m / z=194.1;Found:194.0.

[0913] Step 3: 2-cyclobutyloxy-4-(3,5-dibromo-1H-pyrazol-1-yl)pyridine

[0914] 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 at 90°C under oxygen protection overnight. Filter, dilute the filtrate with water (50 mL), and extract with ethyl acetate (30 mL x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 59-4 (1.20 g, 31.0% yield, yellow solid). LCMS calculation for C 12 H 12 Br2N3O[M+H] + :m / z=371.9 / 373.9 / 375.9; Found:372.0 / 374.0 / 376.0.

[0915] Step 4: 4-(3-bromo-5-(2-methylprop-1-en-1-yl)-1H-pyrazol-1-yl)-2-cyclobutoxypyridine

[0916] Under a 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)Cl2 (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. The residue was purified by column chromatography (PE:EA = 8:1) to obtain compound 59-5 (750 mg, 66.9% yield, yellow solid). LCMS calc. for C 16 H 19 BrN3O[M+H] + :m / z=348.1 / 350.1; Found:348.1 / 350.1.

[0917] Step 5: 4-(3-bromo-5-isobutyl-1H-pyrazol-1-yl)-2-cyclobutoxypyridine

[0918] 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 give compound 59-6 (600 mg, yield 92.3%, yellow solid). LCMS calculation for C 16 H 21 BrN3O[M+H] + :m / z=350.1 / 352.1; Found:350.1 / 352.1.

[0919] Step 6: 2-((1-(2-cyclobutyloxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinate

[0920] Under nitrogen, 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. The mixture was cooled, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 10:1) to obtain compound 59-7 (300 mg, 37.9% yield, yellow solid). LCMS calculation for C 27 H 30 N5O3S[M+H] +:m / z=504.2;Found:504.2.

[0921] Step 7: 2-((1-(2-cyclobutyloxypyridin-4-yl)-5-isobutyl-1H-pyrazol-3-yl)amino)-5-(thiophen-2-yl)nicotinic acid

[0922] Compound 59-7 (300 mg, 596 μmol) was dissolved in a mixture of tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL). Lithium hydroxide (114 mg, 4.77 mmol) was added, and the system was stirred at room temperature for 1 hour. After the reaction, 1N hydrochloric acid was added to adjust the pH to 2-4. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried and concentrated to obtain the crude product. Compound Cpd-59 (115 mg, 39.4% yield, pale yellow solid) was obtained through preparative purification. LCMS calculation for C 26 H 28 N5O3S[M+H] + :m / z=490.2;Found:490.2; 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.82(d,J=2.6Hz...

Claims

1. 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, X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ; R 3 , R 4 , R 5 and R 6 Each is 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 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is 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 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 cycloalkoxy, -NR x1 R y1 , C3-C6 cycloalkyl, 3-8 membered heterocyclic group, -C(O)OR z ; R x1 and R y1 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R z is hydrogen or C1-C6 alkyl; R 2 The group consisting of 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; Substituents in Group A include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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:

2. 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 one of the following options 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, X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ; R 3 , R 4 , R 5 and R 6 Each of them is 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 aromatic hydrocarbon which is unsubstituted or substituted by 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 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is substituted by one or more substituents selected from the following: deuterium, halogen, hydroxyl, carboxyl, cyano, -CONR 7 R 8 、-NR 8 CO-R 7 、-NR 7 R 8 、-SO2R 7 、-SO2NR 7 R 8 , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; 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 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl; R 2 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; Substituents in Group A include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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 pharmaceutical preparation thereof The acceptable salt of formula (I) is selected from the following structures: in, X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ; R 3 , R 4 , R 5 and R 6 Each is 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 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 The substituted C1-C6 alkyl group is 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 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 cycloalkoxy, -NR x1 R y1 , C3-C6 cycloalkyl; R x1 and R y1 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R 2 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, -SF5、-S-CH3、-CONH2、-(CH2) i SO2R 9 ,-(CH2) i SO2NH2、-(CH2) i SO2NR 13 R 11 ,-(CH2) i P(O)R 9 R 10 ,-(CH2) i C(O)-OR 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 ,-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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, X 1 N or CR 3 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ; R 3 , R 4 , R 5 and R 6 Each is 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 Selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; R 1 R is selected from hydrogen, C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; 1 Zhongsuo The substituted C1-C6 alkyl group refers to a substituted C1-C6 alkyl group selected from the group consisting of 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 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 cycloalkoxy, -NR x1 R y1 , C3-C6 cycloalkyl, 3-8 membered heterocyclic group, -C(O)OR z ; R x1 and R y1 Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R z is hydrogen or C1-C6 alkyl; R 2 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; Substituents in Group A include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 are independently hydrogen or C1-C6 alkyl; R 13 is hydrogen or C1-C6 alkyl; R 11 and R 12 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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.

3. 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: X 1 N or CR 3 , X 2 CR 4 , X 3 CR 5 , X 4 N or CR 6 .

4. 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: Among them, R 0 , R 1 , R 2 and R 5 The definition is the same as that in claim 3; Alternatively, when formula (I) is formula (I-1) or (I-4), R 2 When R is selected from unsubstituted C1-C8 alkyl, 1 is selected from C3-C6 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, and C1-C6 alkyl which is unsubstituted or substituted; R 0 and R 5 The definition is the same as that described in claim 3.

5. 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 meets one or more of the following conditions: (1)R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R z , R x , R y , in the substituents of Group C, the substituents of Group B and the substituents of 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; (2)R 2 In the C1-C8 alkyl group which is unsubstituted or substituted by one or more substituents selected from Group A, the C1-C8 alkyl group 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; (3)R 3 , R 4 , R 5 , R 6 , 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 unsubstituted or substituted C1-C6 alkoxy group selected from Group A are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; (4)R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 In the substituents of Group B, the C6-C10 aryl, the C6-C10 aryl in the C6-C10 aryl that is unsubstituted or substituted with one or more substituents selected from Group A, the C6-C10 aryl in the C6-C10 aryl that is unsubstituted or substituted with one or more substituents selected from Group C, and the C6-C10 aryl in the C6-C10 aryl that is unsubstituted or substituted are independently phenyl or naphthyl; (5)R 2 , R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , 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 with one or more substituents selected from Group A, 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, and the heteroatoms are N and / or S, the number is 1, 2 or 3, preferably pyridyl, pyridazinyl, 1H-pyrazolyl or thienyl; (6)R 1 , R 11 , R 12 , 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; (7)R 2 wherein 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 In the above, 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.

6. 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 meets 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)R 1 is selected from hydrogen, C3-C6 cycloalkyl, unsubstituted or substituted C1-C6 alkyl; R 1 The substituted C1-C6 alkyl group 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; R 1 The substituted C1-C6 alkyl group refers to a group selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, phenyl, halophenyl, pyridine, halopyridyl, cyclopropyl, cyclohexyl, and piperidinyl substituted with -C(O)O C1-C6 alkyl; More preferably, R 1 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl, (3) In formula (I) and (I-1) to (I-6), R 4 and R 6 Each is 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 5-10 membered heteroaryl 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 -(CH2) i R 12 ; R 12 is a C1-C6 alkyl group; Preferably, R 5 for and (5) In formula (I) and (I-1) to (I-6), R 2 Selected from C1-C6 alkyl or halogenated C1-C6 alkyl, in, n is 0, 1, 2, 3 or 4; Each R a Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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 Selected from hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl; Preferably, R 2 Select from any of the following structures:

7. 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: R 0 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; R 1 The substituted C1-C6 alkyl group is substituted by one or more selected from deuterium, halogen, amino, hydroxyl, cyano, phenyl, and C3-C6 cycloalkyl; 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 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; R 1 is selected from the group consisting of methyl, ethyl, propyl, n-butyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, cyclopentyl, cyclopropylmethyl, benzyl, R 5 for 8. 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: The compound as shown in formula (I) is any one of the general formulas (II) to (XII): 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 Selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl; Each R a , R b Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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 Selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl; R e Selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -OC(O)C(CH3)3; R a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl; Each R a1 , R b1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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 Selected from hydrogen, deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl; Each R a1 , R b1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i SO2NH2, -(CH2) i SO2NR 13 R 11 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 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 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 cycloalkoxy, -NR x R y 、-CONR x R y 、-NR x CO-R y 、-SO2R x 、-SO2NR x R y , C6-C10 aryl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is 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.

9. The compound of formula (I) according to 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 R a Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 are independently hydrogen or C1-C6 alkyl; R 13 is hydrogen or C1-C6 alkyl; R 11 and R 12 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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(CH3)3; R b1 is methyl, ethyl or halogen; R a2 is hydrogen, halogen, C1-C6 alkyl or halogenated C1-C6 alkyl; Each R a1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 are independently hydrogen or C1-C6 alkyl; R 13 is hydrogen or C1-C6 alkyl; R 11 and R 12 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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 R a1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 are independently hydrogen or C1-C6 alkyl; R 13 is hydrogen or C1-C6 alkyl; R 11 and R 12 is 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, or unsubstituted or substituted C6-C10 aryl; R 11 and R 12 The substitution mentioned herein 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.

10. 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(CH3)3; R b1 is methyl, ethyl or halogen; R a2 is hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl; Each R a1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 are independently hydrogen or C1-C6 alkyl; R 13 is hydrogen or C1-C6 alkyl; R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C6 cycloalkyl group; R 11 and R 12 The substitution mentioned in the above means 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; 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 R a1 Each is independently selected from: oxo, deuterium, halogen, cyano, hydroxyl, amino, carboxyl, thiol, -SF5, -S-CH3, -CONH2, -(CH2) i S02R 9 、-(CH2) i P(O)R 9 R 10 、-(CH2) i C(O)-OR 11 、-(CH2) i OC(O)R 11 、-CONR 13 R 11 、-NR 13 CO-R 11 、-NR 13 R 11 、-O(CH2) i R 12 、-(CH2) i R 12 ; i is 0, 1, 2, or 3; R 9 and R 10 are independently hydrogen or C1-C6 alkyl; R 13 is hydrogen or C1-C6 alkyl; R 11 and R 12 is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C3-C6 cycloalkyl group; R 11 and R 12 The substitution mentioned in the above means 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; Preferably, In formula (II), formula (III), formula (IV) and formula (V), at least one R a -O(CH2) i R 12 , i is 0; In formula (VI), formula (VII), formula (XI) and formula (XII), at least one R a1 -O(CH2) i R 12 , i is 0.

11. The compound of formula (I) according to claim 1, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from the following compounds:

12. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 11, its isotope-labeled substance, enantiomer, diastereomer, solvate or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient.

13. Use of a compound as shown in formula (I) as described in any one of claims 1 to 11, its isotope-labeled substance, enantiomer, diastereomer, solvate or pharmaceutically acceptable salt, or a pharmaceutical composition as described in 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.

14. 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.

15. A method for treating and / or preventing cancer, characterized in that: The method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 11, an isotope-labeled substance, an enantiomer, a diastereomer, a solvate or a pharmaceutically acceptable salt thereof.

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