A class of aromatic heterocyclic compounds, and methods of making and using the same

Abstract

The present application provides a kind of compound as STAT6 inhibitor and its stereoisomer, tautomer or its pharmaceutically acceptable salt, the preparation method of compound and its purposes in treating STAT6 related diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of aromatic heterocyclic compounds, as well as methods for preparing and using said compounds. Background Technology

[0002] Type 2 immune responses are characterized by the activation of Th2 (T helper 2) cells and B cells, and a response involving innate immune cells such as mast cells, ILC2 (type II innate lymphoid) cells, eosinophils, basophils, and M2 macrophages, leading to the production of interleukin-4 (IL-4), IL-5, IL-13, and immunoglobulin E (IgE). Dysregulation of Th2 immune responses drives the development of many allergic diseases, including atopic dermatitis and asthma. The STAT family of signal transducer and activator of transcription proteins are transcription factors that respond to various extracellular cytokine and growth factor signals. In mammals, this family includes STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. All genes are located on different chromosomes but share a conserved SH2 sequence structure. STAT6 is a key transcription factor in the IL-4 / IL-13-JAK-STAT signaling pathway, mediating Th2 cell proliferation and differentiation, regulating Th2 immune responses, and serving as a major driver of Th2 inflammation in allergic / atopic diseases. STAT6 also promotes B cell proliferation and maturation, regulates isotype conversion of immunoglobulins, mediates MHC-II and IgE expression, and plays a crucial role in mast cell activation. STAT6 also induces the expression of homing-related genes in immune cells, participating in innate immunity. Specifically, IL-4 and IL-13 bind to cell membrane receptors such as the IL-4α receptor (IL-4Rα), leading to the phosphorylation of certain intracellular tyrosine residues of IL-4Rα by receptor-associated Janus kinases (JAKs). Subsequently, STAT6 binds to the phosphorylation site of IL-4Rα through its Src homology 2 (SH2) domain and is phosphorylated by JAKs or other kinases. Phosphorylated STAT6 proteins recognize phosphotyrosine-containing peptides through their SH2 domains, forming homodimers that translocate to the nucleus, bind to target DNA, and initiate gene transcription. STAT6 is essential for IL-4 and IL-13 signaling and is located downstream of the JAK-STAT pathway. It is not utilized by other cytokines and growth factors, resulting in fewer side effects from targeting it, making it a unique and valuable drug target.

[0003] Multiple functional mutations in STAT6 have been shown to contribute to severe allergic / atopic diseases in humans. Asthma patients exhibit elevated levels of IL-4 and IL-13 in the airways and elevated pSTAT6 levels in the bronchial epithelium. STAT6 knockout mice, however, do not exhibit airway hyperresponsiveness (AHR) or asthma-related lung pathology. Furthermore, STAT6 is aberrantly activated in atopic dermatitis, autoimmune diseases, and various solid tumors. This pathway has been demonstrated in multiple allergic / atopic indications by the IL-4Rα monoclonal antibody dupilumab and JAK inhibitors that block the IL-4 / 13 signaling pathway. Therefore, targeting STAT6 for the treatment of Th2 inflammatory diseases (such as atopic dermatitis or asthma) has received genetic and clinical validation. However, in clinical practice, dupilumab has shown moderate efficacy and is used in only a small number of patients. Oral JAK inhibitors (such as upadacitinib) have boxed warnings regarding serious infections, malignancies, adverse cardiac events, and thrombosis. Orally administered, safe, and effective small-molecule STAT6 inhibitors offer a differentiated alternative to injectable immunotherapies and JAK inhibitors, avoiding the complexity and cost of biologics such as monoclonal antibodies. However, because STAT6 functions through protein-protein and protein-DNA interactions, developing highly active and selective STAT6 inhibitors is challenging, and no drugs in this field have yet been approved for marketing. Summary of the Invention

[0004] In a first aspect, the present invention provides compounds of formula (A), their stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0005] (A)

[0006] in, R' is -C(O)NR a R b -NR a -C(O)NR a R b Optional substitutions include: 5-12 membered heterocyclic alkyl, 5-12 membered heterocyclic alkenyl, and 5-12 membered heteroaryl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C1-6 oxane; R a R b They are hydrogen, deuterium, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl; R is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, amino-C 1-6 Alkyl-, C 1-6 Oxyalkyl, N-acetamido-C 1-6 Alkyl-, C 1-6 alkyl-amino-formyl-, N-methyl-C 1-6 alkyl-amino-formyl-, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-, C 1-6 Alkyl-4-6-membered heterocyclic alkyl-, 5-6-membered heteroaryl, phenyl, C 1-6 Alkyl-5-6-membered heteroaryl-, C 1-6 alkyl-phenyl-, 5-6-membered heteroaryl-, C 1-6 Alkyl-5-6-membered heteroaryl-5-6-membered heteroaryl-,-C(=O)NR 11 R 12 -S(O)2NR 11 R 12 hydroxyl C 1-6 Alkyl-5-6-membered heteroaryl-, amino C 1-6 Alkyl-5-6-membered heteroaryl-hydroxy C 1-6 Alkyl-4-6-membered heterocyclic alkyl-, amino-C 1-6 Alkyl-4-6-membered heterocyclic alkyl-,-C 0-2 Alkylene-NR 11 -C(O)NR 11 R 12 -C 0-2 Alkylene C(O)NR 11 R 12 ; R'' represents hydrogen, deuterium, or -C. 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; Ring A is an 8-15 member heteroaryl group; R 11 For hydrogen, deuterium, -C 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino-C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 Thioalkyl; R A Each time it appears, it is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 -P(O)R a4 R a5 -NR a2 R a3 Optional replacement: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 cycloalkyl, C 4-10Cycloalkenyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl, carboxyl, amino, -N(CH3)2, -NHCH3; R a1 R a2 R a3 R a4 R a5 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl; each substituent is independently selected from: deuterium, hydroxyl, halogen, amino, oxo, C 1-6 Alkyl, C 1-6 oxane, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 oxane; X1 is CR x1 Or N; X2 is CR x2 Or N; X4 is CR x4 Or N; X5 is CR x5 Or N; and X1, X2, X4, and X5 are not all N at the same time; Rx1, Rx2, Rx4, and Rx5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; Y1, Y2, Y3, and Y4 are each independently CR Y1 CR Y2 CR Y3 CR Y4 Or N; and Y1, Y2, Y3, Y4 are not all N at the same time; R Y1 R Y2 R Y3 R Y4 Each element is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; m is 1, 2, 3, or 4; The prerequisite is that ring A is not , , , , , ; The end is the one that connects to the carbonyl group; Unless otherwise stated, the heteroatoms in the above heteroalkyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0007] The present invention also provides compounds of formula (I), their stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0008] (I)

[0009] in, R is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, amino-C 1-6 Alkyl-, C 1-6 Oxyalkyl, N-acetamido-C 1-6 Alkyl-, C 1-6 alkyl-amino-formyl-, N-methyl-C 1-6 alkyl-amino-formyl-, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-, C 1-6 Alkyl-4-6-membered heterocyclic alkyl-, 5-6-membered heteroaryl, phenyl, C 1-6 Alkyl-5-6-membered heteroaryl-, C 1-6 alkyl-phenyl-, 5-6-membered heteroaryl-, C 1-6 Alkyl-5-6-membered heteroaryl-5-6-membered heteroaryl-,-C(=O)NR 11 R 12 -S(O)2NR 11 R 12 ; Ring A is an 8-12 membered heteroaryl group; R 11 For hydrogen, deuterium, or optional substitution: C1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino-C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 Thioalkyl; R A Each time it appears, it is independently hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 -P(O)R a4 R a5 -NR a2 R a3 Optional replacement: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl; R a1 R a2 R a3 R a4 R a5 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl; each substituent is independently selected from: deuterium, hydroxyl, halogen, amino, oxo, C 1-6 Alkyl, C 1-6 oxane, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 oxane; X1 is CR x1 Or N; X2 is CR x2 Or N; X4 is CR x4 Or N; X5 is CR x5 Or N; and X1, X2, X4, and X5 are not all N at the same time; Rx1, Rx2, Rx4, and Rx5 are independently selected from hydrogen, deuterium, halogen, cyano, and C, respectively. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; Y1, Y2, Y3, and Y4 are each independently CR Y1 CR Y2 CR Y3 CR Y4 Or N; and Y1, Y2, Y3, Y4 are not all N at the same time; R Y1 R Y2 R Y3 R Y4 Each element is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; m is 1, 2, 3, or 4; The prerequisite is that ring A is not , , , , , ; The end is the one that connects to the carbonyl group; Unless otherwise stated, the heteroatoms in the above heteroalkyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0010] In the compounds of formula (A) or formula (I) above: In some implementations, R' is -C(O)NR a R b -NR a -C(O)NR a R b Optional substitutions include: 5-10 membered heterocyclic alkyl, 5-10 membered heterocyclic alkenyl, and 5-10 membered heteroaryl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, oxo, C 1-3 Alkyl, C 1-3 Oxyalkyl, phenyl, 5-6 quinone heteroaryl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Oxyalkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane; Among them, R a R b They are hydrogen, deuterium, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl; further, R a R b They are, independently, hydrogen, deuterium, methyl, and ethyl; further, R a R b They are hydrogen and methyl groups, which are independent of each other. In some embodiments, R' is optionally substituted: a 5-membered heterocyclic alkenyl group or a 5-membered heteroaryl group; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, halogen, cyano, oxo, C 1-3 Alkyl, C 1-3 Oxyalkyl, phenyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Oxyalkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane; In some implementations, R' is , ; In some implementations, R' is , Further optimization, R' is ; In some implementations, R is C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, amino-C 1-4 Alkyl-, C 1-4 Oxyalkyl, N-acetamido-C 1-4 Alkyl-, C 1-4 alkyl-amino-formyl-, N-methyl-C 1-4 alkyl-amino-formyl-, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-, C 1-4 Alkyl-4-6-membered heterocyclic alkyl-, 5-6-membered heteroaryl, phenyl, C 1-4 Alkyl-5-6-membered heteroaryl-, C 1-4 alkyl-phenyl-, 5-6-membered heteroaryl-, C 1-4 Alkyl-5-6-membered heteroaryl-5-6-membered heteroaryl-,-C(=O)NR 11 R 12 -S(O)2NR 11 R 12 hydroxyl C 1-4 Alkyl-5-6-membered heteroaryl-, amino C 1-4 Alkyl-5-6-membered heteroaryl-hydroxy C 1-4 Alkyl-4-6-membered heterocyclic alkyl-, amino-C 1-4 Alkyl-4-6-membered heterocyclic alkyl-,-C 0-2 Alkylene-NR 11 -C(O)NR 11 R 12 -C 0-2 Alkylene C(O)NR 11 R 12 ; R 11 For hydrogen, deuterium, -C 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-3 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino-C 1-4 Alkyl, deuterated C 1-4 Oxyalkyl, halogenated C 1-4 Oxyalkyl, deuterated C 1-4 Thioalkyl, halogenated C 1-4 Thioalkyl; In some implementations, R is -C(=O)NR 11 R 12 -S(O)2NR 11 R 12 hydroxyl C 1-3 alkyl-5-6-membered heteroaryl-,-methylene-NR 11 -C(O)NR 11 R 12 -NR 11 -C(O)NR 11 R 12 ,-methylene C(O)NR 11 R 12 ;; R 11 For hydrogen, deuterium, methylene-OP(O)(OH)2, or optionally substituted: C 1-4 Alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-3 Alkyl, C 3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; In some implementations, R is -C(=O)NHR 12 -S(O)2NHR 12 ; R 12 For hydrogen, deuterium, or optional substitution: C 1-3 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkenyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; further preferred, R 12 The substituted group is hydrogen, deuterium, or optionally substituted: methyl, ethyl, isopropyl, 5-6 membered heteroaryl, 6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl; further preferably, R 12 For hydrogen, methyl or , , , , , , , or , R1 and R2 are hydrogen, deuterium, halogen, cyano, amino, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or hydroxyethyl; more preferably, R 12 For hydrogen, methyl, , , , , , , , , , , , , ; In some implementations, R is , , , , , , , , , , , , , , , , , , , Further optimization, R is ; In some implementations, R'' is hydrogen, deuterium, or -C. 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-4 Alkyl, C 1-4 Oxyalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; In some implementations, R'' is hydrogen, deuterium, or -C. 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-3 Alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; In some implementations, R'' is hydrogen, methyl, , ; In some implementations, ring A is an 8-13 membered heteroaryl group; In some embodiments, ring A is an 8-10 membered heteroaryl group; more preferably, ring A is an 8-9 membered heteroaryl group. In some implementations, ring A is or Ring A is In the case where (i) ring C is phenyl or a 5-6-membered heteroaryl, and ring B is a 5-membered heteroaryl; or (ii) ring C is a 5-membered heteroaryl, and ring B is phenyl or a 6-membered heteroaryl, and Not for , , , , , ; or ring A is In this ring, ring C is phenyl or a 5-6 membered heteroaryl, ring B is a 5 membered heteroaryl, and ring D is a 5-6 membered heterocyclic group; Further optimization, ring A is , , , , , , , , , , , , , , , , , , , , , , ; The end is the one that connects to the carbonyl group; Further optimization, ring A is ; The end is the one that connects to the carbonyl group; In some implementation schemes, R A Individually, they can be hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 -P(O)R a4 R a5 -NR a2 R a3 Or, alternatively: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 oxane, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl, carboxyl, amino, -N(CH3)2, -NHCH3; R a1 R a2 R a3 R a4 R a5C is selected independently from hydrogen, deuterium, or optionally substituted: 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl; each substituent is independently selected from: deuterium, hydroxyl, halogen, amino, oxo, C 1-3 Alkyl, C 1-3 oxane, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 oxane; In some implementation schemes, R A Individually, they can be hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 Or, alternatively: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 oxane, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, carboxyl, -N(CH3)2; R a1 R a2 R a3 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-4 Alkyl, C 3-6 Cycloalkyl; each of the substituents is independently selected from: deuterium, hydroxyl, halogen, amino, oxo group; In some implementation schemes, R A They are, independently, hydrogen, deuterium, halogens (F, Cl, Br), cyano, and -S(O)2R. a1 Or, alternatively: C 1-4 Alkyl, C 1-4 oxane, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, carboxyl, -N(CH3)2; R a1 Selected from hydrogen, deuterium, and C1-4 alkyl; In some implementation schemes, R A Individually, they are hydrogen, F, Cl, cyano, oxo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methanesulfonyl, oxetane, difluoromethyl, trifluoromethyl, deuterated methyl, , , , , , , , , Further optimization, R A Each of the following can be independently represented as hydrogen, F, Cl, cyano, methyl, or ethyl; more preferably, R A They can be identified independently as F, Cl, methyl, and ethyl; In some implementation schemes, X1, X2, X4, and X5 are independently designated as CRx1, CRx2, CRx4, and CRx5, respectively. In some implementation schemes, X1, X4, and X5 are independently CRx1, CRx4, and CRx5, respectively; and X2 is N; In some implementation schemes, X2, X4, and X5 are independently CRx2, CRx4, and CRx5, respectively; and X1 is N; In some implementations, Rx1, Rx2, Rx4, and Rx5 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, halogenated C 1-4 Alkyl, Halogenated C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; In some implementations, Rx1, Rx2, Rx4, and Rx5 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; In some embodiments, Rx1, Rx2, Rx4, and Rx5 are independently hydrogen, deuterium, halogen, and hydroxyl, respectively; more preferably, Rx1, Rx4, and Rx5 are all hydrogen; Rx2 is hydrogen, F, Cl, or hydroxyl; furthermore, Rx1, Rx2, Rx4, and Rx5 are all hydrogen. In some implementation schemes, X1, X2, X4, and X5 are all CH; In some implementation schemes, X1, X4, and X5 are all CH, and X2 is N; In some implementation schemes, Y1, Y2, Y3, and Y4 are each independently designated as CR. Y1 CR Y2 CR Y3 CR Y4 ; In some implementation schemes, Y1 is N; and Y2, Y3, and Y4 are each independently CR. Y2 CR Y3 CR Y4 ; In some implementations, Y2 is N; and Y1, Y3, and Y4 are each independently CR. Y1 CR Y3 CR Y4 ; In some implementation schemes, R Y1 R Y2 R Y3 R Y4 The components are hydrogen, deuterium, halogen, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, halogenated C 1-4 Alkyl, Halogenated C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; In some implementation schemes, R Y1 R Y2 R Y3 R Y4 The components are hydrogen, deuterium, halogen, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; In some implementation schemes, R Y1 R Y2 R Y3 R Y4 Hydrogen and halogen are respectively independent; further preferred, R Y1 R Y2 R Y3 R Y4 Hydrogen and F are independently selected; further preferred, R Y1 R Y2 R Y3 R Y4 All are hydrogen; In some implementation schemes, Y1, Y2, Y3, and Y4 are all CH; In some implementations, m is 1 or 2; In some implementations, m is 1; In some embodiments, the compound represented by formula (I) is a compound of formula (II-A) or formula (II-B) or the compound represented by it: ,

[0011] (Ⅱ-A) (Ⅱ-B)

[0012] Among them, rings A and R A ,X1,X2,Y1,Y2,Y3,Y4,m,R 12 As described in compound (I); In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-A) or formula (III-B): ,

[0013] (Ⅲ-A) (Ⅲ-B)

[0014] Among them, rings A and R A X1, X2, Y1, Y2, Y3, Y4, m are as described in compound (I); In some embodiments, the compound represented by formula (I) is a compound represented by formula (IV):

[0015] (Ⅳ)

[0016] Among them, R A ,X1,X2,Y1,Y2,Y3,Y4,R 12 As described in compounds of formula (I) or (A), wherein Z is CH or N.

[0017] In some embodiments, the compound represented by formula (A) is a compound represented by formula (A1):

[0018] (A1)

[0019] Among them, rings A and R A X1, X2, R'', R are as described in compound (A); In the above embodiments of the present invention, except for the defined groups, the definitions of other groups are as described in the present invention, and will not be described one by one to save space.

[0020] The above embodiments of the present invention can be combined arbitrarily, and the resulting embodiments are all embodiments of the present invention.

[0021] In a second aspect, the present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compounds are selected from:

[0022] Thirdly, the present invention provides a method for preparing the compound represented by formula (I). Including but not limited to the following methods: General preparation method one:

[0023] Rings A and R A X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, m, R, R' are defined as above. Hal is a halogen, such as chlorine, bromine, or iodine. M1 is boric acid and boric acid analogues such as B(OH)2, B(Pin), and BF3K.

[0024] Compounds A1 and A2 react under alkaline conditions (potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, etc.) in the presence of a palladium catalyst (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, etc.) and in the presence or absence of ligands (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, etc.) to yield compound A3. Alternatively, A1 reacts with boric acid derivatives (such as pinacol diborate, neopentyl diborate, etc.) in the presence of a palladium catalyst (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, etc.) under alkaline conditions (potassium acetate, potassium phosphate, cesium carbonate, sodium carbonate, etc.) to obtain compound A4. Compounds A4 and A5 react in the presence of a palladium catalyst (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, etc.) and ligands (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, etc.) under alkaline conditions (potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, etc.) to yield compound A3. Compound A3 is then hydrolyzed under alkaline conditions (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) to yield compound A4. Compounds A4 and A5 react in a condensing agent ( N , N , N ', N '-Tetramethylchloromethanesulfonyl hexafluorophosphate, O -(7-azabenzotriazol-1-yl)- N , N , N ', N '-Tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-chloro-1-methylpyridine iodide, etc.) and under alkaline conditions ( N -Methylimidazole, triethylamine, N , N The reaction of diisopropylethylamine, etc., yields compound (A).

[0025] General preparation method two:

[0026] Rings A and R AX1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, m, R, R' are defined as above. Hal is a halogen, such as chlorine, bromine, or iodine. M1 is boric acid and boric acid analogues such as B(OH)2, B(Pin), and BF3K.

[0027] B1 hydrolyzes under alkaline conditions (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) to give compound B2. Compounds B2 and B3 react in a condensing agent ( N , N , N ', N '-Tetramethylchloromethanesulfonyl hexafluorophosphate, O -(7-azabenzotriazol-1-yl)- N , N , N ', N '-Tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-chloro-1-methylpyridine iodide, etc.) and under alkaline conditions ( N -Methylimidazole, triethylamine, N , N The reaction of compounds B4 and B5 with palladium catalysts (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, etc.) in the presence or absence of ligands (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, etc.) under alkaline conditions (potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, etc.) yields compound (I). Alternatively, B4 reacts with boric acid derivatives (such as pinacol diborate, neopentyl diborate, etc.) in the presence of a palladium catalyst (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, etc.) under alkaline conditions (potassium acetate, potassium phosphate, cesium carbonate, sodium carbonate, etc.) to yield compound B6. Compounds B6 and B7 react under alkaline conditions (potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, etc.) in the presence of a palladium catalyst (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, etc.) and in the presence or absence of ligands (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, etc.) to give compound (A).

[0028] Fourthly, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention (a compound of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), or formula (IV)) or a compound of the second aspect of the present invention, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, optionally, the pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0029] Fifthly, the present invention provides the use of the compounds described in the first aspect of the present invention (compounds represented by formula (I), (II-A), (II-B), (III-A), (III-B), and (IV)) or the compounds described in the second aspect of the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the fourth aspect, as a medicament or in the preparation of a medicament; preferably, the medicament is a medicament for regulating STAT6 activity; more preferably, the medicament is a medicament for preventing and / or treating diseases regulated by STAT6; more preferably, the medicament is a medicament for treating and / or preventing diseases or conditions caused by STAT6 abnormalities; more preferably, the medicament is a medicament for treating and / or preventing STAT6-related allergic diseases and inflammatory diseases, autoimmune disorders, and other diseases or conditions; more preferably, the medicament is a medicament for treating and / or preventing Th2-type inflammatory diseases, autoimmune diseases, tumors, and other diseases or conditions.

[0030] In some embodiments, the use of the compounds of the first aspect (compounds shown in formula (I), (II-A), (II-B), (III-A), (III-B), and (IV)) or the compounds of the second aspect, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the fourth aspect, in the preparation of a medicament for treating and / or preventing diseases or conditions caused by STAT6 abnormalities; preferably, the medicament is for treating and / or preventing STAT6-related allergic and inflammatory diseases, autoimmune disorders, etc.; more preferably, the medicament is for treating and / or preventing atopic dermatitis (AD). Diseases or conditions such as asthma, allergic rhinitis (AR), chronic spontaneous urticaria (CSU), eosinophilic esophagitis (EoE), nodular prurigo (PN), chronic sinusitis with nasal polyps (CRSwNP), adult bullous pemphigoid (BP), certain forms of chronic obstructive pulmonary disease (COPD), and tumors (including malignant lymphoma, pancreatic cancer, colorectal cancer, prostate cancer, and breast cancer).

[0031] In a sixth aspect, the present invention provides a method for preventing and / or treating STAT6-regulated diseases using compounds of the first aspect of the present invention (compounds represented by formula (I), (II-A), (II-B), (III-A), (III-B), or (IV)) or compounds of the second aspect, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the fourth aspect; more preferably, a method for treating and / or preventing diseases or conditions caused by STAT6 abnormalities; more preferably, a method for treating and / or preventing STAT6-related allergic diseases and inflammatory diseases, autoimmune disorders, and other diseases or conditions; more preferably, the pharmaceutical is a method for treating and / or preventing Th2-type inflammatory diseases, autoimmune diseases, tumors, and other diseases or conditions.

[0032] In a seventh aspect, the present invention provides synthetic intermediates for the compounds of the present invention or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof, such as synthetic intermediates in general preparation methods or synthetic intermediates in specific embodiments.

[0033] definition

[0034] Unless otherwise stated, the following terms as used in this invention have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0035] C in this article m-n This refers to the part having an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0036] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl groups, more preferably containing 1-4 carbon atoms (i.e., C464-C ... 1-4 Alkyl groups, more preferably containing 1-3 carbon atoms (i.e., C464-C ... 1-3 Alkyl), for example, "C 1-6"Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0037] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0038] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylinyl group), 2-3 carbon atoms (i.e., C 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0039] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, I; preferably F, Cl, Br; more preferably F, Cl.

[0040] The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms (e.g., 3, 4, 5, 6, 7, 8) or all of the hydrogen atoms are replaced by a halogen, such as C. 1-6 Alkyl substitution by halogens refers to C 1-6 Haloalkyl groups, such as CCl3, CH2F, CHF2, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0041] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl. For example, a cycloalkyl group may contain 3 to 16 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). Even further, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include those having 5 to 12, more such as 7 to 12 or 5 to 10 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or arranged in a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include rings arranged in a bicyclic arrangement selected from the [5,6] and [6,6] ring systems.

[0042] Unless otherwise specified, "cycloalkenyl" refers to a system composed of monocyclic, bicyclic, and spirocyclic hydrocarbon rings as daughter groups; however, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C12-C22). 3-12 Cycloalkenyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 (Cycloalkenyl).

[0043] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbon atoms (and associated hydrogen atoms) are replaced by oxygen, such as "alkoxy" or "alkoxyalkyl". Examples include methoxy, ethoxy, propoxy, methoxypropyl, etc. The term oxaalkyl means as understood in the art [see Nomenclature and Index of Chemical Substances for Chemical Extraction, published by the American Chemical Society, 196, but not limited to 127(a)], that is, it refers to a compound in which oxygen is bonded to its adjacent atoms by a single bond (forming an ether bond); it does not refer to the double oxygen bond found in the carbonyl group.

[0044] "Alkoxy" refers to -O-alkyl, and the alkyl group is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0045] Unless otherwise specified, the terms "thioalkyl" and "nitroalkyl" refer to the replacement of oxygen with sulfur or nitrogen in the term "oxaalkyl".

[0046] Unless otherwise specified, the term "aminoalkyl" refers to -NH-alkyl, -N-dialkyl, -alkyl-NH2, -alkyl-NH-alkyl, -alkyl-N-dialkyl, and -dialkyl-N-alkyl, wherein the alkyl group is defined as above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, -NH-methyl, -NH-ethyl, -NH-isopropyl, -methylamino, -ethylamino, -isopropylamino, -dimethylamino, and -N-methylethylamino.

[0047] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, having a non-aromatic structure, containing 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-14 ring atoms, 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused (or fused) and bridged heterocyclic groups. The heterocyclic group may be attached (e.g., bridged, spiro-attached, or fused (or fused)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point must be on a carbon atom or heteroatom of the heterocyclic group. Each heterocyclic group or other cyclic group may be optionally substituted, as defined herein with respect to each individual section.

[0048] The term "heterocyclic alkyl" refers to a saturated "heterocyclic group" as defined above, comprising 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it comprises 3-14 ring atoms, 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms, or 7-9 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Bicyclic or polycyclic heterocyclic alkyl groups include spirocyclic, fused (or fused) ring, and bridged ring heterocyclic alkyl groups. Examples of bicyclic or polycyclic heterocyclic alkyl groups may include, but are not limited to, 4,6-diazaspiro[2,4]heptane, 6-oxa-4-azaspiro[2,4]heptane, 5,7-diazaspiro[3,4]octane, 4-azaspiro[2,4]heptane, and hexahydro-1 H -pyrrolo[1,2- c Imidazole, etc. The heterocyclic alkyl group may be attached (e.g., bridged, screwed, or fused (or paralleled)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point to the parent group must be on a carbon atom or heteroatom of the heterocyclic alkyl group. Each heterocyclic alkyl group or other cyclic group may be optionally substituted, as defined herein with respect to each individual part.

[0049] The term "heterocyclic alkenyl" refers to a partially unsaturated heterocyclic group as defined above, comprising 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it comprises 3-14 ring atoms, 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Bicyclic or polycyclic heterocyclic alkenyl groups include spirocyclic, fused (or fused) ring, and bridged ring heterocyclic alkenyl groups. The heterocyclic alkenyl group may be attached (e.g., bridged, helicaled, or fused (or paralleled)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point to the parent group must be on a carbon atom or heteroatom of the heterocyclic alkenyl group. As defined herein with respect to each individual section, each heterocyclic alkenyl or other cyclic group may be optionally substituted.

[0050] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms (6-16 membered aryl), 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, or pyrene. "Aryl" also includes ring systems in which the aryl group as defined above is fused or fused with one or more cycloalkyl, heterocyclic, or heteroaryl groups, but the point of attachment to the parent group must be on a carbon atom of the aryl group. As defined herein with respect to each individual section, each aryl or other cyclic group may be optionally substituted.

[0051] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four; more preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, and pyrazolo[1,5-a]. Pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc. "Heteroaryl" also includes ring systems in which the heteroaryl groups as defined above are fused or fused with one or more cycloalkyl, heterocyclic, or aryl groups, but the point of attachment to the parent group must be on an atom of the heteroaryl group. As defined herein for each individual part, each aryl or other cyclic group may be optionally substituted.

[0052] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0053] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include optical isomers, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (or cis / trans isomers), and trans-reactive isomers. Any mixture of stereoisomers can be separated into pure or substantially pure optical isomers, geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0054] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0055] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0056] Unless otherwise indicated, the structural formulas described in this invention include all "isotope derivatives," which are compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 2 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized by starting with a labeled starting material, using known synthetic techniques similar to those used to synthesize non-isotope-labeled compounds.

[0057] Unless otherwise indicated, the structural formulas described in this invention also include their terms "solvate" or "solvent," where "solvate" or "solvent" refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0058] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6The alkoxy group is substituted by one or more substituents, wherein the oxo group refers to a double bond formed by replacing two H atoms at the same substitution position with the same O atom group. Preferably, the substituents are selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C. 2-4 Alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or C 1-4 The alkoxy group is substituted by one or more substituents. Preferably, the substituents are selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaromatic, wherein the C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaromatic rings may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 It is replaced by one or more substituents in the alkoxy group.

[0059] The terms “optional” or “optional” mean that the event or situation described below may but does not have to happen, and the description includes the occasions in which the event or situation does not occur.

[0060] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0061] The term “subject” can also be referred to as “individual” or “subject”, referring to a cell or animal, including but not limited to mammals such as laboratory animals or humans.

[0062] "Effective amount" means an amount of the compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease or the relief of its symptoms. In some embodiments, for example, the amount may be a dose that can induce a specific response in cells, or a dose that exerts a therapeutic effect on a disease in a model animal. The specific amount will vary depending on, for example, the specific compound selected, the type of subject and their age / pre-existing health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue of administration, and the physical delivery system carrying it.

[0063] Some of the compounds in this invention are optically active. The compounds in this application can be racemic, optical isomers or mixtures thereof. The optical isomers in the compounds of this invention can be synthesized either by using the starting materials of the optical isomers or by separating the racemic mixtures.

[0064] Unless otherwise specified, the term "pharmaceuticalally acceptable carrier," also known as "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable excipient," refers to a generally recognized medium in the field of delivering bioactive agents to animals (specifically, mammals). Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These include (but are not limited to) the type and nature of the formulated active agent, the subject to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. The preparation of pharmaceutical compositions described herein includes, but is not limited to, mixing, for example, the compounds described in the first or second aspect, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier.

[0065] The above embodiments represent exemplary embodiments of the present invention, but the present invention is not limited to the above embodiments. Furthermore, the various technical features in the above embodiments of the present invention can be combined with each other to constitute one or more new technical solutions, and these new technical solutions also fall within the scope of the present invention, as long as such new technical solutions are technically feasible. Detailed Implementation

[0066] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0067] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The instruments used for NMR determination were a Bruker 400 MHz and / or a Varian 400 MHz; the instruments used for LC-MS were an Agilent 1260 Infinity II-6120 / 6125MSD and / or a Waters Acquity Qda; and the instruments used for HPLC were a Waters Acquity UPLC and / or a Shimadzu LC2030 / LC-2010C HT / LC-2010A HT / LC-2050C and / or an Agilent 1260 Infinity II.

[0068] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0069] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0070] Intermediate 1-3: 3-amino- N -(1-methyl-1 H Preparation of 3-pyrazole-3-yl)benzamide

[0071] first step: N -(1-methyl-1 H Preparation of pyrazol-3-yl)-3-nitrobenzamide (intermediates 1-2)

[0072] Dissolve 1.00 g of 3-nitrobenzoyl chloride in 10 mL of dichloromethane, and then add 1-methyl-1-nitrobenzoyl chloride sequentially. H3-Pyrazole-3-amine (0.52 g) and triethylamine (2.34 mL). The reaction was stirred at 25 °C for 1 hour. The reaction was detected by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%-50%) to give the title compound (1.04 g). LCMS (ESI) [M+H] + = 247.2.

[0073] Step 2: 3-Amino- N -(1-methyl-1 H Preparation of pyrazol-3-yl)benzamide (intermediate 1-3)

[0074] Intermediate 1-2 (940 mg) was dissolved in methanol (10 mL), and 10 wt% palladium / carbon (122 mg) was added. The reaction was carried out under a hydrogen atmosphere and stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (918 mg, crude product). LCMS (ESI) [M+H] + = 217.1.

[0075] Intermediate 8-3: 3-amino- N -(1-methyl-1 H Preparation of 1,2,4-triazol-3-yl)benzamide

[0076] Referring to the synthetic methods of intermediates 1-3, 1-methyl-1 H -Pyrazole-3-amine (1-1) is replaced with 1-methyl-1 H -1,2,4-triazol-3-amine, following a similar method and procedure, yielded the title compound (220 mg). LCMS (ESI) [M+H] + = 218.0

[0077] Intermediate 19-2: 5-chloro-1-methyl-1 H -pyrazolo[4,3- b Preparation of pyridine-3-carboxylic acid

[0078] Step 1: 5-Chloro-1-methyl-1 H -pyrazolo[4,3- b Preparation of methyl pyridine-3-carboxylate (intermediate 19-1)

[0079] 5-chloro-1 H -pyrazolo[4,3- bMethyl pyridine-3-carboxylate (1.65 g) dissolved in N , N Dimethylformamide (20 mL) was added sequentially with potassium carbonate (1.62 g) and methyl iodide (1.16 g) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine (100 mL × 3). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%–60%) to give the title compound (461 mg). LCMS (ESI) [M+H] + = 226.0

[0080] Step 2: 5-Chloro-1-methyl-1 H -pyrazolo[4,3- b Preparation of pyridine-3-carboxylic acid (intermediate 19-2)

[0081] Intermediate 19-1 (461 mg) was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL). 4M sodium hydroxide aqueous solution (5 mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL), and the pH was adjusted to 1 with 1N hydrochloric acid solution. Extraction was performed with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (320 mg, crude product). LCMS (ESI) [M+H] + = 211.9

[0082] Intermediate 40-6: 5-bromo-4-cyano-1-methyl-1 H Preparation of methyl indazole-3-carboxylate

[0083] Step 1: 5-Bromo-3-iodine-1 H Preparation of methyl indazole-4-carboxylate (intermediate 40-1)

[0084] Methyl 5-bromo-1H-indazole-4-carboxylate (1500 mg) was dissolved in... N , NIn 15 mL of dimethylformamide, potassium hydroxide (660 mg) and elemental iodine (1791 mg) were added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with ice water (20 mL), extracted with ethyl acetate (40 mL × 2), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2000 mg, crude product). LCMS (ESI) [M+H] + =380.8.

[0085] Step 2: 5-Bromo-3-iodo-1-methyl-1 H Preparation of methyl indazole-4-carboxylate (intermediate 40-2)

[0086] Dissolve intermediate 40-1 (2.00 g, obtained from the previous step) in... N , N In dimethylformamide (20 mL), a 60 wt% sodium hydride mineral oil mixture (315 mg) was added at 0 °C, and the mixture was stirred at room temperature for 30 minutes. Iodomethane (0.39 mL) was then added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with water (30 mL), resulting in the precipitation of a solid. The solid was filtered, washed with water (20 mL), and lyophilized to obtain the title compound (1.50 g, crude product). LCMS (ESI) [M+H] + =394.8.

[0087] Step 3: 5-Bromo-3-iodo-1-methyl-1 H Preparation of -indazole-4-carboxylic acid (intermediate 40-3)

[0088] Intermediate 40-2 (1.50 g, obtained from the previous step) was dissolved in a mixed solution of methanol (15 mL) and water (5 mL), and sodium hydroxide (1520 mg) was added. The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL). The pH was adjusted to 5-6 with 2N hydrochloric acid aqueous solution. The mixture was filtered, and the filter cake was washed with water (20 mL) and dried to obtain the title compound (1.40 g, crude product). LCMS (ESI) [M+H] + =380.9

[0089] Step 4: 5-Bromo-3-iodo-1-methyl-1 H Preparation of 4-indazole-4-carboxamide (intermediate 40-4)

[0090] Dissolve intermediate 40-3 (1.35 g, obtained from the previous step) in... N , N Add to dimethylformamide (20 mL) O -(7-azabenzotriazol-1-yl)- N , N , N ', N '-Tetramethylurea hexafluorophosphate (2021 mg), N , N A solution of diisopropylethylamine (1.2 mL) and 0.4 M ammonia in tetrahydrofuran (17.7 mL) was stirred at 50 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give the title compound (1.10 g). LCMS (ESI) [M+H] + =379.8.

[0091] Step 5: 5-Bromo-4-cyano-3-iodo-1-methyl-1 H Preparation of methyl indazole-4-carboxylate (intermediate 40-5)

[0092] Intermediate 40-4 (1030 mg) was dissolved in phosphorus oxychloride (10 mL), and the reaction solution was stirred at 70 °C for 3 hours under a nitrogen atmosphere. The reaction was confirmed by LCMS, and a solid precipitated from the reaction solution. The solid was filtered, lyophilized, and the crude compound (500 mg) was obtained. LCMS (ESI) [M+H] + =361.8.

[0093] Step 6: 5-Bromo-4-cyano-1-methyl-1 H Preparation of methyl indazole-3-carboxylate (intermediate 40-6)

[0094] Intermediate 40-5 (400 mg, obtained from the previous step) was dissolved in methanol (5 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (81 mg) and triethylamine (0.3 mL) were added. The reaction mixture was stirred at 80 °C for 16 hours under a carbon monoxide atmosphere and at 1 atm. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give the title compound (100 mg). LCMS (ESI) [M+H]+ =294.0.

[0095] Preparation of intermediate 41-3: methyl 5-bromo-1,4-dimethyl-1H-indazole-3-carboxylate

[0096] Step 1: 5-Bromo-3-iodo-4-methyl-1 H Preparation of -indazole (intermediate 41-1)

[0097] 5-bromo-4-methyl-1 H -Indazole (1.00 g) soluble in N , N In 15 mL of dimethylformamide, potassium hydroxide (532 mg) and elemental iodine (1443 mg) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with water (25 mL), resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed with water (20 mL) and lyophilized to obtain the title compound (1.50 g, crude product). LCMS (ESI) [M+H] + =336.9

[0098] Step 2: 5-Bromo-3-iodo-1,4-dimethyl-1 H Preparation of -indazole (intermediate 41-2)

[0099] Dissolve intermediate 41-1 (1.50 g, obtained from the previous step) in... N , N In 15 mL of dimethylformamide, a mixture of 60 wt% sodium hydride (267 mg) and mineral oil was added at 0 °C. The mixture was stirred at room temperature for 0.5 h, followed by the addition of 0.36 mL of iodomethane. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 h. LCMS analysis confirmed the reaction was complete. The reaction mixture was quenched in 30 mL of ice water, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed with 30 mL of water and lyophilized to obtain the title compound (1550 mg, crude product). LCMS (ESI) [M+H] + =350.9.

[0100] Step 3: 5-Bromo-1,4-Dimethyl-1 H Preparation of methyl indazole-3-carboxylate (intermediate 41-3)

[0101] Intermediate 41-2 (1.55 g, obtained from the previous step) was dissolved in anhydrous methanol (10 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (167 mg) and triethylamine (1.3 mL) were added. The reaction mixture was reacted in a sealed container at 90 °C for 16 hours under a carbon monoxide atmosphere. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30-100%) to give the title compound (880 mg). LCMS (ESI) [M+H] + =282.9.

[0102] Intermediate 69-2: 5-bromo-1-ethyl-4-fluoro-1 H Preparation of methyl indazole-3-carboxylate

[0103] Step 1: 5-Bromo-1-ethyl-4-fluoro-3-iodine-1 H Preparation of -indazole (intermediate 69-1)

[0104] 5-bromo-4-fluoro-3-iodine-1 H -Indazole (500 mg) dissolved in N , N Dimethylformamide (10 mL) was added to a mixture of 60 wt% sodium hydride (88 mg) and mineral oil at 0 °C under nitrogen protection. After stirring at 0 °C for 0.5 hours, iodoethane (343 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 3%–10%) to give the title compound (353 mg). LCMS (ESI) [M+H] + = 368.8

[0105] Step 2: 5-Bromo-1-ethyl-4-fluoro-1 H Preparation of methyl indazole-3-carboxylate (intermediate 69-2)

[0106] Intermediate 69-1 (303 mg) was dissolved in methanol (20 mL), followed by the addition of triethylamine (166 mg) and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (60 mg). The reaction mixture was stirred at 90 °C for 16 hours under a carbon monoxide atmosphere. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–30%) to give the title compound (157 mg). LCMS m / z (ESI) [M+H] + =301.0

[0107] Preparation of intermediate 70-3: methyl 5-bromo-4-chloro-1-methyl-1H-indazole-3-carboxylate

[0108] Referring to the synthetic method of intermediate 41-3, 5-bromo-4-methyl-1 H -Indazole replaced with 5-bromo-4-chloro-1 H -Indazole, following a similar method and procedure, yielded the title compound (200 mg). LCMS (ESI) [M+H] + =302.9.

[0109] Intermediate 72-3: 5-bromo-4-fluoro-6-methyl-1 H Preparation of -indazole

[0110] Step 1: Preparation of 3-fluoro-2,5-dimethylaniline (intermediate 72-1)

[0111] 1-Fluoro-2,5-dimethyl-3-nitrobenzene (4.30 g) was dissolved in methanol (40 mL). 10 wt% palladium / carbon (400 mg) was added at room temperature, and the mixture was purged three times with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (3.40 g, crude product). LCMS (ESI) [M+H] + = 140.1.

[0112] Step 2: Preparation of 4-bromo-3-fluoro-2,5-dimethylaniline (intermediate 72-2)

[0113] Intermediate 72-1 (3.37 g, obtained from the previous step) was dissolved in dichloromethane (30 mL). At room temperature, [the solution was added] N- Bromosuccinimide (4.31 g). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was confirmed by LCMS. The reaction was quenched with ice water (200 mL), extracted with ethyl acetate (300 mL × 2), and the combined organic phases were washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%–50%) to give the title compound (3.20 g). LCMS (ESI) [M+H] + = 218.0.

[0114] Step 3: 5-Bromo-4-fluoro-6-methyl-1 H Preparation of -indazole (intermediate 72-3)

[0115] Intermediate 72-2 (1.57 g) was dissolved in acetic acid (10 mL) and water (1 mL). Sodium nitrite (546 mg) was added at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%–50%) to give the title compound (1.60 g). LCMS (ESI) [M+H] + = 229.0.

[0116] Intermediate 72-4: 5-bromo-4-fluoro-1,6-dimethyl-1 H Preparation of methyl indazole-3-carboxylate

[0117] Referring to the synthetic method of intermediate 41-3, 5-bromo-4-methyl-1 H The title compound (500 mg) was obtained by replacing the indazole with intermediate 72-3 and following a similar method and procedure. LCMS (ESI) [M+H] + =300.9.

[0118] Intermediate 74-2: 3-amino- N Preparation of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide

[0119] first step: N Preparation of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-nitrobenzamide (intermediate 74-1)

[0120] 5-amino-1,3-dimethylpyrimidine-2,4(1 H ,3 H 270 mg of 3-nitrobenzoyl chloride was dissolved in 5 mL of dichloromethane. Under ice bath conditions, 323 mg of 3-nitrobenzoyl chloride and 0.49 mL of triethylamine were added sequentially. The reaction mixture was stirred at 25 °C for 1 hour. The reaction was confirmed by LCMS. The reaction was quenched with 100 mL of saturated ammonium chloride solution, extracted with 300 mL × 2 ethyl acetate solutions, and the combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 40%–50%) to give the title compound (300 mg). LCMS (ESI) [M+H] + = 305.0.

[0121] Step 2: 3-Amino- N Preparation of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide (intermediate 74-2)

[0122] Intermediate 74-1 (270 mg) was dissolved in methanol (5 mL). At room temperature, 10 wt% palladium / carbon (20 mg) was added, and the mixture was purged three times with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (100 mg, crude product). LCMS (ESI) [M+H] + = 275.1.

[0123] Intermediate 75-2: 5-bromo-4-fluoro-1-(2-((tetrahydro-2-) H -pyran-2-yl)oxy)ethyl)-1 H Preparation of methyl indazole-3-carboxylate

[0124] Referring to the synthetic method of intermediate 69-2, iodoethane was replaced with 2-(2-bromoethoxy)tetrahydro-2- H -Pyran, following a similar method and procedure, yielded the title compound (330 mg). LCMS m / z (ESI) [M+Na] + =422.9

[0125] Intermediate 76-2: 5-bromo-1-(2-(dimethylamino)ethyl)-4-fluoro-1 H Preparation of methyl indazole-3-carboxylate

[0126] Referring to the synthetic method of intermediate 69-2, replace iodoethane with 2-bromo- N , N -Dimethyl-1-ethylamine hydrobromide, following a similar method and procedure, yielded the title compound (220 mg). LCMS (ESI) [M+H] + = 344.0

[0127] Intermediate 77-2: 1-Allyl-5-bromo-4-fluoro-1 H Preparation of methyl indazole-3-carboxylate

[0128] Following the synthetic method for intermediate 69-2, replacing iodoethane with 3-bromopropene, and adhering to similar methods and steps, the title compound (119 mg) was obtained. LCMS m / z (ESI) [M+H] + =312.9.

[0129] Intermediate 78-2: 5-bromo-4-fluoro-1-(tetrahydro-2-) H -pyran-2-yl)-1 H Preparation of methyl indazole-3-carboxylate

[0130] Step 1: 5-Bromo-4-Fluoro-3-iodide-1-(tetrahydro-2-) H -pyran-2-yl)-1 H Preparation of -indazole (intermediate 78-1)

[0131] 5-bromo-4-fluoro-3-iodine-1 H -Indazole (300 mg) was dissolved in dichloromethane (5 mL), and p-toluenesulfonic acid (30 mg) and 3,4-dihydro-2-dichloromethane were added. H -Pyran (111 mg), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 25-35%) to give the title compound (270 mg). 1 H NMR (400 MHz, DMSO-) d 6) δ 7.69 – 7.63 (m, 2H), 5.88 (dd, J1.60 – 1.54 (m, 2H).

[0132] Step 2: 5-Bromo-4-fluoro-1-(tetrahydro-2-) H -pyran-2-yl)-1 H Preparation of methyl indazole-3-carboxylate (intermediate 78-2)

[0133] Intermediate 78-1 (270 mg) was dissolved in methanol (2 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (47 mg) and triethylamine (130 mg) were added. The reaction mixture was stirred at 90 °C for 16 hours under a carbon monoxide atmosphere. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%) to give the title compound (150 mg). LCMS (ESI) [M+Na] + =378.9.

[0134] Intermediate 81-1: 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1 H Preparation of -1,2,3-triazol-4-yl)aniline

[0135] 2-(4-(3-aminophenyl)-1 H -1,2,3-triazol-1-yl)ethanol (223 mg) dissolved in N , N In dimethylformamide (5 mL), imidazole (149 mg) and tert-butyldimethylchlorosilane (247 mg) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to give the title compound (96 mg). LCMS (ESI) [M+H] + = 319.1

[0136] Intermediate 85-3: 5-chloro-4-fluoro-1-methyl-1 H-pyrazolo[3,4- c Preparation of methyl pyridine-3-carboxylate

[0137] Referring to the synthetic method of intermediate 41-3, 5-bromo-4-methyl-1 H -Indazole replaced with 5-chloro-4-fluoro-1 H -pyrazolo[3,4- c Pyridine, following a similar method and procedure, yielded the title compound (396 mg). LCMS m / z (ESI) [M+H] + =243.9.

[0138] Intermediate 88-2: 7-chloro-3-methylimidazolium [1,5- a Preparation of ethyl pyridine-1-carboxylate

[0139] Step 1: Preparation of ethyl 2-acetamido-2-(4-bromopyridin-2-yl)acetate (intermediate 88-1)

[0140] Ethyl 2-amino-2-(4-bromopyridin-2-yl)acetate (450 mg) was dissolved in dichloromethane (27 mL). Sodium bicarbonate (730 mg) and acetyl chloride (164 mg) were added under ice bath conditions. The reaction was continued under ice bath conditions for 15 minutes, followed by reaction at room temperature for 2 hours. LC-MS analysis confirmed complete reaction of the starting material. The reaction mixture was poured into water (50 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to give the title compound (230 mg). LC-MS (ESI) [M+H] + =301.0.

[0141] Step 2: 7-Chloro-3-methylimidazole [1,5- a Preparation of ethyl pyridine-1-carboxylate (intermediate 88-2)

[0142] Intermediate 88-1 (180 mg) was added to phosphorus oxychloride (3 mL) and reacted at 90 °C for 5 hours. LCMS showed complete reaction of the starting material. The reaction solution was concentrated, and the residue was diluted with dichloromethane. The organic phase was washed with sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in acetonitrile, and purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to give the title compound (80 mg). LCMS (ESI) [M+H] + =239.0.

[0143] Intermediate 94-1: N -(1-methyl-1 H Preparation of pyrazol-3-yl)-3-(methylamino)benzamide

[0144] Intermediate 1-3 (500 mg) was dissolved in methanol (10 mL), paraformaldehyde (347 mg) and sodium methoxide (625 mg) were added, and the reaction was carried out at 50 °C for 6 hours. Sodium borohydride (262 mg) was added under ice bath conditions, and the reaction was continued at 50 °C for another 4 hours. LCMS analysis showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature and quenched with water (70 mL). Extraction was performed using a 10 / 10 dichloromethane / methanol mixture (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (490 mg). LCMS (ESI) [M+H] + =231.1

[0145] Intermediate 99-2: 4-Fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazol-3-yl)carbamoyl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1 H Preparation of 3-indazole-3-carboxamide

[0146] Step 1: 5-Bromo-4-fluoro-1-methyl N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (intermediate 99-1)

[0147] 5-bromo-4-fluoro-1-methyl-1 H-Indazole-3-carboxylic acid (150 mg) was dissolved in acetonitrile (3 mL), and then added... N , N , N ', N '-Tetramethylchloromethylamidine hexafluorophosphate (308 mg), N 0.18 mL of methylimidazole and intermediate 1-3 (178 mg) were reacted and stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0-10%) to give the title compound (250 mg). LCMS (ESI) [M+H] + =471.0.

[0148] Step 2: 4-Fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazol-3-yl)carbamoyl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1 H Preparation of 3-indazole-3-carboxamide (intermediate 99-2)

[0149] Intermediate 99-1 (120 mg) was dissolved in 1,4-dioxane (3 mL), and pinacol diborate (97 mg), potassium acetate (50 mg), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (19 mg) were added. The reaction mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0-10%) to give the title compound (130 mg). LCMS (ESI) [M+H] + =519.2.

[0150] Preparation of Intermediate 101-2: 3-(3-aminobenzyl)-1,1-dimethylurea hydrochloride

[0151] Step 1: Preparation of tert-butyl (3-((3,3-dimethylureo)methyl)phenyl)carbamate (intermediate 101-1)

[0152] 200 mg of tert-butyl (3-(aminomethyl)phenyl)carbamate was dissolved in 8 mL of dichloromethane, followed by the addition of triethylamine (273 mg) and dimethylcarbamoyl chloride (145 mg). The reaction mixture was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to give the title compound (230 mg). LCMS (ESI) [M+H] + = 294.1

[0153] Step 2: Preparation of 3-(3-aminobenzyl)-1,1-dimethylurea hydrochloride (intermediate 101-2)

[0154] Intermediate 101-1 (200 mg) was dissolved in 1,4-dioxane (3 mL), and 4M hydrogen chloride-dioxane solution (3 mL) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction was confirmed by LCMS, and the solution was concentrated under reduced pressure to give the title compound (190 mg, crude product). LCMS (ESI) [M+H] + = 194.1

[0155] Example 1: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 1)

[0156] Step 1: 5-Bromo-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (intermediates 1-5)

[0157] 5-bromo-1-methyl-1 H -Indazole-3-carboxylic acid (200 mg), soluble at room temperature in N , N -Dimethylformamide (5 mL), add sequentially N , N -Diisopropylethylamine (304 mg), O -(7-azabenzotriazol-1-yl)- N , N , N', N '-Tetramethylurea hexafluorophosphate (447 mg) and 3-amino- N -(1-methyl-1 H 3-Pyrazol-3-yl)benzamide (203 mg). The reaction solution was stirred at room temperature for 12 hours. The target product was detected by LCMS. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0–5%) to give the title compound (350 mg). LCMS (ESI) [M+H] + = 453.0

[0158] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 1)

[0159] Intermediate 1-5 (50 mg, 0.11 mmol) and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H 1,2,4-Triazol-3-one (52 mg) was dissolved in a mixed solvent of dioxane (4 mL) and water (0.5 mL). Cesium carbonate (72 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (5 mg), and crotonyl(2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (4 mg) were added sequentially at room temperature. The reaction mixture was stirred at 90 °C for 12 hours under nitrogen protection. The reaction was detected by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 30-60%, 10 min) to give the title compound (11 mg). LCMS (ESI) [M+H] + = 562.1. 1H NMR (400 MHz, DMSO- d 6) δ 10.78 (s, 1H), 10.55 (s,1H), 8.56 – 8.52 (m, 2H), 8.03 (dd, J = 8.1, 2.2 Hz, 1H), 7.97 – 7.87 (m,4H), 7.72 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 4.26 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 2.14 (s, 3H).

[0160] Example 2: N -(3-Carbamoyl-2-fluorophenyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro- 4H -1,2,4-Triazol-4-yl)phenyl)-1-methyl- 1H- Preparation of indazole-3-carboxamide (compound 5)

[0161] Step 1: 5-Bromo- N -(3-carbamoyl-2-fluorophenyl)-1-methyl- 1H Preparation of pyrazole-3-carboxamide (intermediate 2-1)

[0162] To 5-bromo-1-methyl- 1H Add the following to a solution of 0.40 g of indazole-3-carboxylic acid in 7.5 mL of acetone: N , N , N ', N' -Tetramethylchloroformamidine hexafluorophosphate (1.32 g), N0.77 g of methylimidazole and 0.36 g of 3-amino-2-fluorobenzamide were added. The mixture was stirred at 50 °C for 4 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction solution was concentrated to obtain a crude product, which was then purified by rapid chromatography (silica gel, methanol / dichloromethane = 0-5%). The purified product was further slurried with methanol and filtered to obtain the title compound (440 mg). LCMS (ESI) [M+H] + = 391.1.

[0163] Step Two: N -(3-Carbamoyl-2-fluorophenyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro- 4H -1,2,4-Triazol-4-yl)phenyl)-1-methyl- 1H- Preparation of indazole-3-carboxamide (compound 5)

[0164] Under nitrogen protection, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (51 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (37 mg), cesium carbonate (250 mg), and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3-dioxane were added sequentially to an anhydrous dioxane (2 mL) solution of intermediate 2-1 (200 mg). H -1,2,4-triazol-3-one (242 mg) and water (0.2 mL). Stirred at 90 °C for 16 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction mixture was filtered through silica gel, and the filter cake was washed with ethyl acetate (50 mL). The organic phase was concentrated to obtain the crude product, which was then purified by rapid chromatography (silica gel, dichloromethane / methanol = 0-5%). Further purification by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, ACN) yielded the title compound (106 mg). LCMS (ESI) [M+H] + = 500.3; 1 H NMR (400 MHz, DMSO) δ 9.94(s, 1H), 8.46 (s, 1H), 8.06 – 7.98 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.91(dd, J = 8.9, 1.7 Hz, 1H), 7.88 (d, J= 8.5 Hz, 2H), 7.78 (s, 1 H), 7.67 (s, 1 H), 7.55 (d, J = 8.6 Hz, 2H), 7.46 (ddd, J = 8.1, 6.5, 1.8 Hz, 1H), 7.29(t, J = 7.9 Hz, 1H), 4.25 (s, 3H), 3.36 (s, 3H), 2.14 (s, 3H).

[0165] Example 3: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro- 4H -1,2,4-Triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)- 1H Preparation of -indole-3-carboxamide (compound 18)

[0166] Step 1: 5-Bromo-1-methyl- N -(3-((1-methyl- 1H -pyrazole-3-yl)carbamoyl)phenyl)- 1H Preparation of 3-indole-3-carboxamide (intermediate 3-1)

[0167] Add the following to a solution of 1-methyl-5-bromo-3-indolecarboxylic acid (470 mg) in acetonitrile (5.6 mL) sequentially: N , N , N ', N' -Tetramethylchloroformamidine hexafluorophosphate (0.78 g), N -Methylimidazole (0.91 g) and 3-amino- N -(1-methyl- 1H 3-Pyrazol-3-yl)benzamide hydrochloride (0.70 g). Stirred at 50 °C for 4 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction solution was concentrated to obtain a crude product, which was then purified by rapid chromatography (silica gel, methanol / dichloromethane = 0-5%). Further slurrying with methanol and filtration yielded the title compound (180 mg). LCMS (ESI) [M+H] + = 452.2.

[0168] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro- 4H-1,2,4-Triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl- 1H -pyrazole-3-yl)carbamoyl)phenyl)- 1H Preparation of -indole-3-carboxamide (compound 18)

[0169] Under nitrogen protection, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (44 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (32 mg), cesium carbonate (216 mg), and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3-dioxane were added sequentially to an anhydrous dioxane (2.5 mL) solution of intermediate 3-1 (200 mg). H -1,2,4-triazol-3-one (209 mg) and water (0.25 mL). Stirred at 90 °C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered through a short silica gel column, the filter cake was washed with ethyl acetate (50 mL), and the organic phase was concentrated to obtain the crude product. After purification by rapid chromatography (silica gel, dichloromethane / methanol = 0-5%), further purification was achieved by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, ACN) to obtain the title compound (55 mg). LCMS (ESI) [M+H] + = 561.3; 1 H NMR (400 MHz, DMSO- d 6) δ = 10.76 (s, 1H),9.99 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.00 (dd, J = 7.8, 1.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.68 (td, J = 8.2, 2.0 Hz, 3H), 7.61 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 6.60 (d, J= 2.2 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 3.36 (s, 3H), 2.13(s, 3H).

[0170] Example 4: 6-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-3-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 1-indole-1-carboxamide (compound 21)

[0171] Step 1: 3-Isocyanate group- N -(1-methyl-1 H Preparation of 3-pyrazol-3-yl)benzamide (intermediate 4-1)

[0172] Intermediate 1-3 (200 mg) was dissolved in dichloromethane (5 mL), and triethylamine (281 mg) and triphosgene (96 mg) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (250 mg, crude product), which was used directly in the next step without purification. LCMS (ESI) [M+MeOH+H] + = 275.0.

[0173] Step 2: 6-Bromo-3-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 1-indole-1-carboxamide (intermediate 4-2)

[0174] 6-bromo-3-methyl-1 H -Indole (120 mg) soluble in N , NIn dimethylformamide (5 mL), a mixture of 60 wt% sodium hydride (46 mg) and mineral oil was added under ice bath conditions. After stirring for 30 minutes, intermediate 4-1 (250 mg, obtained from the previous step) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was confirmed by LCMS. The reaction mixture was quenched with ice water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–3%) to give the title compound (110 mg). LCMS (ESI) [M+H] + = 451.9.

[0175] Step 3: 6-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-3-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 1-indole-1-carboxamide (compound 21)

[0176] Intermediate 4-2 (100 mg) was dissolved in dioxane (4 mL) and water (0.5 mL), and then 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3- H -1,2,4-triazol-3-one (70 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (21 mg), potassium phosphate (47 mg), and crotonyl(2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (15 mg). The reaction solution was stirred at 90 °C under nitrogen protection for 2 hours. The reaction was detected by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%~5%) and preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 45-50%) to give the title compound (4 mg). LCMS (ESI) [M+H] + =561.2. 1 H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.18 (s, 1H), 7.90 – 7.83 (m, 3H), 7.73 – 7.65 (m, 3H), 7.59 (d, J= 8.1 Hz, 1H),7.56 – 7.50 (m, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 2.2 Hz, 1H), 3.84(s, 3H), 3.47 (s, 3H), 2.38 (s, 3H), 2.18 (s, 3H).

[0177] Example 5: 7-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)- N -(3-((1-methyl-1 H -pyrazol-3-yl)amino)phenyl)-3-(trifluoromethyl)imidazol[1,5-] a Preparation of pyridine-1-carboxamide (compound 25)

[0178] Step 1: Preparation of ethyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino)acetate (intermediate 5-1)

[0179] Ethyl 2-(4-bromopyridin-2-yl)ethyl acetate (300 mg) was dissolved in acetic acid (4 mL). Sodium nitrite (85 mg) dissolved in water (1 mL) was slowly added dropwise to the above reaction solution. The reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was confirmed by LCMS. The reaction solution was quenched with ice water (10 mL), and the pH was adjusted to 7-8 with potassium carbonate aqueous solution. The solution was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (300 mg, crude product). LCMS (ESI) [M+H] + =273.0

[0180] Step 2: 7-Bromo-3-(trifluoromethyl)imidazol [1,5- a Preparation of 1-ethyl pyridine (intermediate 5-2)

[0181] Intermediate 5-1 (300 mg, obtained from the previous step) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and trifluoroacetic acid (0.5 mL). Zinc powder (144 mg) and trifluoroacetic anhydride (0.31 mL) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was dissolved in pyridine (4 mL). Trifluoroacetic anhydride (0.31 mL) was added, and the reaction mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. LCMS analysis confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to obtain the title compound (280 mg). LCMS (ESI) [M+H] + = 337.0

[0182] Step 3: 7-Bromo-3-(trifluoromethyl)imidazol [1,5- a Preparation of pyridine-1-carboxylic acid (intermediate 5-3)

[0183] Intermediate 5-2 (280 mg) was dissolved in methanol (3 mL) and water (1 mL), and sodium hydroxide (166 mg) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The pH was adjusted to 4-5 with 1N dilute hydrochloric acid, resulting in the precipitation of a solid. The filter cake was washed with water (10 mL) and lyophilized to give the title compound (170 mg, crude product). LCMS (ESI) [M+H] + = 308.9

[0184] Step 4: 7-Bromo- N -(3-((1-methyl-1 H -pyrazol-3-yl)amino)phenyl)-3-(trifluoromethyl)imidazol[1,5-] a Preparation of pyridine-1-carboxamide (intermediate 5-4)

[0185] Dissolve intermediate 5-3 (170 mg, obtained from the previous step) in acetonitrile (4 mL), and then add the following solutions sequentially: N , N , N ', N '-Tetramethylchloromantadin hexafluorophosphate (309 mg), N0.19 mL of methylimidazole and intermediate 1-3 (178 mg) were reacted and stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–10%) to give the title compound (200 mg). LCMS (ESI) [M+H] + =507.0

[0186] Step 5: 7-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)- N -(3-((1-methyl-1 H -pyrazol-3-yl)amino)phenyl)-3-(trifluoromethyl)imidazol[1,5-] a Preparation of pyridine-1-carboxamide (compound 25)

[0187] Intermediate 5-4 (100 mg) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.5 mL), followed by the addition of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (19 mg), crotonyl(2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (13 mg), cesium carbonate (130 mg), and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one (93 mg) was reacted under nitrogen atmosphere at 90 °C for 3 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, diluted with ice water (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was initially purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to remove impurities. Further purification by preparative liquid chromatography (C18, acetonitrile / 0.1% trifluoroacetic acid aqueous solution = 30-60%) yielded the title compound (34 mg). LCMS (ESI) [M+H] + =616.2. 1 H NMR (400 MHz, DMSO- d6) δ 10.77 (s, 1H), 10.36 (s, 1H), 8.76 – 8.70 (m, 2H), 8.54 (s, 1H), 8.08 – 8.01 (m, 3H), 7.74 – 7.67 (m, 2H), 7.66 – 7.61 (m, 3H), 7.46 (t, J =7.9 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.37 (s, 3H), 2.16 (s, 3H).

[0188] Example 6: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 38)

[0189] Step 1: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of methyl indazole-3-carboxylate (intermediate 6-1)

[0190] 5-bromo-4-fluoro-1-methyl-1 H methyl indazole-3-carboxylate (360 mg) and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H 1,2,4-Triazol-3-one (395 mg) was dissolved in dioxane (8 mL) and water (1 mL), followed by the addition of potassium carbonate (347 mg) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg). The reaction was carried out under nitrogen atmosphere at 95 °C with stirring for 16 hours. The product was detected by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–30%) to give the title compound (390 mg). LCMS (ESI) [M+H] + = 396.0.

[0191] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxylic acid (intermediate 6-2)

[0192] Intermediate 6-1 (100 mg) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). A 4M sodium hydroxide aqueous solution (1 mL) was added at 25 °C, and the reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was directly concentrated under reduced pressure. The residue was added to water (20 mL), and the pH was adjusted to 5-6 with 1M dilute hydrochloric acid. Extraction was performed with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (80 mg, crude product). LCMS (ESI) [M+H] + =382.0.

[0193] Step 3: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 38)

[0194] Dissolve intermediate 6-2 (70 mg, obtained from the previous step) and intermediate 1-3 (40 mg) in acetonitrile (5 mL), and add them sequentially. N -Methylimidazole (45 mg) and N , N , N ', N '-Tetramethylchloromethanesulfonyl hexafluorophosphate (103 mg) was reacted with the solution at room temperature for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) and preparative chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 40–45%) to give the title compound (25 mg). LCMS (ESI) [M+H] + = 580.3. 1 H NMR (400 MHz, DMSO- d6) δ 10.81 (s, 1H), 10.64 (s, 1H), 8.43 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.79 – 7.67 (m, 5H), 7.61 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 6.60 (s,1H), 4.24 (s, 3H), 3.79 (s, 3H), 3.42 (s, 3H), 2.15 (s, 3H).

[0195] Example 7: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1-(2,2,2-trifluoroethyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 55)

[0196] Step 1: 5-Bromo-1-(2,2,2-trifluoroethyl)- 1H Preparation of methyl indazole-3-carboxylate (intermediate 7-1)

[0197] To 5-bromo- 1H methyl indazole-3-carboxylate (2.00 g) N , N In a 24 mL solution of dimethylformamide, potassium carbonate (2.17 g) and 1,1,1-trifluoro-2-iodoethane (3.29 g) were added sequentially. The mixture was stirred at 110 °C for 5 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction solution was quenched with 100 mL of water, extracted with 100 mL of ethyl acetate, washed with 100 mL of water (2 times), and then washed again with saturated sodium chloride solution (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain the crude product. The crude product was purified by rapid chromatography (silica gel, methanol / dichloromethane = 0-10%) to obtain the title compound (1.15 g). LCMS (ESI) [M+H] + = 337.1.

[0198] Step 2: 5-Bromo-1-(2,2,2-trifluoroethyl)- 1HPreparation of 3-indazole-3-carboxylic acid (intermediate 7-2)

[0199] Lithium hydroxide (75 mg) was added to a mixed solution of intermediate 7-1 (0.53 g) in methanol (6 mL) and water (2 mL). The mixture was stirred at 25 °C for 6 hours. The reaction was monitored by LCMS, and the target product was observed. The pH was adjusted to 3-4 with 2 M hydrochloric acid solution, and the reaction solution was concentrated to obtain the crude product. The title compound (290 mg) was purified by rapid chromatography (silica gel, methanol / dichloromethane = 0-5%). LCMS (ESI) [M+H] + = 323.1.

[0200] Step 3: 5-Bromo- N -(3-((1-methyl- 1H -pyrazole-3-yl)carbamoyl)phenyl)-1-(2,2,2-trifluoroethyl)-1 H Preparation of 3-indazole-3-carboxamide (intermediate 7-3)

[0201] Add the following to the acetonitrile (5 mL) solution of intermediate 7-2 (0.29 g) sequentially: N , N , N ', N' -Tetramethylchloroformamidine hexafluorophosphate (0.38 g), N -Methylimidazole (0.44 g) and 3-amino- N -(1-methyl- 1H 3-Pyrazol-3-yl)benzamide hydrochloride (0.34 g). Stirred at 50 °C for 4 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction solution was concentrated to obtain a crude product, which was then purified by rapid chromatography (silica gel, methanol / dichloromethane = 0-5%). The purified solid was concentrated, further slurried with methanol, and filtered to obtain the title compound (206 mg). LCMS (ESI) [M+H] + = 521.1.

[0202] Step 4: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1-(2,2,2-trifluoroethyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 55)

[0203] Under nitrogen protection, crotonyl(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (39 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (27 mg), cesium carbonate (188 mg), and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3-dioxane were added sequentially to an anhydrous dioxane (2.4 mL) solution of intermediate 7-3 (200 mg). H -1,2,4-triazol-3-one (181 mg) and water (0.24 mL). Stirred at 90 °C for 16 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction mixture was filtered through silica gel, and the filter cake was washed with ethyl acetate (50 mL). The organic phase was concentrated to obtain the crude product, which was then purified by rapid chromatography (silica gel, methanol / dichloromethane = 0-5%). Further purification by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, ACN) yielded the title compound (37 mg). LCMS (ESI) [M+H] + = 630.4; 1 H NMR (400 MHz, DMSO)δ 10.79 (s, 1H), 10.59 (s, 1H), 8.55 (d, J = 0.9 Hz, 1H), 8.51 (t, J = 2.0Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.04 (dd, J = 8.1, 1.3 Hz, 1H), 8.00 (dd, J = 8.9, 1.8 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 7.9 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 5.67 (q, J= 8.9 Hz, 2H), 3.79 (s, 3H), 3.37 (s, 3H), 2.14 (s, 3H).

[0204] Example 8: 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 68)

[0205] 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1 H -Indazole-3-carboxylic acid (70 mg) was dissolved in acetonitrile (5 mL), and intermediates 1-3 (47 mg) were added sequentially. N -Methylimidazole (177 mg) and N , N , N ', N '-Tetramethylchloromethanesulfonyl hexafluorophosphate (182 mg). The reaction solution was stirred at room temperature for 5 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–10%), followed by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 35–37%) to obtain the title compound (13 mg). LCMS (ESI) [M+H] + =523.2. 1 H NMR (400 MHz, MeOD) δ 8.96 – 8.92 (m, 1H), 8.73 (d, J = 1.5 Hz, 1H), 8.32 (t, J = 1.8 Hz, 1H), 8.23 ​​(dd, J = 8.9, 1.6 Hz, 1H), 8.06 (d, J =8.3 Hz, 1H), 8.02 – 7.96 (m, 2H), 7.76 (d, J = 8.9 Hz, 1H), 7.68 (s, 1H), 7.56 – 7.49 (m, 2H), 6.64 (d, J= 2.2 Hz, 1H), 4.23 (s, 3H), 3.84 (s, 3H), 3.15 (s, 3H), 3.11 (s, 3H).

[0206] Example 9: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -1,2,4-triazol-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 8)

[0207] Following the synthetic method of compound 1, intermediates 1-3 were replaced with intermediate 8-3, and the title compound (10 mg) was obtained by following similar methods and steps. LCMS (ESI) [M+H] + =563.4. 1 H NMR (400 MHz, DMSO- d 6) δ10.64 (s, 1H), 10.58 (s, 1H), 8.54 – 8.51 (m, 2H), 8.39 (s, 1H), 8.09 – 8.05 (m, 1H), 7.96 – 7.87 (m, 4H), 7.70 – 7.66 (m, 1H), 7.57 – 7.53 (m, 2H), 7.48(t, J = 7.9 Hz, 1H), 4.26 (s, 3H), 3.86 (s, 3H), 3.37 (s, 3H), 2.14 (s, 3H).

[0208] Example 10: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H -pyrazolo[4,3- b ]pyridine- 3 Preparation of -formamide (compound 19)

[0209] Step 1: 5-Chloro-1-methyl- N-(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H -pyrazolo[4,3- b Preparation of pyridine-3-carboxamide (intermediate 19-3)

[0210] Intermediate 19-2 (100 mg) and intermediate 1-3 (102 mg) were dissolved in acetonitrile (3 mL), and then added sequentially at room temperature. N -Methylimidazole (116 mg) and N , N , N ', N '-Tetramethylchloromethanesulfonyl hexafluorophosphate (212 mg) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 3%–10%) to give the title compound (113 mg). LCMS (ESI) [M+H] + = 410.1

[0211] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H -pyrazolo[4,3- b ]pyridine- 3 Preparation of -formamide (compound 19)

[0212] Intermediate 19-3 (93 mg) and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H1,2,4-triazol-3-one (107 mg) was dissolved in dioxane (8 mL) and water (1 mL). Cesium carbonate (148 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (11 mg) and crotonyl(2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (8 mg) were added sequentially at room temperature. The reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction was detected by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 3%–10%), followed by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 0–95%) to obtain the title compound (16 mg). LCMS (ESI) [M+H] + = 563.2. 1 H NMR (400 MHz, DMSO- d 6) δ 11.08 (s, 1H), 10.93 (s, 1H), 8.53(d, J = 9.0 Hz, 1H), 8.48 (d, J = 8.5 Hz, 2H), 8.33 – 8.27 (m, 2H), 8.16 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.1 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 4.28 (s,3H), 3.74 (s, 3H), 3.38 (s, 3H), 2.11 (s, 3H).

[0213] Example 11: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H -pyrazolo[3,4-c Preparation of pyridine-3-carboxamide (compound 20)

[0214] Step 1: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl-1 H -pyrazolo[3,4- c Preparation of methyl pyridine-3-carboxylate (intermediate 20-1)

[0215] 5-chloro-1-methyl-1 H -pyrazolo[3,4- c Methyl pyridine-3-carboxylate (110 mg) was dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3-carboxylate was added at room temperature. H -1,2,4-triazol-3-one (154 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (46 mg), crotonyl(2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (33 mg) and cesium carbonate (318 mg). The reaction mixture was purged three times with nitrogen and stirred at 90 °C for 2 hours under nitrogen atmosphere. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%–30%) to give the title compound (120 mg). LCMS (ESI) [M+H] + = 379.0.

[0216] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl-1 H -pyrazolo[3,4- c Preparation of pyridine-3-carboxylic acid (intermediate 20-2)

[0217] Intermediate 20-1 (110 mg) was dissolved in methanol (3 mL) and water (1 mL). Sodium hydroxide (58 mg) was added at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The pH was adjusted to 3-5 with 1N hydrochloric acid. The residue was filtered, and the filter cake was collected and dried to give the title compound (90 mg, crude product). LCMS (ESI) [M+H]+ = 364.9.

[0218] Step 3: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H -pyrazolo[3,4- c Preparation of pyridine-3-carboxamide (compound 20)

[0219] Intermediate 20-2 (80 mg, obtained from the previous step) was dissolved in acetonitrile (2 mL), and then added sequentially at room temperature. N , N , N ', N '-Tetramethylchloromethylamidine hexafluorophosphate (92 mg), N -Methylimidazole (0.05 mL) and intermediate 1-3 (47 mg). The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS until completion. Ice water (10 mL) was added, followed by extraction with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 0-40%) to give the title compound (23 mg). LCMS (ESI) [M+H] + = 563.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.80 (s,1H), 10.72 (s, 1H), 9.47 – 9.44 (m, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.29 (d, J = 8.5 Hz, 2H), 8.05 – 8.01 (m, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.62 (d, J =2.1 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H), 4.38 (s, 3H), 3.80 (s, 3H), 3.37 (s, 3H), 2.15 (s, 3H).

[0220] Example 12: 4-Cyano-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 40)

[0221] Step 1: 4-Cyano-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl-1 H Preparation of methyl indazole-3-carboxylate (intermediate 40-7)

[0222] Intermediate 40-6 (40 mg) was dissolved in 1,4-dioxane (2 mL) and water (0.25 mL), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13 mg), crotonyl(2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)palladium chloride (9 mg), potassium phosphate (29 mg), and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one (64 mg) was reacted under nitrogen atmosphere at 90 °C for 16 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1-10%) to give the title compound (50 mg). LCMS (ESI) [M+H] + =403.1.

[0223] Step 2: 4-Cyano-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl-1 H Preparation of 3-indazole-3-carboxylic acid (intermediate 40-8)

[0224] Intermediate 40-7 (40 mg) was dissolved in a mixture of methanol (2 mL) and water (0.7 mL), and lithium hydroxide (12 mg) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The pH was adjusted to 5-6 with a saturated citric acid solution, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed with water (10 mL) and dried to give the title compound (15 mg, crude product). LCMS (ESI) [M+H] + =389.2.

[0225] Step 3: 4-Cyano-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 40)

[0226] Dissolve intermediate 40-8 (15 mg, obtained from the previous step) in acetonitrile (2 mL), and add... N , N , N ', N '-Tetramethylchloromethylamidine hexafluorophosphate (22 mg), N 0.01 mL of methylimidazole and intermediate 1-3 (17 mg) were reacted and stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was initially purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to remove impurities. Further purification was achieved by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 30-60%) to obtain the title compound (3 mg). LCMS (ESI) [M+H] + = 587.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 10.80 (s, 1H), 8.42 – 8.40 (m, 1H), 8.30 (d, J =8.9 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.82 – 7.78 (m, 3H), 7.75 (d, J= 7.7Hz, 1H), 7.65 – 7.60 (m, 2H), 7.50 – 7.44 (m, 2H), 6.60 (d, J = 2.1 Hz, 1H), 4.29 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 2.17 (s, 3H).

[0227] Example 13: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1,4-dimethyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 41)

[0228] Following the synthetic method of compound 40, by replacing intermediate 40-6 with intermediate 41-3 and lithium hydroxide with sodium hydroxide, the title compound (57 mg) was obtained by adhering to similar methods and procedures. LCMS (ESI) [M+H] + =576.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.81 (s, 1H), 10.72 (s, 1H), 8.42 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.56 – 7.50 (m, 4H), 7.48 – 7.41 (m, 2H), 6.60 (d, J = 2.1 Hz, 1H), 4.19 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 2.62 (s, 3H), 2.15(s, 3H).

[0229] Example 14: 1-Cyclopropyl-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)- N-(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 45)

[0230] Following the synthetic method of compound 55, intermediate 7-1 was replaced with 5-bromo-1-cyclopropyl-1- H methyl indazole-3-carboxylate, following a similar method and procedure, yielded the title compound (16 mg). LCMS (ESI) [M+H] + = 588.4. 1 HNMR (400 MHz, DMSO- d 6) δ 10.79 (s, 1H), 10.40 (s, 1H), 8.52 – 8.50 (m, 2H), 8.09 – 8.05 (m, 1H), 7.98 – 7.86 (m, 4H), 7.74 (dt, J = 7.9, 1.3 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.57 – 7.53 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 6.61(d, J = 2.3 Hz, 1H), 4.03 (tt, J = 7.2, 3.7 Hz, 1H), 3.80 (s, 3H), 3.37 (s,3H), 2.14 (s, 3H), 1.38 – 1.31 (m, 2H), 1.29 – 1.22 (m, 2H).

[0231] Example 15: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-ethyl-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of -indazole-3-carboxamide (compound 69)

[0232] Referring to the synthetic method of compound 20, 5-chloro-1-methyl-1 H -pyrazolo[3,4- cBy replacing intermediate 69-2 with methyl pyridine-3-carboxylate and following a similar method and procedure, the title compound (64 mg) was obtained. LCMS (ESI) [M+H] + = 594.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.81 (s, 1H), 10.58 (s, 1H), 8.41 (s,1H), 8.01 (d, J = 7.9 Hz, 1H), 7.83 – 7.67 (m, 5H), 7.61 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 4.63 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.36 (s, 3H), 2.15 (s, 3H), 1.52 (t, J = 7.2 Hz, 3H).

[0233] Example 16: 4-Chloro-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of -indazole-3-carboxamide (compound 70)

[0234] Following the synthetic method of compound 40, by replacing intermediate 40-6 with intermediate 70-3 and lithium hydroxide with sodium hydroxide, the title compound (32 mg) was obtained by adhering to similar methods and procedures. LCMS (ESI) [M+H] + =596.1. 1 H NMR (400 MHz, DMSO- d 6) δ 10.84 – 10.81 (m, 2H), 8.34 (s, 1H), 7.91(d, J = 9.3 Hz, 1H), 7.88 (d, J= 8.7 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.55(d, J = 8.4 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 4.20(s, 3H), 3.78 (s, 3H), 3.36 (s, 3H), 2.15 (s, 3H).

[0235] Example 17: 5-(5-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)pyridin-2-yl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 71)

[0236] Step 1: 4-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1 H Preparation of methyl indazole-3-carboxylate (intermediate 71-1)

[0237] 5-bromo-4-fluoro-1-methyl-1 H Methyl indazole-3-carboxylate (100 mg) was dissolved in 1,4-dioxane (2 mL), followed by the addition of pinacol diboronate (177 mg), potassium acetate (103 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (51 mg). The reaction mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–30%) to give the title compound (50 mg). LCMS m / z (ESI) [M+H] + =335.1.

[0238] Step 2: 5-(5-(1,3-dimethyl-5-oxo-1,5-dihydro-4-)H -1,2,4-triazol-4-yl)pyridin-2-yl)-4-fluoro-1-methyl-1 H Preparation of methyl indazole-3-carboxylate (intermediate 71-2)

[0239] Intermediate 71-1 (60 mg) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), and then 4-(6-bromopyridin-3-yl)-2,5-dimethyl-2,4-dihydro-3-yl was added sequentially. H -1,2,4-triazol-3-one (48 mg), potassium carbonate (503 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg). The reaction solution was stirred at 95 °C under nitrogen protection for 16 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–4%) to give the title compound (40 mg). LCMS (ESI) [M+H] + = 397.0

[0240] Step 3: 5-(5-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)pyridin-2-yl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxylic acid (intermediate 71-3)

[0241] Intermediate 71-2 (40 mg) was dissolved in methanol (4 mL) and water (1 mL), and sodium hydroxide (40 mg) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure. Water (15 mL) was added to the residue, and the pH was adjusted to 4-5 with 2N hydrochloric acid. The aqueous phase was concentrated under reduced pressure. The residue was dissolved in dichloromethane / methanol (10 / 1, 10 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (25 mg, crude product). LCMS (ESI) [M+H] + = 383.0

[0242] Step 4: 5-(5-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)pyridin-2-yl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 71)

[0243] Intermediate 71-3 (25 mg, obtained from the previous step) was dissolved in...N , N - Dimethylformamide (3 mL), followed by intermediates 1-3 (16 mg), triethylamine (13 mg), and... O -(7-azabenzotriazol-1-yl)- N , N , N ', N '-Tetramethylurea hexafluorophosphate (37 mg). The reaction solution was stirred at room temperature for 3 hours. The reaction was detected by LCMS to indicate completion. The reaction solution was then extracted with ice water (10 mL) and ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was initially purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%), followed by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 25–40%) to obtain the title compound (6 mg). LCMS (ESI) [M+H] + = 581.0. 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 2.2 Hz, 1H),8.21 – 8.11 (m, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.88 (dd, J = 8.5, 2.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.57 – 7.49 (m, 2H), 7.40 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 4.26 (s, 3H), 3.87 (s, 3H), 3.54 (s, 3H), 2.29 (s, 3H).

[0244] Example 18: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1,6-dimethyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 72)

[0245] Referring to the synthetic method of compound 20, 5-chloro-1-methyl-1 H -pyrazolo[3,4- c The title compound (39 mg) was obtained by replacing intermediate 72-4 with methyl pyridine-3-carboxylate and following a similar method and procedure. LCMS (ESI) [M+H] + = 594.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.77 (s, 1H), 10.54 (s, 1H), 8.38 (s,1H), 7.99 – 7.94 (m, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.64 – 7.59 (m, 2H), 7.56(d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 6.59(d, J = 2.1 Hz, 1H), 4.20 (s, 3H), 3.78 (s, 3H), 3.37 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H).

[0246] Example 19: 5-(4-(dimethylcarbamoyl)phenyl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of -indazole-3-carboxamide (compound 73)

[0247] Referring to the synthetic method of compound 1, intermediates 1-4 were replaced with 5-bromo-4-fluoro-1-methyl-1H-indazole-3-carboxylic acid, and 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H The title compound (22 mg) was obtained by replacing 1,2,4-triazol-3-one with (4-(dimethylcarbamoyl)phenyl)boronic acid, following a similar method and procedure. LCMS (ESI) [M+H] + = 540.2. 1 H NMR (400 MHz, DMSO- d6) δ10.82 (s, 1H), 10.64 (s, 1H), 8.43 (s, 1H), 8.00 – 7.96 (m, 1H), 7.77 – 7.66(m, 5H), 7.62 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.46 (t, J = 7.9Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 4.24 (s, 3H), 3.79 (s, 3H), 3.01 (s, 3H), 2.98 (s, 3H).

[0248] Example 20: N -(3-((1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)carbamoyl)phenyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-yl)carbamoyl)phenyl H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (compound 74)

[0249] Intermediate 6-2 (50 mg) and intermediate 74-2 (36 mg) were dissolved in... N , N -Dimethylformamide (5 mL), then added N , N -Diisopropylethylamine (51 mg) and O -(7-azabenzotriazol-1-yl)- N , N , N ', N '-Tetramethylurea hexafluorophosphate (100 mg). The reaction was stirred at room temperature for 2 hours. The reaction was confirmed by LCMS. Water (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give the title compound (44 mg). LCMS (ESI) [M+H] + = 638.2. 1 H NMR (400 MHz, DMSO- d6) δ 10.72 (s, 1H), 9.32 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.80 –7.69 (m, 4H), 7.65 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.51 (t, J = 7.9 Hz, 1H), 4.24 (s, 3H), 3.38 (s, 3H), 3.36 (s, 3H), 3.25 (s, 3H), 2.14(s, 3H).

[0250] Example 21: 5-(4-4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-(2-hydroxyethyl)- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 75)

[0251] Step 1: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1-(2-((tetrahydro-2-yl)carbamoyl)phenyl)-1-(2- ... H -pyran-2-yl)oxy)ethyl)-1 H Preparation of 3-indazole-3-carboxamide (intermediate 75-3)

[0252] Following the synthetic method for compound 25, intermediate 5-2 was replaced with intermediate 75-2, and the title compound (100 mg) was obtained by following similar methods and steps. LCMS (ESI) [M+H] + =693.8.

[0253] Step 2: 5-(4-4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-(2-hydroxyethyl)- N -(3-((1-methyl-1H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 75)

[0254] Intermediate 75-3 (100 mg) was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (27 mg) was added. The reaction was stirred at room temperature for 2 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%), followed by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution) to obtain the title compound (9 mg). LCMS (ESI) [M+H] + = 610.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.78 (s,1H), 10.55 (s, 1H), 8.40 – 8.34 (m, 1H), 7.99 – 7.94 (m, 1H), 7.76 – 7.71 (m,3H), 7.71 – 7.62 (m, 2H), 7.58 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 4.59 (t, J = 5.2 Hz, 2H), 3.90 (t, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.34 (s, 3H), 2.11 (s, 3H).

[0255] Example 22: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-1-(2-(dimethylamino)ethyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 76)

[0256] Referring to the synthetic method of compound 38, 5-bromo-4-fluoro-1-methyl-1 HBy replacing methyl indazole-3-carboxylate with intermediate 76-2 and following a similar method and procedure, the formate salt of the title compound (10 mg) can be obtained. LCMS (ESI) [M+H] + = 637.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 10.59 (s, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 7.7 Hz, 2H), 7.75 – 7.66 (m, 2H), 7.62 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 4.67 (t, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.36 (s, 3H), 2.84 (t, J = 6.3 Hz, 2H), 2.22(s, 6H), 2.15 (s, 3H).

[0257] Example 23: 1-(2,3-dihydroxypropyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of -indazole-3-carboxamide (compound 77)

[0258] Step 1: 1-Allyl-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 HPreparation of 3-indazole-3-carboxamide (intermediate 77-3)

[0259] Referring to the synthetic method of compound 20, 5-chloro-1-methyl-1 H -pyrazolo[3,4- c The title compound (55 mg) was obtained by replacing intermediate 77-2 with methyl pyridine-3-carboxylate and following a similar method and procedure. LCMS m / z (ESI) [M+H] + = 606.2.

[0260] Step 2: 1-(2,3-dihydroxypropyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 77)

[0261] Intermediate 77-3 (45 mg) was dissolved in tetrahydrofuran (12.5 mL) and water (2.5 mL), and then added sequentially at room temperature. N 87 mg of methylmorpholine oxide and 5 mg of potassium osmium tetroxide dihydrate were reacted and stirred at room temperature for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched with water (15 mL), extracted with ethyl acetate (15 mL × 2), and the combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 3%–10%), followed by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 0–95%) to obtain the title compound (21 mg). LCMS (ESI) [M+H] + = 640.0. 1 H NMR (400MHz, DMSO- d 6) δ 10.83 (s, 1H), 10.59 (s, 1H), 8.41 (s, 1H), 8.03 – 7.99 (m,1H), 7.80 – 7.65 (m, 5H), 7.62 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1H), 6.60 (d,J = 2.2 Hz, 1H), 5.10 (d, J = 5.3 Hz, 1H), 4.95 – 4.89 (m, 1H), 4.65 (dd, J = 14.1, 3.5 Hz, 1H), 4.50 (dd, J = 14.1, 8.1Hz, 1H), 4.09 – 4.01 (m, 1H), 3.79 (s, 3H), 3.54 – 3.42 (m, 2H), 3.37 (s,3H), 2.15 (s, 3H).

[0262] Example 24: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 78)

[0263] Step 1: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1-(tetrahydro-2 ... H -pyran-2-yl)-1 H Preparation of 3-indazole-3-carboxamide (intermediate 78-3)

[0264] Referring to the synthetic method of compound 38, 5-bromo-4-fluoro-1-methyl-1 H The title compound (90 mg) was obtained by replacing methyl indazole-3-carboxylate with intermediate 78-2 and following a similar method and procedure. LCMS (ESI) [M+H] + =650.0.

[0265] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 HPreparation of 3-indazole-3-carboxamide (compound 78)

[0266] Intermediate 78-3 (70 mg) was dissolved in a mixed solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.25 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 30-60%) to give the title compound (25 mg). LCMS (ESI) [M+H] + =566.2. 1 H NMR (400 MHz, DMSO- d 6) δ 14.12 (s, 1H), 10.81 (s, 1H), 10.65 (s, 1H), 8.43 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.68 – 7.60 (m, 3H), 7.56 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.37 (s, 3H), 2.15 (s, 3H).

[0267] Example 25: N -(3-((2 H -tetrazol-5-yl)carbamoyl)phenyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4 ... H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (compound 80)

[0268] Step 1: 3-(5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of methyl benzoate (intermediate 80-1) with indazole-3-carboxamido)

[0269] Intermediate 6-2 (80 mg), methyl 3-aminobenzoate (32 mg), N , N , N ', N '-Tetramethylchloromethylammonium hexafluorophosphate (118 mg) and N 86 mg of methylimidazole was added to 3 mL of acetonitrile and reacted at room temperature for 0.5 h. LCMS showed that the starting material reacted completely. The reaction solution was quenched with 20 mL of water, extracted with 10 mL × 3 ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid chromatography (silica gel, ethyl acetate) to give the title compound (80 mg). LCMS (ESI) [M+H] + =515.3

[0270] Step 2: 3-(5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxamido)benzoic acid (intermediate 80-2)

[0271] Intermediate 80-1 (70 mg) and sodium hydroxide (27 mg) were added to methanol (2 mL) and water (2 mL) and reacted at 60 °C for 1 hour. LC-MS showed that the starting material reacted completely. The reaction solution was concentrated, and the residue was diluted with water. The pH was adjusted to acidic with dilute hydrochloric acid, and the mixture was extracted with a dichloromethane / methanol mixture of 10 / 1. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (55 mg, crude product). LC-MS (ESI) [M+H + =501.1

[0272] Step 3: N -(3-((2 H -tetrazol-5-yl)carbamoyl)phenyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4 ... H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (compound 80)

[0273] Intermediate 80-2 (45 mg, obtained from the previous step), 2 H -Tetrazolium-5-amine (15 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg) and 1-hydroxybenzotriazole (24 mg) were addedN , N The reaction mixture was reacted in dimethylformamide (1 mL) at 40 °C for 2 hours. LCMS showed complete reaction of the starting material. The reaction solution was filtered, and the filtrate was purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to give the title compound (6 mg). LCMS (ESI) [M+H] + =568.3; 1 H NMR (400 MHz, DMSO- d 6) δ 16.06 (s, 1H), 12.07 (s, 1H), 10.72 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H), 8.07 (dd, J = 7.5, 2.2 Hz, 1H), 7.85– 7.69 (m, 5H), 7.61 – 7.50 (m, 3H), 4.25 (s, 3H), 3.37 (s, 3H), 2.15 (s, 3H).

[0274] Example 26: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-(1-(2-hydroxyethyl)-1 H -1,2,3-triazol-4-yl)phenyl)-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (compound 81)

[0275] first step: N -(3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1 H -1,2,3-triazol-4-yl)phenyl)-5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-yl) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (intermediate 81-2)

[0276] Intermediates 6-2 (80 mg) and 81-1 (67 mg) were dissolved in dichloromethane (4 mL). Triethylamine (42 mg) and 2-chloro-1-methylpyridine iodide (80 mg) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 16 hours. LC-MS analysis confirmed the reaction was complete. The reaction mixture was then poured into water (10 mL), extracted with dichloromethane (10 mL × 2), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to give the title compound (68 mg). LC-MS (ESI) [M+H] + =682.0.

[0277] Step 2: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N -(3-(1-(2-hydroxyethyl)-1 H -1,2,3-triazol-4-yl)phenyl)-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (compound 81)

[0278] Intermediate 81-2 (58 mg) was dissolved in tetrahydrofuran (6 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.9 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. LCMS analysis showed the reaction was complete. The mixture was diluted with ethyl acetate (20 mL), washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 0-95%) to give the title compound (4 mg). LCMS (ESI) [M+H + = 568.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.57 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.81 – 7.68 (m, 5H), 7.60 – 7.53 (m, 3H), 7.43(t, J = 7.9 Hz, 1H), 5.09 (t, J = 5.2 Hz, 1H), 4.46 (t, J = 5.3 Hz, 2H), 4.24(s, 3H), 3.84 (q, J= 5.1 Hz, 2H), 3.37 (s, 3H), 2.15 (s, 3H).

[0279] Example 27: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H -pyrazolo[3,4- c Preparation of pyridine-3-carboxamide (compound 85)

[0280] Referring to the synthetic method of compound 20, 5-chloro-1-methyl-1 H -pyrazolo[3,4- c The title compound (29 mg) was obtained by replacing methyl pyridine-3-carboxylate with intermediate 85-3 and following a similar method and procedure. LCMS (ESI) [M+H] + = 581.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.84 (s, 1H), 10.78 (s, 1H), 9.31 (d, J = 1.9 Hz, 1H), 8.46 – 8.44 (m, 1H), 8.10 (d, J = 7.6 Hz, 2H), 8.02 – 7.98(m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 8.6Hz, 2H), 7.48 (t, J = 7.9 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 4.38 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 2.16 (s, 3H).

[0281] Example 28: 7-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-3-methyl- N-(3-((1-methyl-1 H -pyrazol-3-yl)carbamoyl)phenyl)imidazo[1,5- a Preparation of pyridine-1-carboxamide (compound 88)

[0282] Referring to the synthetic method of compound 38, 5-bromo-4-fluoro-1-methyl-1 H The title compound (20 mg) was obtained by replacing methyl indazole-3-carboxylate with intermediate 88-2 and following a similar method and procedure. LCMS (ESI) [M+H] + =562.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.72 (s, 1H), 10.07 (s, 1H), 8.55 (t, J =2.0 Hz, 1H), 8.50 – 8.45 (m, 2H), 8.06 – 8.01 (m, 1H), 8.00 – 7.97 (m, 2H),7.66 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.60 – 7.57 (m, 2H), 7.45– 7.38 (m, 2H), 6.61 (d, J = 2.3 Hz, 1H), 3.79 (s, 3H), 3.37 (s, 3H), 2.76 (s, 3H), 2.15 (s, 3H).

[0283] Example 29: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)-4-fluoro- N ,1-Dimethyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 94)

[0284] Following the synthetic method for compound 38, intermediates 1-3 were replaced with intermediate 94-1, and the title compound (39 mg) was obtained by following similar methods and steps. LCMS (ESI) [M+H] + =594.3.1 H NMR (400 MHz, DMSO- d 6)δ 10.90 (s, 1H), 8.04 (s, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 2.3 Hz, 1H), 7.57 – 7.53 (m, 2H), 7.51 – 7.46 (m, 2H), 7.35– 7.24 (m, 2H), 6.57 (d, J = 2.2 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 3.50 (s, 3H), 3.37 (s, 3H), 2.11 (s, 3H).

[0285] Example 30: 4-Fluoro-1-methyl-5-(4-(1-methyl-1) H -imidazol-2-yl)phenyl)- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 97)

[0286] Referring to the synthetic method of compound 1, intermediates 1-4 were replaced with 5-bromo-4-fluoro-1-methyl-1- H -Indazole-3-carboxylic acid, with 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one is replaced with 1-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)-1 H -Imidazole, following a similar method and procedure, yielded the title compound (16 mg). LCMS (ESI) [M+H] + =549.0. 1 H NMR (400 MHz, DMSO- d 6) δ 10.79 (s, 1H), 10.62 (s, 1H), 8.43 (s, 1H), 8.01 – 7.96 (m, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.78 – 7.69 (m, 5H), 7.61 (d, J = 2.2 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 0.8 Hz, 1H), 7.01 (d, J = 1.0 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 4.24 (s, 3H), 3.82 (s, 3H), 3.79(s, 3H).

[0287] Example 31: 5-(4-(3,3-dimethylurea)phenyl)-4-fluoro-1-methyl- N -(3-((1-methyl-1 H -pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 98)

[0288] Referring to the synthetic method of compound 1, intermediates 1-4 were replaced with 5-bromo-4-fluoro-1-methyl-1- H -Indazole-3-carboxylic acid, with 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-dihydro-3 H The title compound (44 mg) was obtained by replacing 1,1-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)urea with 1,1-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)urea using a similar method and procedure. LCMS (ESI) [M+H] + =555.2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.81 (s, 1H), 10.61 (s, 1H), 8.44 – 8.40 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.74 – 7.68 (m, 2H), 7.65 (d, J = 6.4 Hz, 1H), 7.63– 7.59 (m, 3H), 7.49 (d, J = 8.6 Hz, 2H), 7.45 (d, J= 7.9 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 4.22 (s, 3H), 3.79 (s, 3H), 2.95 (s, 6H).

[0289] Example 32: 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-4-fluoro-1-methyl- N -(3-((1-methyl-1H-pyrazole-3-yl)carbamoyl)phenyl)-1 H Preparation of 3-indazole-3-carboxamide (compound 99)

[0290] Intermediate 99-2 (100 mg) was dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (14 mg), potassium carbonate (53 mg), and 6-chloro- N , N - Dimethylnicotinamide (39 mg) was reacted with the solution under nitrogen atmosphere at 90 °C for 16 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–10%) to obtain the crude product. The crude product was further purified by preparative liquid chromatography (C18, acetonitrile / 0.1% formic acid aqueous solution = 50–90%) to obtain the title compound (10 mg). LCMS (ESI) [M+H] + =541.3. 1 H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 10.68 (s, 1H), 8.82 – 8.76 (m, 1H), 8.46 – 8.40 (m, 1H), 8.13 (dd, J = 8.8, 6.6 Hz, 1H), 8.01 – 7.97 (m,3H), 7.77 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.60 (d, J= 2.2 Hz, 1H), 4.24 (s, 3H), 3.79 (s, 3H), 3.04 (s, 3H), 3.01 (s, 3H).

[0291] Example 33: 5-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4-) H -1,2,4-triazol-4-yl)phenyl)- N -(3-((3,3-dimethylureo)methyl)phenyl)-4-fluoro-1-methyl-1 H Preparation of 3-indazole-3-carboxamide (compound 101)

[0292] Following the synthetic method for compound 38, intermediates 1-3 were replaced with intermediate 101-2, and the title compound (6 mg) was obtained by following similar methods and steps. LCMS (ESI) [M+H] + = 557.0. 1 H NMR (400 MHz, CD3OD)δ 7.80 (d, J = 7.6 Hz, 2H), 7.70 – 7.62 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.39 (s, 2H), 4.22 (s, 3H), 3.47 (s, 3H), 2.94 (s, 6H), 2.20 (s, 3H).

[0293] The following compounds can be obtained by referring to the preparation method of the above embodiments:

[0294] Biological test cases

[0295] Test Example 1: Determination of the competitive binding activity of a compound to full-length STAT6 / pIL-4Ra using time-resolved fluorescence resonance energy transfer (TR-FRET).

[0296] The compound was diluted to the desired concentration with DMSO, and 0.1 μL of the compound was added to a 384-well plate using an Echo converter. Human recombinant full-length STAT6 protein was diluted to the desired concentration with TR-FRET buffer. 5 μL of STAT6 protein was added to a 384-well plate and incubated at 23 °C for 15 min. 5 μL of a mixture of the fluorescent peptide pIL-4Ra (5-FAM-ApYKPFQDLI-NH2) and Tb-anti-his-antibody (Invitrogen, Cat NO. PV5863) was added to a 384-well plate, centrifuged at 1000 rpm for 1 min, and then incubated at 23 °C for 90 min. In the assay system, the final concentrations were: STAT6 protein 1 nM, fluorescent peptide 250 nM, Tb-anti-his antibody 1 nM, and DMSO 1%. Envision was used to read the 520 nm / 485 nm signal values, the TR-FRET ratio was calculated, the suppression ratio was calculated based on the ratio value, and the IC was calculated using a nonlinear fitting formula. 50 value.

[0297] Inhibition rate calculation formula: %Inhibition=(Data 化合物 - Data 0% inhibition ) / (Data 100% inhibition -Data 0% inhibition ) 100, where 100% inhibition means no STAT6 protein was added and all other components were added, and 0% inhibition means no compound was added and all other components were added.

[0298] Table 1

[0299] “A”: IC 50 < 10 nM; “B”: 10 nM ≤ IC 50 < 100 nM; “C”: 100 nM ≤ IC 50 <1000 nM; “D”: IC 50 ≥ 1000 nM;

[0300] Test Example 2: Determining the inhibitory effect of the compound on pSTAT6 using HEK-Blue™ IL-4 / IL-13 cells.

[0301] The compound was diluted with DMSO and transferred 50 nL to a 96-well plate. An equal volume of DMSO was added to the control group. 40 μL of HEK-Blue™ IL-4 / IL-13 cell suspension (Invivogen, Cat No. hkb-il413) was seeded into each 96-well plate at 10,000 cells per well and incubated at 37°C in a CO2 incubator for 1 hour. 10 μL of recombinant human IL-4 protein (R&D, Cat No. 204-IL-050 / CF) was transferred to each 96-well plate containing cells, resulting in a final concentration of 0.4 ng / mL. The plates were then incubated at 37°C in a CO2 incubator for 16 hours. Sixteen hours later, 45 μL of QUANTI-Blue solution (Invivogen, CatNo.rep-qbS2) was added to a new 384-well plate, and 5 μL of the cell culture supernatant was transferred to the 384-well plate. After centrifugation, the plate was incubated at 37°C for 1 hour. SEAP levels were measured at 620 nm using a spectrophotometer.

[0302] Tests have shown that the compounds of this invention have a strong inhibitory effect on pSTAT6 levels.

[0303] Table 2

[0304] “A”: IC 50 < 10 nM; “B”: 10 nM ≤ IC 50 < 100 nM; “C”: 100 nM ≤ IC 50 <1000 nM; “D”: IC 50 ≥ 1000 nM;

[0305] Test Example 3: ELISA Detection Method for IL-4-Induced TARC Release in Human Whole Blood

[0306] 1. Compound preparation and treatment: The compound was serially diluted 3-fold in 384-well PP plates to a total of 10 concentration points, and 150 nL of the compound was transferred to 96-well cell culture plates.

[0307] 2. Whole blood processing: Whole blood (with sodium heparin as anticoagulant) was added at 140 μL / well to a 96-well cell culture plate containing the test compound. After centrifugation and mixing, the plate was incubated at 37 ℃ / 5% CO2 for 1 hour (the final incubation top concentration of the test compound was 10 μM, with a 3-fold concentration gradient).

[0308] 3. Stimulation and Cultivation: After treating the compound for 1 hour, add 10 μL of rhIL-4 to each well, incubate with shaking (final concentration 10 ng / mL), and incubate in a 37℃ / 5% CO2 incubator for 24 hours. Then collect the supernatant for analysis.

[0309] 4. ELISA test (according to the instructions): Following the instructions, add standards and test samples to the ELISA plate, incubate in the dark for 90 minutes, then wash the plate 5 times with washing buffer (350 μL / well). Add 100 μL of antibody to the plate, incubate for 60 minutes, then wash the plate 5 times with washing buffer (350 μL / well). Add 100 μL of enzyme-linked polymerase to each well, incubate for 30 minutes, then wash the plate 5 times with washing buffer (350 μL / well). Add 100 μL of chromogenic substrate to each well, and develop the color for 10-20 minutes in the dark. Add 100 μL of stop solution to each well, and measure the OD450 nm value using Ensight.

[0310] Tests have shown that the compounds of this invention have a good inhibitory effect on IL-4-induced release of TARC protein in human whole blood.

[0311] Table 3

[0312] “A”: IC 50 < 100 nM; “B”: 100 nM ≤ IC 50 < 1000 nM; “C”: IC 50 ≥ 1000nM.

Claims

1. The compound represented by formula (A), its stereoisomers, tautomers, or pharmaceutically acceptable salts: (A) in, R' is -C(O)NR a R b -NR a -C(O)NR a R b Optional substitutions include: 5-12 membered heterocyclic alkyl, 5-12 membered heterocyclic alkenyl, and 5-12 membered heteroaryl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 6-10 Aryl, 5-10 quinone heteroaryl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; R a R b They are hydrogen, deuterium, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl; R is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, amino-C 1-6 Alkyl-, C 1-6 Oxyalkyl, N-acetamido-C 1-6 Alkyl-, C 1-6 alkyl-amino-formyl-, N-methyl-C 1-6 alkyl-amino-formyl-, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-, C 1-6 Alkyl-4-6-membered heterocyclic alkyl-, 5-6-membered heteroaryl, phenyl, C 1-6 Alkyl-5-6-membered heteroaryl-, C 1-6 alkyl-phenyl-, 5-6-membered heteroaryl-, C 1-6 Alkyl-5-6-membered heteroaryl-5-6-membered heteroaryl-,-C(=O)NR 11 R 12 -S(O)2NR 11 R 12 hydroxyl C 1-6 Alkyl-5-6-membered heteroaryl-, amino C 1-6 Alkyl-5-6-membered heteroaryl-hydroxy C 1-6 Alkyl-4-6-membered heterocyclic alkyl-, amino-C 1-6 Alkyl-4-6-membered heterocyclic alkyl-,-C 0-2 Alkylene-NR 11 -C(O)NR 11 R 12 -C 0-2 Alkylene C(O)NR 11 R 12 ; R'' represents hydrogen, deuterium, or -C. 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; Ring A is an 8-15 member heteroaryl group; R 11 For hydrogen, deuterium, -C 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino-C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 Thioalkyl; R A Each time it appears, it is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 -P(O)R a4 R a5 -NR a2 R a3 Optional replacement: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl, carboxyl, amino, -N(CH3)2, -NHCH3; R a1 R a2 R a3 R a4 R a5 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl; each substituent is independently selected from: deuterium, hydroxyl, halogen, amino, oxo, C 1-6 Alkyl, C 1-6 oxane, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 oxane; X1 is CR x1 Or N; X2 is CR x2 Or N; X4 is CR x4 Or N; X5 is CR x5 Or N; and X1, X2, X4, and X5 are not all N at the same time; Rx1, Rx2, Rx4, and Rx5 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; Y1, Y2, Y3, and Y4 are each independently CR Y1 CR Y2 CR Y3 CR Y4 Or N; and Y1, Y2, Y3, Y4 are not all N at the same time; R Y1 R Y2 R Y3 R Y4 Each element is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; m is 1, 2, 3, or 4; The prerequisite is that ring A is not , , , , , ; The end is the one that connects to the carbonyl group; Unless otherwise stated, the heteroatoms in the above heteroalkyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

2. The compound represented by formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts: (I) in, R is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, amino-C 1-6 Alkyl-, C 1-6 Oxyalkyl, N-acetamido-C 1-6 Alkyl-, C 1-6 alkyl-amino-formyl-, N-methyl-C 1-6 alkyl-amino-formyl-, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-, C 1-6 Alkyl-4-6-membered heterocyclic alkyl-, 5-6-membered heteroaryl, phenyl, C 1-6 alkyl-5-6-membered heteroaryl-, C 1-6 alkyl-phenyl-, 5-6-membered heteroaryl-, C 1-6 Alkyl-5-6-membered heteroaryl-5-6-membered heteroaryl-,-C(=O)NR 11 R 12 -S(O)2NR 11 R 12 ; Ring A is an 8-12 membered heteroaryl group; R 11 For hydrogen, deuterium, or optional substitution: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino-C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 Thioalkyl; R A Each time it appears, it is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 -P(O)R a4 R a5 -NR a2 R a3 Optional replacement: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 oxane, C 1-6 Thioalkyl, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl; R a1 R a2 R a3 R a4 R a5 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl; each substituent is independently selected from: deuterium, hydroxyl, halogen, amino, oxo, C 1-6 Alkyl, C 1-6 oxane, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 oxane; X1 is CR x1 Or N; X2 is CR x2 Or N; X4 is CR x4 Or N; X5 is CR x5 Or N; and X1, X2, X4, and X5 are not all N at the same time; Rx1, Rx2, Rx4, and Rx5 are independently selected from hydrogen, deuterium, halogen, cyano, and C, respectively. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; Y1, Y2, Y3, and Y4 are each independently CR Y1 CR Y2 CR Y3 CR Y4 Or N; and Y1, Y2, Y3, Y4 are not all N at the same time; R Y1 R Y2 R Y3 R Y4 Each element is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Oxyalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Oxyalkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxane; m is 1, 2, 3, or 4; The prerequisite is that ring A is not , , , , , ; The end is the one that connects to the carbonyl group; Unless otherwise stated, the heteroatoms in the above heteroalkyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

3. The compound of claim 1 or 2, its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: R' is -C(O)NR a R b -NR a -C(O)NR a R b Optional substitutions include: 5-10 membered heterocyclic alkyl, 5-10 membered heterocyclic alkenyl, and 5-10 membered heteroaryl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, oxo, C 1-3 Alkyl, C 1-3 Oxyalkyl, phenyl, 5-6 quinone heteroaryl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Oxyalkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane; Among them, R a R b They are hydrogen, deuterium, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl; further, R a R b They are, independently, hydrogen, deuterium, methyl, and ethyl; further, R a R b They are hydrogen and methyl groups, which are independent of each other. Preferably, R' is optionally substituted: a 5-membered heterocyclic alkenyl group or a 5-membered heteroaryl group; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, halogen, cyano, oxo, C 1-3 Alkyl, C 1-3 Oxyalkyl, phenyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Oxyalkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane; More preferably, R' is , Or, R' is , .

4. The compound according to any one of claims 1-3, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the compound, wherein: R is C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl-, amino-C 1-4 Alkyl-, C 1-4 Oxyalkyl, N-acetamido-C 1-4 Alkyl-, C 1-4 alkyl-amino-formyl-, N-methyl-C 1-4 alkyl-amino-formyl-, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Alkyl-C 3-6 cycloalkyl-, C 1-4 Alkyl-4-6-membered heterocyclic alkyl-, 5-6-membered heteroaryl, phenyl, C 1-4 Alkyl-5-6-membered heteroaryl-, C 1-4 alkyl-phenyl-, 5-6-membered heteroaryl-, C 1-4 Alkyl-5-6-membered heteroaryl-5-6-membered heteroaryl-,-C(=O)NR 11 R 12 -S(O)2NR 11 R 12 hydroxyl C 1-4 Alkyl-5-6-membered heteroaryl-, amino C 1-4 Alkyl-5-6-membered heteroaryl-hydroxy C 1-4 Alkyl-4-6-membered heterocyclic alkyl-, amino-C 1-4 Alkyl-4-6-membered heterocyclic alkyl-,-C 0-2 Alkylene-NR 11 -C(O)NR 11 R 12 -C 0-2 Alkylene C(O)NR 11 R 12 ; R 11 For hydrogen, deuterium, -C 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-4 Cycloalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-3 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino-C 1-4 Alkyl, deuterated C 1-4 Oxyalkyl, halogenated C 1-4 Oxyalkyl, deuterated C 1-4 Thioalkyl, halogenated C 1-4 Thioalkyl; Preferably, R is -C(=O)NR 11 R 12 -S(O)2NR 11 R 12 hydroxyl C 1-3 alkyl-5-6-membered heteroaryl-,-methylene-NR 11 -C(O)NR 11 R 12 -NR 11 -C(O)NR 11 R 12 ,-methylene C(O)NR 11 R 12 ;; R 11 For hydrogen, deuterium, methylene-OP(O)(OH)2, or optionally substituted: C 1-4 Alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; R 12 For hydrogen, deuterium, or optional substitution: C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; More preferably, R is -C(=O)NHR 12 -S(O)2NHR 12 ; R 12 For hydrogen, deuterium, or optional substitution: C 1-3 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkenyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; further preferred, R 12 The substituted group is hydrogen, deuterium, or optionally substituted: methyl, ethyl, isopropyl, 5-6 membered heteroaryl, 6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl; further preferably, R 12 For hydrogen, methyl or , , , , , , , or , R1 and R2 are hydrogen, deuterium, halogen, cyano, amino, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or hydroxyethyl; more preferably, R 12 For hydrogen, methyl, , , , , , , , , , , , , ; Further preferred, R is , , , , , , , , , , , , , , , , , , , .

5. The compound according to any one of claims 1-4, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the compound, wherein: R'' represents hydrogen, deuterium, or -C. 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-4 Alkyl, C 1-4 Oxyalkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; Preferably, R'' is hydrogen, deuterium, or -C. 0-2 Alkylene-OP(O)(OH)2, or optionally substituted: C 1-3 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from: deuterium, halogen, cyano, amino, hydroxyl, oxo; more preferably, R'' is hydrogen, methyl, , .

6. The compound according to any one of claims 1-5, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the compound, wherein: Ring A is an 8-13 member heteroaryl group; Preferably, ring A is an 8-10 member heteroaryl group; more preferably, ring A is an 8-9 member heteroaryl group. Further optimization, ring A is or Ring A is In the case where (i) ring C is phenyl or a 5-6-membered heteroaryl, and ring B is a 5-membered heteroaryl; or (ii) ring C is a 5-membered heteroaryl, and ring B is phenyl or a 6-membered heteroaryl, and Not for , , , , , ; or ring A is In this ring, ring C is phenyl or a 5-6 membered heteroaryl, ring B is a 5 membered heteroaryl, and ring D is a 5-6 membered heterocyclic group; Further optimization, ring A is , , , , , , , , , , , , , , , , , , , , , , ; The end is the connection point with the carbonyl group.

7. The compound according to any one of claims 1-6, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt of the compound, wherein: R A Individually, they can be hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 -P(O)R a4 R a5 -NR a2 R a3 Or, alternatively: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 oxane, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl, carboxyl, amino, -N(CH3)2, -NHCH3; R a1 R a2 R a3 R a4 R a5 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl; each substituent is independently selected from: deuterium, hydroxyl, halogen, amino, oxo, C 1-3 Alkyl, C 1-3 oxane, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, 4-6 membered heterocyclic alkenyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 oxane; Preferred, R A Individually, they can be hydrogen, deuterium, halogen, cyano, hydroxyl, oxo group, or -S(O)R. a1 -S(O)2R a1 -S(O)=NR a2 R a3 -S(O)2NR a2 R a3 Or, alternatively: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 oxane, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, carboxyl, -N(CH3)2; R a1 R a2 R a3 C is selected independently from hydrogen, deuterium, or optionally substituted: 1-4 Alkyl, C 3-6 Cycloalkyl; each of the substituents is independently selected from: deuterium, hydroxyl, halogen, amino, oxo group; More preferably, R A They are, independently, hydrogen, deuterium, halogens (F, Cl, Br), cyano, and -S(O)2R. a1 Or, alternatively: C 1-4 Alkyl, C 1-4 oxane, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from: deuterium, hydroxyl, halogen, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, carboxyl, -N(CH3)2; R a1 Selected from hydrogen, deuterium, and C 1-4 alkyl; Further preferred, R A Individually, they are hydrogen, F, Cl, cyano, oxo, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methanesulfonyl, oxetane, difluoromethyl, trifluoromethyl, deuterated methyl, , , , , , , , , .

8. The compound according to any one of claims 1-7, wherein the stereoisomer, tautomer or pharmaceutically acceptable salt of the compound, wherein X1, X2, X4 and X5 are independently CRx1, CRx2, CRx4 and CRx5, respectively; Alternatively, X1, X4, and X5 can be independently represented as CRx1, CRx4, and CRx5, respectively; and X2 is N. Alternatively, X2, X4, and X5 can be independently represented as CRx2, CRx4, and CRx5, respectively; and X1 can be N.

9. The compound according to any one of claims 1-8, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the compound, wherein: Rx1, Rx2, Rx4, and Rx5 are respectively hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C. 1-4 Alkyl, C 1-4 Oxyalkyl, halogenated C 1-4 Alkyl, Halogenated C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; Preferably, Rx1, Rx2, Rx4, and Rx5 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; More preferably, Rx1, Rx2, Rx4, and Rx5 are hydrogen, deuterium, halogen, and hydroxyl, respectively; even more preferably, Rx1, Rx4, and Rx5 are all hydrogen; and Rx2 is hydrogen, F, Cl, or hydroxyl.

10. The compound according to any one of claims 1-9, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the compound, wherein: Y1, Y2, Y3, and Y4 are each independently CR Y1 CR Y2 CR Y3 CR Y4 ; Alternatively, Y1 is N; and Y2, Y3, and Y4 are each independently CR. Y2 CR Y3 CR Y4 ; Alternatively, Y2 is N; and Y1, Y3, and Y4 are each independently CR. Y1 CR Y3 CR Y4 .

11. The compound according to any one of claims 1-10, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of the compound, wherein: R Y1 R Y2 R Y3 R Y4 The components are hydrogen, deuterium, halogen, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, halogenated C 1-4 Alkyl, Halogenated C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; Preferred, R Y1 R Y2 R Y3 R Y4 The components are hydrogen, deuterium, halogen, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Oxyalkyl, deuterated C 1-4 Alkyl, deuterated C 1-4 oxane; More preferably, R Y1 R Y2 R Y3 R Y4 Hydrogen and halogen are respectively independent; further preferred, R Y1 R Y2 R Y3 R Y4 They are hydrogen and F, respectively.

12. The compound of claims 1-11, wherein the stereoisomer, tautomer, or pharmaceutically acceptable salt of the compound, wherein: m is 1 or 2; preferably, m is 1.

13. A compound of formula (II-A) or formula (II-B) or shown therein, a stereoisomer, tautomer, or pharmaceutically acceptable salt of said compound, wherein: 、 (Ⅱ-A) (Ⅱ-B) in, Rings A and R A ,X1,X2,Y1,Y2,Y3,Y4,m,R 12 As described in claims 1-12, of formula (A) or (I).

14. A compound of formula (Ⅲ-A) or (Ⅲ-B), its stereoisomer, tautomer, or pharmaceutically acceptable salt: 、 (Ⅲ-A) (Ⅲ-B) in, Rings A and R A X1, X2, Y1, Y2, Y3, Y4, m are as described in claims 1-12 of formula (A) or (I).

15. A compound of formula (IV), its stereoisomer, tautomer, or pharmaceutically acceptable salt: (Ⅳ) in, R A ,X1,X2,Y1,Y2,Y3,Y4,R 12 As described in claims 1-12, of formula (A) or (I), wherein Z is CH or N.

16. A compound of formula (A1), its stereoisomer, tautomer, or pharmaceutically acceptable salt: (A1) in, Rings A and R A X1, X2, R'', R are as described in claims 1-12 of formula (A) or (I).

17. A compound, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: 。 18. A pharmaceutical composition comprising the compound of any one of claims 1 to 17, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

19. Use of the compound of any one of claims 1-17, a stereoisomer of the compound, a tautomer of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18 in the preparation of a medicament for treating and / or preventing STAT6-related diseases.

20. The use as described in claim 19, wherein, The STAT-related diseases are STAT6-related allergic and inflammatory diseases, autoimmune disorders, and other diseases or conditions; more preferably, the diseases are those used to treat and / or prevent atopic dermatitis, asthma, allergic rhinitis, chronic spontaneous urticaria, eosinophilic esophagitis, nodular prurigo, chronic sinusitis with nasal polyps, adult bullous pemphigoid, and certain forms of chronic obstructive pulmonary disease, tumors (including malignant lymphoma, pancreatic cancer, colorectal cancer, prostate cancer, and breast cancer), etc.

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