Compounds as TRK and / or RET inhibitors and their uses

Abstract

The present invention relates to a compound and its use as a TRK inhibitor drug or a RET inhibitor drug. Specifically, the present invention discloses the use of a compound represented by formula (G), or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a TRK inhibitor drug and / or a RET inhibitor drug. [Formula 1] TIFF2025525428000150.tif54137

Description

[Technical Field]

[0001] The present invention provides the use of a class of compounds for TRK kinase and / or RET kinase. The invention further relates to compositions comprising said compounds and the use of said compounds and said compositions in the manufacture of a medicament for the treatment and / or prevention of a disease or condition associated with TRK and / or RET. [Background technology]

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine kinases and serine / threonine kinases. Inappropriate kinase activity due to mutations, overexpression or improper regulation, abnormal or impaired regulation, and overproduction or underproduction of growth factors or cytokines is associated with numerous diseases, including, but not limited to, cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases (e.g., Alzheimer's disease). Inappropriate kinase activity triggers multiple biological cellular responses related to cell growth, differentiation, function, survival, apoptosis, and motility in these related diseases. Therefore, protein kinases have become important enzyme targets for therapeutic intervention.

[0003] TRK kinases are high-affinity receptor tyrosine kinases activated by a group of soluble growth factors (called neurotrophic factors (NTs)). The TRK family includes three members: TRKA, TRKB, and TRKC. Among them, TRKA is activated by nerve growth factor (NGF), TRKB is activated by brain-derived nerve growth factor (BDNF) and NT-4 / 5, and TRKC is activated by NT3. TRKs are widely expressed in neuronal tissues and are involved in the maintenance, signal transduction, and survival of neuronal cells.

[0004] Inhibitors of the TRK / neurotrophin pathway have been demonstrated to be effective in numerous preclinical animal models of pain. Because NGF secreted by tumor cells and tumor-infiltrating macrophages is known to directly stimulate surrounding pain fibers, inhibitors of TrkA and / or other Trk kinases may provide effective treatments for chronic pain conditions and cancer-related pain. Overexpression, activation, amplification, and / or mutation of Trk kinases have also been reported to be associated with many cancers, including neuronal carcinoma, colorectal cancer, melanoma, gastric cancer, lung cancer, and breast cancer. In 2018, the US FDA officially approved the first oral TRK inhibitor ever, Vitrakvi (also known as larotrectinib, larotinib, or LOXO101), produced by Loxo Oncology, Inc., for use in treating patients with solid tumors harboring neurotrophic tyrosine kinase (NTRK) gene fusions. Vitrakvi has demonstrated extremely high therapeutic efficacy against a variety of cancers. Furthermore, TRK inhibitors have been found to be useful in the treatment of inflammatory and autoimmune diseases.

[0005] RET kinase is also a very important drug target. In May 2020, the FDA approved the world's first RET kinase inhibitor, selpercatinib (Retevmo), developed by Loxo Oncology, for the treatment of non-small cell lung cancer, thyroid myeloid carcinoma, and other types of thyroid cancer. Then, in September 2020, the FDA approved pralsetinib, a RET kinase inhibitor developed by Blueprint Medicines, for the treatment of adult patients with RET fusion-positive metastatic non-small cell lung cancer.

[0006] Currently, several TRK or RET inhibitors have been approved on the market, and a large number of TRK or RET inhibitors are under clinical research, but these TRK / RET inhibitors have not been able to achieve the expected therapeutic efficacy or safety. Therefore, there is a constant need for TRK inhibitors or RET inhibitors with better therapeutic efficacy and / or fewer side effects. Summary of the Invention

[0007] One object of the present invention is to provide a novel TRK inhibitor that can replace conventional TRK inhibitors, thereby providing many options for the treatment of TRK-related diseases.

[0008] A further object of the present invention is to provide a novel TRK inhibitor that is more effective and / or safer than conventional TRK inhibitors.

[0009] Another object of the present invention is to provide a novel RET inhibitor that can replace conventional RET inhibitors, thereby providing more options for the treatment of RET-related diseases.

[0010] A further object of the present invention is to provide a new type of RET inhibitor that is more effective and / or safer than conventional RET inhibitors.

[0011] Another objective of the present invention is to provide alternative or more effective therapies for TRK- and / or RET-related diseases, such as pruritus, psoriasis, atopic dermatitis, acne, vitiligo, alopecia areata, asthma, rhinitis, ulcerative colitis, cervicitis, pneumonia, and cancer (tumor), thereby providing more options for treating these diseases. Chinese Patent CN111606908B (equivalent to U.S. Patent Publication US2022 / 0073524A1) discloses a class of compounds as pan-JAK inhibitors. JAK, an abbreviation for Janus kinase, is a cytoplasmic tyrosine kinase that transmits cytokine signals from membrane receptors to STAT transcription factors. JAK is a highly important drug target and is involved in many important biological processes, such as cell proliferation, differentiation, apoptosis, and immunoregulation. JAK inhibitors developed against this target are primarily used in the treatment of hematological diseases, tumors, rheumatoid arthritis, and other conditions. The JAK protein family includes four members: JAK1, JAK2, JAK3, and TYK2. As described in CN111606908B, the disclosed compound has high inhibitory activity against JAK1, JAK2, JAK3, and TYK2, and is a highly efficient pan-JAK inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0012] During the course of research, the inventors unexpectedly discovered that the compounds disclosed in CN111606908B are pan-TRK inhibitors, which have very high inhibitory activity against TRK kinases, and also have very good inhibitory activity against TRKA, TRKB, and TRKC.

[0013] Furthermore, the inventors have unexpectedly discovered that the compounds disclosed in CN111606908B also have extremely high inhibitory activity against RET kinase.

[0014] Pegcantratinib (SNA-125), developed by Sienna Pharm, can simultaneously inhibit JAK3 and TRKA, but its inhibitory effect on JAK kinase and other members of the TRK kinase family is poor, and it has been reported that clinical trials for psoriasis ultimately failed. To the inventors' knowledge, no compound has yet been reported that simultaneously exhibits broad and efficient inhibitory activity against JAK kinase and TRK kinase, and the compound of the present application is the first reported pan-JAK / pan-TRK inhibitor.

[0015] Due to their dual or multiple broad-spectrum inhibitory activity against JAK, TRK, and RET, the compounds described in the present invention can provide superior therapeutic effects to conventional drugs for the treatment of many diseases and can also treat acne, a side effect caused by other JAK inhibitors (Int. J. Dermatol. 2021 Aug. 22. doi:10.1111 / ijd.15853. PMID:34423443). The compounds of the present application have been found to be particularly suitable for the treatment of autoimmune diseases, particularly cutaneous autoimmune diseases. Furthermore, animal models have demonstrated that the compounds of the present application are effective in treating diseases such as pruritus, psoriasis, atopic dermatitis, cutaneous side effects caused by EGFR inhibitors (e.g., those diseases listed in CN112933095 A), acne, vitiligo, alopecia areata, asthma, rhinitis, ulcerative colitis, cervicitis, pneumonia, slow wound healing (due to diabetes), diabetes, and diabetic complications (e.g., diabetic foot).

[0016] The inventors also unexpectedly discovered that the compounds disclosed in CN111606908B have excellent therapeutic effects on chronic wound healing, including diabetic foot and pressure ulcers. Diabetic foot, a common diabetic complication, affects nearly 400 million people worldwide. Approximately 30% of patients ultimately undergo amputation due to poor wound healing. Currently, effective drugs for the treatment of diabetic foot are lacking. Recent studies have shown that adipocytes must lipolyze and transform into myofibroblasts for wound healing and skin repair, but patients with diabetic foot have poorer ability to do so (Cell Stem Cell 26, 1-16, June 4, 2020). The inventors unexpectedly discovered that the compounds disclosed in CN111606908B can effectively promote adipocyte lipolysis in vitro, whereas another JAK inhibitor, tofacitinib, has no similar effect, and no JAK inhibitors have been reported to promote adipocyte lipolysis to date. The inventors also discovered that the compounds disclosed in CN111606908B significantly increase the number of myofibroblasts in wounds of diabetic animals in vivo and promote wound healing in diabetic animals. Given that conventional JAK inhibitors are ineffective in promoting adipocyte lipolysis, the inventors believe that the therapeutic effects of the compounds disclosed in CN111606908B in diabetic foot animals are due to the ubiquitous JAK / ubiquitous TRK dual inhibitory activity or the ubiquitous JAK / ubiquitous TRK / RET multiple inhibitory activity of these compounds. The inventors believe that JAK / TRK dual inhibitors (preferably ubiquitous JAK / ubiquitous TRK dual inhibitors) or JAK / TRK / RET multiple inhibitors (preferably ubiquitous JAK / ubiquitous TRK / RET multiple inhibitors) will have favorable effects on chronic wound healing, including, but not limited to, diabetic foot and pressure ulcers.

[0017] In a first aspect, the present invention provides a compound of formula (G): [ka] or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein: L is C=O, O=S=O, CH2 or a bond; X1 is N or CR 14 and X2 is N or CR 15 and X3 is N or CR 16 and R 14 , R 15 , R 16 are H, -OH, -SH, -CN, halogens, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein each independently selected from -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl and 3- to 7-membered heterocycloalkyl are halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 alkyl)2, -N(C 1-4 alkyl)(C(=O)C 1-4 alkyl), C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents selected from haloalkoxy; R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -SR 12 , -OR 12 , -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, or 5- to 11-membered bicycloheteroalkyl, and R 13 is substituted with 0, 1, 2, 3, or 4 R1, where R 17 , R 18 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and —OH, —CN, —SH, halogen, —NO2, —SF5, —SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 and optionally substituted with one or more substituents each independently selected from the group consisting of: 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11)(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 or R 17 , R 18 form a 3-14 membered ring together with the N atom to which they are attached, The number of R2 is 0, 1, 2, 3, or 4, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, or -SC. 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein said -SC is selected from 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein said -SC is selected from 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl is optionally substituted with 1, 2, 3, or 4 R4; R3 and R4 are H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R5)(R6), -N(R 11 )(C(=O)R 12 ), -CON(R7)(R8), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein each C is independently selected from 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 and R5, R6, R7, R8, R9, R 10 , R 11 , R 12 are each independently H or C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each member within the group is selected from the group consisting of halogen, —CF3, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy.

[0018] In some preferred embodiments of the present invention, isotopically labeled compounds of the compound of formula (G) are used. In some more preferred embodiments of the present invention, isotopically labeled compounds of the compound of formula (G) are used, wherein all H are each independently optionally replaced with D.

[0019] In some preferred embodiments of the present invention, in formula (G), X1 is N. In some preferred embodiments of the present invention, in formula (G), X2 is N. In some preferred embodiments of the present invention, in formula (G), X3 is N. In some preferred embodiments of the present invention, in formula (G), X1 is CR 14 and X2 is N or CR 15 and X3 is CR 16 In some preferred embodiments of the present invention, in formula (G), X1 is CR 14 and X2 is CR 15 and X3 is CR 16 In some preferred embodiments of the present invention, in formula (G), X1 is CR 14 and X2 is CR 15 and X3 is CR 16 and R 14 , R 15 , R 16 are H, -OH, halogen, and C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 In some preferred embodiments of the present invention, in formula (G), X is selected from CR14 , X2 is N, and X3 is CR 16 and R 14 , R 16 are H, -OH, halogen, and C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 In some preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are the same. In some preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all CH. In some preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all N. In some preferred embodiments of the present invention, in formula (G), X1 is C(CH3), and X2 and X3 are all CH. In some preferred embodiments of the present invention, in formula (G), X2 is C(CH3), and X1 and X3 are all CH. In some preferred embodiments of the present invention, in formula (G), X3 is C(CH3), and X1 and X2 are all CH. In some preferred embodiments of the present invention, in formula (G), X1 is N, and X2 and X3 are all CH. In some preferred embodiments of the present invention, in formula (G), X2 is N, and X1 and X3 are all CH. In some preferred embodiments of the present invention, in formula (G), X3 is N, and X1 and X2 are both CH.

[0020] In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, and X1, X2, and X3 are the same. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, and X1, X2, and X3 are all CH. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, and X1 is C(CH3), and X2 and X3 are all CH. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, and X2 is C(CH3), and X1 and X3 are all CH. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, X3 is C(CH3), and X1 and X2 are both CH. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, X1 is N, and X2 and X3 are both CH. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, X2 is N, and X1 and X3 are both CH. In some more preferred embodiments of the present invention, an isotopically labeled compound of a compound of formula (G) is used, wherein all H are each separately optionally replaced with D, X3 is N, and X1 and X2 are both CH.

[0021] In some preferred embodiments of the present invention, in formula (G), L is C=O, O=S=O, or CH2. In some particularly preferred embodiments of the present invention, in formula (G), L is C=O. In some particularly preferred embodiments of the present invention, in formula (G), L is O=S=O. In some particularly preferred embodiments of the present invention, in formula (G), L is CH2. In other some embodiments of the present invention, in formula (G), L is a bond.

[0022] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all CH, and L is C=O.

[0023] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all CH, and L is O=S=O.

[0024] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all CH, and L is CH2.

[0025] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all CH, and L is a bond.

[0026] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all N, and L is C=O.

[0027] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all N, and L is O=S=O.

[0028] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all N, and L is CH2.

[0029] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are all N, and L is a bond.

[0030] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are each CR 14 where R 14 -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and L is C=O.

[0031] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are each CR 14 where R 14 -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and L is O=S=O.

[0032] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are each CR 14 where R 14 -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and L is CH2.

[0033] In some particularly preferred embodiments of the present invention, in formula (G), X1, X2, and X3 are each CR 14 where R 14 -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, and L is a bond.

[0034] In some particularly preferred embodiments of the present invention, in formula (G), X1 is C(CH3), X2 and X3 are both CH, and L is C=O.

[0035] In some particularly preferred embodiments of the present invention, in formula (G), X1 is C(CH3), X2 and X3 are both CH, and L is O=S=O.

[0036] In some particularly preferred embodiments of the present invention, in formula (G), X1 is C(CH3), X2 and X3 are both CH, and L is CH2.

[0037] In some particularly preferred embodiments of the present invention, in formula (G), X1 is C(CH3), X2 and X3 are both CH, and L is a bond.

[0038] In some particularly preferred embodiments of the present invention, in formula (G), X2 is C(CH3), X1 and X3 are both CH, and L is C=O.

[0039] In some particularly preferred embodiments of the present invention, in formula (G), X2 is C(CH3), X1 and X3 are both CH, and L is O=S=O.

[0040] In some particularly preferred embodiments of the present invention, in formula (G), X2 is C(CH3), X1 and X3 are both CH, and L is CH2.

[0041] In some particularly preferred embodiments of the present invention, in formula (G), X2 is C(CH3), X1 and X3 are both CH, and L is a bond.

[0042] In some particularly preferred embodiments of the present invention, in formula (G), X3 is C(CH3), X1 and X2 are both CH, and L is C=O.

[0043] In some particularly preferred embodiments of the present invention, in formula (G), X3 is C(CH3), X1 and X2 are both CH, and L is O=S=O.

[0044] In some particularly preferred embodiments of the present invention, in formula (G), X3 is C(CH3), X1 and X2 are both CH, and L is CH2.

[0045] In some particularly preferred embodiments of the present invention, in formula (G), X3 is C(CH3), X1 and X2 are both CH, and L is a bond.

[0046] In some particularly preferred embodiments of the present invention, in formula (G), X1 is N, X2 and X3 are both CH, and L is C=O.

[0047] In some particularly preferred embodiments of the present invention, in formula (G), X1 is N, X2 and X3 are both CH, and L is O=S=O.

[0048] In some particularly preferred embodiments of the present invention, in formula (G), X1 is N, X2 and X3 are both CH, and L is CH2.

[0049] In some particularly preferred embodiments of the present invention, in formula (G), X1 is N, X2 and X3 are both CH, and L is a bond.

[0050] In some particularly preferred embodiments of the present invention, in formula (G), X2 is N, X1 and X3 are both CH, and L is C=O.

[0051] In some particularly preferred embodiments of the present invention, in formula (G), X2 is N, X1 and X3 are both CH, and L is O=S=O.

[0052] In some particularly preferred embodiments of the present invention, in formula (G), X2 is N, X1 and X3 are both CH, and L is CH2.

[0053] In some particularly preferred embodiments of the present invention, in formula (G), X2 is N, X1 and X3 are both CH, and L is a bond.

[0054] In some particularly preferred embodiments of the present invention, in formula (G), X3 is N, X1 and X2 are both CH, and L is C=O.

[0055] In some particularly preferred embodiments of the present invention, in formula (G), X3 is N, X1 and X2 are both CH, and L is O=S=O.

[0056] In some particularly preferred embodiments of the present invention, in formula (G), X3 is N, X1 and X2 are both CH, and L is CH2.

[0057] In some particularly preferred embodiments of the present invention, in formula (G), X3 is N, X1 and X2 are both CH, and L is a bond.

[0058] In some preferred embodiments of the present invention, in formula (G), R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl or C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and R 17 , R 18 are H, C separately.1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5, where R 13 is optionally substituted with 1, 2, 3, or 4 R. In some preferred embodiments of the present invention, in formula (G), R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, or 11-15 membered tricyclo, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, 3, or 4 R. In some preferred embodiments of the present invention, in formula (G), R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, or 5-7 membered heteroaryl, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, 3, or 4 R. In some preferred embodiments of the present invention, in formula (G), R 13 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6Alkyl, C 3-7 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, or 3 R. In some preferred embodiments of the present invention, in formula (G), R 13 -N(R 17 )(R 18 ), C 1-3 Alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, or C 1-4 alkyl, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, or 3 R. In some preferred embodiments of the present invention, in formula (G), R 13 is -N(H)(C 1-3 alkyl), -N(H)(3-6 membered cycloalkyl), -N(H)(4-6 membered heterocycloalkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl), C 1-3 Alkoxy, C 3-6 cycloalkyl, 4-6 membered azacycloalkyl or oxacycloalkyl, phenyl, 5-6 membered azaaryl, or C 1-4 alkyl or R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a 4-10 membered ring together with the N atom to which they are attached (where R 13 is optionally substituted with 1, 2, or 3 R. In some particularly preferred embodiments of the present invention, in formula (G), R 13is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, -N(H)(CH), -N(H)(CHCH), -N(H)(CHCHOH), -N(H)(CHCHCN), -N(CH)(CH), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl, pyrrolidinyl, pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl, piperazinyl or tetrahydropyranyl; or R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached (where R 13 is optionally substituted with 1, 2, or 3 R. In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(H)(CH). In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(H)(CHCHOH). In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(CH)(CH). In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (G), R 13 is —N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (G), R13 is —N(H) (tetrahydropyranyl). In some particularly preferred embodiments of the present invention, in formula (G), R 13 -N(R 17 )(R 18 ) and R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached.

[0059] In some preferred embodiments of the present invention, in formula (G), R 17 , R 18 are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 In some preferred embodiments of the present invention, in formula (G), R 17 , R 18 are H, C separately. 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 In some preferred embodiments of the present invention, in formula (G), R 17 , R 18 are H, C separately. 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 In some preferred embodiments of the present invention, in formula (G), R 17 , R 18are each independently selected from H, methyl, ethyl, propyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, and are optionally substituted with one or more of -OH, -CN. In some preferred embodiments of the present invention, in formula (G), R 17 , R 18 In some preferred embodiments of the present invention, in formula (G), R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached.

[0060] In some particularly preferred embodiments of the present invention, in formula (G), L is C=O and R 13 -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5 or -SC 1-4 alkyl, and R 13 is substituted with 0, 1, 2, 3 or 4 R1, where R 17 , R 18 are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5, or R 17 , R 18 form a 3-14 membered ring together with the N atom to which they are attached. In some particularly preferred embodiments of the present invention, in formula (G), L is C=O and R 13 -N(R 17 )(R 18 ), C 1-6 alkoxy, where R 17 , R 18 are H, C separately. 1-6 Alkyl, C 3-7Cycloalkyl, C 3-7 heterocycloalkyl and optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5, or R 17 , R 18 form a 3-10 membered ring together with the N atom to which they are attached. In some particularly preferred embodiments of the present invention, in formula (G), L is C=O and R 13 is methoxy, ethoxy, propoxy, -N(H)(CH), -N(H)(CHCH), -N(H)(CHCHOH), -N(H)(CHCHCN), -N(CH)(CH), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), or R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a 7-membered ring together with the N atom to which they are attached. In some particularly preferred embodiments of the present invention, in formula (G), L is C=O and R 13 In some particularly preferred embodiments of the present invention, in formula (G), L is C=O and R 13 In some particularly preferred embodiments of the present invention, in formula (G), L is C=O and R 13 is —N(H)(CH). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 is —N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 is —N(H)(CHCHOH). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 is —N(H)(CHCHCN). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 is —N(CH)(CH). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13is —N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 is —N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 is —N(H) (tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (G), L is C═O and R 13 -N(R 17 )(R 18 ) and R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached.

[0061] In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1, 2, or 3, and R2 is H, halogen, —OH, —NO2, —CN, —SF5, —SH, —SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with halogen, -OH, -NH, -NH(CH), -N(CH), -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1, 2, or 3, and R2 is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl, and C3-6 Cycloalkyl is a group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1, 2, or 3, and R2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, wherein said C 1-6 Alkyl is a halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1 or 2, and R2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C 1-6In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, methyl, ethyl, n-propyl, and isopropyl. In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1 or 2, and R2 is selected from fluorine, methyl, and ethyl. In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1 or 2, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (G), the number of R2 is 1, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (G), the number of R2 is 2, and R2 is selected from fluorine and ethyl. In some particularly preferred embodiments of the present invention, in formula (G), there are two R2, which are fluorine and ethyl, respectively. In some particularly preferred embodiments of the present invention, there is one R2 in formula (G), and R2 is ethyl.

[0062] In some preferred embodiments of the present invention, in formula (G), R 13 is substituted with 1, 2, 3, or 4 R2, and each R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7- to 11-membered bicycloheteroaryl, wherein said -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, wherein said C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicycloaryl, 7-11 membered bicycloheteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (G), R 13 is substituted with 1, 2, 3, or 4 R2, and each R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, and 5- to 7-membered heteroaryl, wherein said -SC 1-4 Alkyl, C 1-8 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, wherein said C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 The aryl, 5-7 membered heteroaryl is substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (G), R 13 is substituted with 1, 2, 3, or 4 R2, and each R1 is halogen, -OH, -CN, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5- to 7-membered heteroaryl, wherein 1-8 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, wherein said C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 The aryl, 5-7 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (G), R 13is substituted with 1, 2, 3, or 4 R2, and each R1 is halogen, -OH, -CN, C 1-8 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein 1-8 The alkyl is optionally substituted with 1, 2, or 3 R3, wherein the C 3-7 The cycloalkyl, 3- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R4. In some preferred embodiments of the present invention, in formula (G), R 13 is substituted with 0 or 1 R1, and each R1 is halogen, -OH, -CN, C 1-6 Alkyl, C 3-7 cycloalkyl, 5- to 7-membered heterocycloalkyl, wherein 1-6 The alkyl is optionally substituted with 1, 2, or 3 R3, wherein the C 3-7 The cycloalkyl, 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R4. In some preferred embodiments of the present invention, in formula (G), R 13 is substituted with 0 or 1 R1, and each R1 is halogen, -OH, -CN, C 1-4 Alkyl, C 3-6 cycloalkyl, 5- to 7-membered heterocycloalkyl, wherein 1-4 The alkyl is optionally substituted with one or two R3, wherein the C 3-6 Cycloalkyl, 5-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R4. In some particularly preferred embodiments of the present invention, in formula (G), R 13 is substituted with zero or one R1, each R1 being independently selected from methyl, ethyl, hydroxyl, -CN, piperidinyl, morpholinyl, piperazinyl, and cyclopropyl, wherein piperidinyl, morpholinyl, and piperazinyl are substituted with one, two, three, or four C 1-3 In some particularly preferred embodiments of the present invention, in formula (G), R 13is substituted with zero or one R1, and each R1 is independently selected from methyl, ethyl, hydroxyl, -CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is absent. In some particularly preferred embodiments of the present invention, in formula (G), R1 is 1-methylpiperazinyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is methyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is ethyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is piperidinyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is hydroxyl. In some particularly preferred embodiments of the present invention, in formula (G), R1 is -CN. In some particularly preferred embodiments of the present invention, in formula (G), R1 is cyclopropyl.

[0063] In each of the above preferred embodiments, the preferred options for each of the substituents mentioned above can be combined with each other, and each type of combination also falls within the scope of the present invention.

[0064] In the compound of formula (G), when X1, X2 and X3 are the same, the compound of formula (G) can also be represented as a compound of the following formula (G').

[0065] [ka] where X is N or CR 14 and R 14 , R 13 The definitions of R1, L, and R2 are as described in the compound of formula (G).

[0066] In one preferred embodiment, the present invention provides a compound of formula (G'): [ka] or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is provided for use as a TRK inhibitor drug and / or a RET inhibitor drug, or in the manufacture of a TRK inhibitor drug and / or a RET inhibitor drug, wherein: X is CH or N; L is C=O, O=S=O, CH2 or a bond; R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -SR 12 , -OR 12 , -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, or 5- to 11-membered bicycloheteroalkyl; R 13 is substituted with 0, 1, 2, 3, or 4 R1, where R 17 , R 18 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and —OH, —CN, —SH, halogen, —NO2, —SF5, —SC 1-4 Alkyl, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 and optionally substituted with one or more substituents each independently selected from the group consisting of: 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 or R 17 , R 18 form a 3-14 membered ring together with the N atom to which they are attached, The number of R2 is 0, 1, 2, 3, or 4, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, or -SC. 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein said -SC is selected from 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R10 ), -SR 12 , and -OR 12 wherein said -SC is selected from 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl is substituted with 1, 2, 3, or 4 R4; R3 and R4 are H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R5)(R6), -N(R 11 )(C(=O)R 12 ), -CON(R7)(R8), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein each C is independently selected from 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C1-6 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 and optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of: R5, R6, R7, R8, R9, R 10 , R 11 , R 12 are each independently H or C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each member within the group is selected from the group consisting of halogen, —CF3, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and haloalkoxy.

[0067] In some preferred embodiments of the present invention, an isotopically labeled compound of the compound of formula (G') is used. In some more preferred embodiments of the present invention, an isotopically labeled compound of the compound of formula (G') is used, wherein all H are each independently optionally replaced with D.

[0068] In some preferred embodiments of the present invention, in formula (G), X is N. In some more preferred embodiments of the present invention, in formula (G), X is CH.

[0069] In some more preferred embodiments of the present invention, an isotopically labeled compound of formula (G') is utilized, wherein all H are each separately optionally replaced with D and X is N. In some more preferred embodiments of the present invention, an isotopically labeled compound of formula (G') is utilized, wherein all H are each separately optionally replaced with D and X is CH.

[0070] In some preferred embodiments of the present invention, in formula (G'), L is C=O, O=S=O, or CH2. In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O. In some particularly preferred embodiments of the present invention, in formula (G'), L is O=S=O. In some particularly preferred embodiments of the present invention, in formula (G'), L is CH2. In some other embodiments of the present invention, in formula (G'), L is a bond.

[0071] In some particularly preferred embodiments of the present invention, in formula (G'), X is CH and L is C=O.

[0072] In some particularly preferred embodiments of the present invention, in formula (G'), X is CH and L is O=S=O.

[0073] In some particularly preferred embodiments of the present invention, in formula (G'), X is CH and L is CH2.

[0074] In some particularly preferred embodiments of the present invention, in formula (G'), X is CH and L is a bond.

[0075] In some particularly preferred embodiments of the present invention, in formula (G'), X is N and L is C=O.

[0076] In some particularly preferred embodiments of the present invention, in formula (G'), X is N and L is O=S=O.

[0077] In some particularly preferred embodiments of the present invention, in formula (G'), X is N and L is CH2.

[0078] In some particularly preferred embodiments of the present invention, in formula (G'), X is N and L is a bond.

[0079] In some preferred embodiments of the present invention, in formula (G′), R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl or C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and R 17 , R 18are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5, where R 13 is optionally substituted with 1, 2, 3, or 4 R. In some preferred embodiments of the present invention, in formula (G'), R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl or C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, 3, or 4 R. In some preferred embodiments of the present invention, in formula (G'), R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, C 1-6 Alkyl or C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, 3, or 4 R. In some preferred embodiments of the present invention, in formula (G'), R 13 is -N(R 17 )(R 18 ), C 1-6Alkoxy, C 1-6 Alkyl or C 3-7 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, or 3 R. In some preferred embodiments of the present invention, in formula (G'), R 13 is -N(R 17 )(R 18 ), C 1-3 Alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, or C 1-4 alkyl, and R 17 , R 18 is limited as above (where R 13 is optionally substituted with 1, 2, or 3 R. In some preferred embodiments of the present invention, in formula (G'), R 13 is -N(H)(C 1-3 alkyl), -N(H)(3-6 membered cycloalkyl), -N(H)(4-6 membered heterocycloalkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl), C 1-3 Alkoxy, C 3-6 cycloalkyl, 4-6 membered azacycloalkyl or oxacycloalkyl, phenyl, 5-6 membered azaaryl, or C 1-4 alkyl or R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a 4-10 membered ring together with the N atom to which they are attached (where R 13 is optionally substituted with 1, 2, or 3 R. In some particularly preferred embodiments of the present invention, in formula (G'), R 13is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, -N(H)(CH), -N(H)(CHCH), -N(H)(CHCHOH), -N(H)(CHCHCN), -N(CH)(CH), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl, pyrrolidinyl, pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl, piperazinyl or tetrahydropyranyl; or R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached (where R 13 is optionally substituted with 1, 2, or 3 R. In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 In some particularly preferred embodiments of the present invention, in formula (G'), R 13 is —N(H)(CH). In some particularly preferred embodiments of the present invention, in formula (G′), R 13 is —N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (G'), R 13 is —N(H)(CHCHOH). In some particularly preferred embodiments of the present invention, in formula (G′), R 13 is —N(H)(CH2CH2CN). In some particularly preferred embodiments of the present invention, in formula (G'), R 13 is —N(CH)(CH). In some particularly preferred embodiments of the present invention, in formula (G′), R 13 is —N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (G′), R13 is —N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (G′), R 13 is —N(H) (tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (G′), R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached.

[0080] In some preferred embodiments of the present invention, in formula (G′), R 17 , R 18 are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 In some preferred embodiments of the present invention, in formula (G'), R 17 , R 18 are H, C separately. 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 In some preferred embodiments of the present invention, in formula (G'), R 17 , R 18 are H, C separately. 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 In some preferred embodiments of the present invention, in formula (G'), R 17 , R 18are each independently selected from H, methyl, ethyl, propyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, and are optionally substituted with one or more of -OH, -CN. In some preferred embodiments of the present invention, in formula (G'), R 17 , R 18 form a 4-10 membered ring together with the N atom to which they are attached. In some preferred embodiments of the present invention, in formula (G'), R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached.

[0081] In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O and R 13 is -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5 or -SC 1-4 alkyl, and R 13 is substituted with 0, 1, 2, 3 or 4 R1, where R 17 , R 18 are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5, or R 17 , R 18 form a 3-14 membered ring together with the N atom to which they are attached. In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O and R 13 is -N(R 17 )(R 18 ), C 1-6 alkoxy, where R 17 , R 18 is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C3-7 heterocycloalkyl, and optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO, -SF, or R 17 , R 18 form a 3-10 membered ring together with the N atom to which they are attached. In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O and R 13 is methoxy, ethoxy, propoxy, -N(H)(CH), -N(H)(CHCH), -N(H)(CHCHOH), -N(H)(CHCHCN), -N(CH)(CH), -N(H)(cyclopropyl), -N(H)(cyclobutyl), -N(H)(tetrahydrofuranyl), or R 13 is -N(R 17 )(R 18 ) and R 17 , R 18 form a 7-membered ring together with the N atom to which they are attached. In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O and R 13 In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O and R 13 In some particularly preferred embodiments of the present invention, in formula (G'), L is C=O and R 13 is —N(H)(CH). In some particularly preferred embodiments of the present invention, in formula (G′), L is C═O and R 13 is —N(H)(CH2CH3). In some particularly preferred embodiments of the present invention, in formula (G'), L is C═O and R 13 is —N(H)(CHCHOH). In some particularly preferred embodiments of the present invention, in formula (G′), L is C═O and R 13 is —N(H)(CHCHCN). In some particularly preferred embodiments of the present invention, in formula (G′), L is C═O and R 13 is —N(CH3)(CH3). In some particularly preferred embodiments of the present invention, in formula (G'), L is C═O and R 13is —N(H)(cyclopropyl). In some particularly preferred embodiments of the present invention, in formula (G′), L is C═O and R 13 is —N(H)(cyclobutyl). In some particularly preferred embodiments of the present invention, in formula (G′), L is C═O and R 13 is —N(H) (tetrahydrofuranyl). In some particularly preferred embodiments of the present invention, in formula (G′), L is C═O and R 13 -N(R 17 )(R 18 ) and R 17 , R 18 form a seven-membered ring together with the N atom to which they are attached.

[0082] In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1, 2, or 3, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with halogen, -OH, -NH, -NH(CH), -N(CH), -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1, 2, or 3, and R2 is selected from the group consisting of halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl and C3-6 Cycloalkyl is optionally substituted with halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1, 2, or 3, and R2 is selected from the group consisting of halogen, C 1-6 alkyl, wherein said C 1-6 Alkyl is a halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1 or 2, and R2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C 1-6In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, methyl, ethyl, n-propyl, and isopropyl. In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1 or 2, and R2 is selected from fluorine, methyl, and ethyl. In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1 or 2, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 1, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (G'), the number of R2 is 2, and R2 is selected from fluorine and ethyl. In some particularly preferred embodiments of the present invention, there are two R2 in formula (G'), which are fluorine and ethyl, respectively. In some particularly preferred embodiments of the present invention, there is one R2 in formula (G'), which is ethyl.

[0083] In some preferred embodiments of the present invention, in formula (G′), R 13 is substituted with 1, 2, 3, or 4 R2, and each R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7- to 11-membered bicycloheteroaryl, wherein said -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, wherein said C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicycloaryl, 7-11 membered bicycloheteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (G'), R 13 is substituted with 1, 2, 3, or 4 R2, and each R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, and 5- to 7-membered heteroaryl, wherein said -SC 1-4 Alkyl, C 1-8 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 The aryl, 5-7 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (G'), R 13 is substituted with 1, 2, 3, or 4 R2, and each R1 is halogen, -OH, -CN, C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5- to 7-membered heteroaryl, wherein 1-8 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 The aryl, 5-7 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the invention, in formula (G'), R 13is substituted with 1, 2, 3, or 4 R2, and each R1 is halogen, -OH, -CN, C 1-8 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein 1-8 The alkyl is optionally substituted with 1, 2, or 3 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R4. In some preferred embodiments of the present invention, in formula (G'), R 13 is substituted with 0 or 1 R1, and each R1 is halogen, -OH, -CN, C 1-6 Alkyl, C 3-7 cycloalkyl, 5- to 7-membered heterocycloalkyl, wherein 1-6 The alkyl is optionally substituted with 1, 2, or 3 R3, and 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R4. In some preferred embodiments of the present invention, in formula (G'), R 13 is substituted with 0 or 1 R1, and each R1 is halogen, -OH, -CN, C 1-4 Alkyl, C 3-6 cycloalkyl, 5- to 7-membered heterocycloalkyl, wherein 1-4 The alkyl is optionally substituted with one or two R3, and 3-6 Cycloalkyl, 5-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R4. In some particularly preferred embodiments of the present invention, in formula (G'), R 13 is substituted with zero or one R1, each R1 being independently selected from methyl, ethyl, hydroxyl, -CN, piperidinyl, morpholinyl, piperazinyl, and cyclopropyl, wherein piperidinyl, morpholinyl, and piperazinyl are each independently selected from 1, 2, 3, or 4 C 1-3 In some particularly preferred embodiments of the present invention, in formula (G'), R 13is substituted with zero or one R1, and each R1 is independently selected from methyl, ethyl, hydroxyl, -CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is absent. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is 1-methylpiperazinyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is methyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is ethyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is piperidinyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is morpholinyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is hydroxyl. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is -CN. In some particularly preferred embodiments of the present invention, in formula (G'), R1 is cyclopropyl.

[0084] In each of the above preferred embodiments, the preferred options for each of the substituents mentioned above can be combined with each other, and each type of combination also falls within the scope of the present invention.

[0085] In the compound of formula (G'), R 13 When is a ring, the compound of formula (G') can also be represented as a compound of formula (I):

[0086] [ka] Here, ring A is C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11bicycloalkyl, or 5-11 membered bicycloheteroalkyl, ring A may be optionally substituted with R1, and the definitions of L, R1, R2, and X are as described in the compound of formula (G').

[0087] In particular, the present invention provides compounds of formula (I): [ka] or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is provided for use as a TRK inhibitor drug and / or a RET inhibitor drug, or in the manufacture of a TRK inhibitor drug and / or a RET inhibitor drug, wherein: L is C=O, O=S=O, CH2, or a bond; X is CH or N; Ring A is C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, The number of R1 is 0, 1, 2, 3, or 4, and R1 is H, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7- to 11-membered bicycloheteroaryl, wherein 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C7-11 bicycloaryl, 7-11 membered bicycloheteroaryl is optionally substituted with 1, 2, 3, or 4 R4; The number of R2 is 0, 1, 2, 3, or 4, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein C is selected from 1-6 Alkyl, C 3-7 Cycloalkyl and 4-10 membered heterocycloalkyl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R3 is halogen, cyano, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -N(R5)(R6), -CON(R7)(R8), or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is substituted with 1, 2, 3 or 4 R4; R4 is halogen, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -NH, -NHCH, or -N(CH); R5, R6, R7, and R8 each independently represent hydrogen or C 1-4 is alkyl, R9 is H, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-7 cycloalkyl; R 10 is H or C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each option within the group is selected from the group consisting of -OH, -NH, -NH(CH), -N(CH), -CN, 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy; R 11 is H, C 1-4 Alkyl, and C 3-7 cycloalkyl; R 12 is C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each option within the group is selected from halogen, —CF3, —CN, —OH, —NH2, —NH(CH3), —N(CH3)2, oxo, —SC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, and C 1-4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0088] In some preferred embodiments of the present invention, in formula (I), L is C=O, O=S=O, or CH2. In some particularly preferred embodiments of the present invention, in formula (I), L is C=O. In some particularly preferred embodiments of the present invention, in formula (I), L is O=S=O. In some particularly preferred embodiments of the present invention, in formula (I), L is CH2. In other some embodiments of the present invention, in formula (I), L is a bond.

[0089] In some particularly preferred embodiments of the present invention, in formula (I), X is CH. In some other embodiments of the present invention, in formula (I), X is N.

[0090] In some particularly preferred embodiments of the present invention, in formula (I), X is CH and L is C=O.

[0091] In some particularly preferred embodiments of the present invention, in formula (I), X is CH and L is O=S=O.

[0092] In some particularly preferred embodiments of the present invention, in formula (I), X is CH and L is CH2.

[0093] In some particularly preferred embodiments of the present invention, in formula (I), X is CH and L is a bond.

[0094] In some particularly preferred embodiments of the present invention, in formula (I), X is N and L is C=O.

[0095] In some particularly preferred embodiments of the present invention, in formula (I), X is N and L is O=S=O.

[0096] In some particularly preferred embodiments of the present invention, in formula (I), X is N and L is CH2.

[0097] In some particularly preferred embodiments of the present invention, in formula (I), X is N and L is a bond.

[0098] In some preferred embodiments of the present invention, in formula (I), ring A is C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7aryl, 5-7 membered heteroaryl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R1). In some preferred embodiments of the present invention, in formula (I), ring A is C 5-6 In some preferred embodiments of the present invention, in formula (I), ring A is 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R). In some preferred embodiments of the present invention, in formula (I), ring A is 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R). In some preferred embodiments of the present invention, in formula (I), ring A is 5-6 membered azacycloalkyl, phenyl, 5-6 membered azaaryl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R). In some preferred embodiments of the present invention, in formula (I), ring A is pyrazinyl, pyrazolyl, piperidinyl, or phenyl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R). In some particularly preferred embodiments of the present invention, in formula (I), ring A is pyrazinyl. In some particularly preferred embodiments of the present invention, in formula (I), ring A is pyrazolyl. In some particularly preferred embodiments of the present invention, in formula (I), ring A is piperidinyl. In some particularly preferred embodiments of the present invention, in formula (I), ring A is phenyl.

[0099] In some preferred embodiments of the present invention, in formula (I), R is absent or R is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, wherein 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 The aryl, 5-7 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is C 1-8 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, wherein 1-8 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 The aryl, 5-7 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is C 1-8 alkyl, 3- to 7-membered heterocycloalkyl, wherein said C 1-8 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is selected from the group consisting of C 1-6 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is selected from the group consisting of C 1-6 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with one or two R3, and the 5-7 membered heterocycloalkyl is optionally substituted with one, two, three, or four C 1-3In some preferred embodiments of the present invention, in formula (I), R is absent or R is C 1-4 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-4 The alkyl is optionally substituted with one or two R3, and the 5-7 membered heterocycloalkyl is optionally substituted with one, two, three, or four C 1-3 In some preferred embodiments of the present invention, in formula (I), R is absent or R is selected from methyl, piperidinyl, morpholinyl, piperazinyl, wherein piperidinyl, morpholinyl, piperazinyl is selected from 1, 2, 3, or 4 C 1-3 It is optionally substituted with alkyl. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is selected from methyl, piperidyl, morpholinyl, and 1-methylpiperazinyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is absent. In some particularly preferred embodiments of the present invention, in formula (I), R1 is 1-methylpiperazinyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is methyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is piperidinyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is morpholinyl.

[0100] In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, 2, or 3, and R2 is selected from the group consisting of halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl, and C 3-6 Cycloalkyl is a group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, 2, or 3, and R2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, wherein said C 1-6 Alkyl is a halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, chlorine, methyl, ethyl, n-propyl, and isopropyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine, methyl, and ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine and ethyl. In some particularly preferred embodiments of the present invention, in formula (I), there are two R2, which are fluorine and ethyl, respectively. In some particularly preferred embodiments of the present invention, in formula (I), there is one R2, and R2 is ethyl.

[0101] In each of the above preferred embodiments, the preferred options for each of the substituents mentioned above can be combined with each other, and each type of combination also falls within the scope of the present invention.

[0102] In particular, the present invention provides compounds of formula (I): [ka] or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is provided for use as a TRK inhibitor drug and / or a RET inhibitor drug, or in the manufacture of a TRK inhibitor drug and / or a RET inhibitor drug, wherein: L is C=O or O=S=O; X is CH; Ring A is a 5-7 membered heteroaryl, C 5-7 is aryl, The number of R1 is 0, 1, 2, 3, or 4, and R1 is C 1-8 alkyl, 3- to 7-membered heterocycloalkyl, wherein said C 1-8 alkyl is optionally substituted with 1, 2, 3, or 4 R3, and wherein said 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4; The number of R2 is 1, 2, or 3, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12, and -OR 12 wherein C is selected from 1-6 Alkyl, C 3-7 Cycloalkyl and 4-10 membered heterocycloalkyl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R3 is halogen, cyano, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -N(R5)(R6), -CON(R7)(R8), or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4; R4 is halogen, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -NH, -NHCH, or -N(CH); R5, R6, R7, and R8 are each independently hydrogen or C 1-4 is alkyl, R9 is H, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-7 cycloalkyl; R 10 is H or C 1-4 Alkyl, C 1-4 Haloalkyl, C3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each option within the group is selected from the group consisting of -OH, -NH, -NH(CH), -N(CH), -CN, 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy; R 11 is H, C 1-4 Alkyl, and C 3-7 cycloalkyl; R 12 is C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4alkyl-, where each option within the group is selected from halogen, —CF3, —CN, —OH, —NH2, —NH(CH3), —N(CH3)2, oxo, —SC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, and C 1-4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0103] In some preferred embodiments of the present invention, in formula (I), L is O=S=O. In some preferred embodiments of the present invention, in formula (I), L is C=O.

[0104] In some preferred embodiments of the present invention, in formula (I), ring A is a 5-6 membered heteroaryl or phenyl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R1). In some preferred embodiments of the present invention, in formula (I), ring A is pyrazinyl, pyrazolyl, or phenyl (wherein ring A is optionally substituted with 1, 2, 3, or 4 R1). In some particularly preferred embodiments of the present invention, in formula (I), ring A is pyrazinyl. In some particularly preferred embodiments of the present invention, in formula (I), ring A is pyrazolyl. In some particularly preferred embodiments of the present invention, in formula (I), ring A is phenyl.

[0105] In some preferred embodiments of the present invention, in formula (I), R is absent or R is C 1-8 alkyl, 3- to 7-membered heterocycloalkyl, wherein said C 1-8The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is selected from the group consisting of C 1-6 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with 1, 2, 3, or 4 R3, and the 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4. In some preferred embodiments of the present invention, in formula (I), R1 is absent or R1 is selected from the group consisting of C 1-6 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with one or two R3, and the 5-7 membered heterocycloalkyl is optionally substituted with one, two, three, or four C 1-3 In some preferred embodiments of the present invention, in formula (I), R is absent or R is C 1-4 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-4 The alkyl is optionally substituted with one or two R3, and the 5-7 membered heterocycloalkyl is optionally substituted with one, two, three, or four C 1-3 In some preferred embodiments of the present invention, in formula (I), R is absent or R is selected from methyl, piperidyl, morpholinyl, wherein piperidyl, morpholinyl is selected from 1, 2, 3, or 4 C 1-3It is optionally substituted with alkyl. In some preferred embodiments of the present invention, in formula (I), R1 is absent, or R1 is methyl, piperidyl, or morpholinyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is absent. In some particularly preferred embodiments of the present invention, in formula (I), R1 is methyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is piperidinyl. In some particularly preferred embodiments of the present invention, in formula (I), R1 is morpholinyl.

[0106] In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is selected from the group consisting of halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl, and C 3-6 Cycloalkyl is a group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 In some preferred embodiments of the present invention, in formula (I), the number of R2 is 1 or 2, and R2 is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, wherein said C 1-6 Alkyl is a halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine, chlorine, methyl, ethyl, n-propyl, and isopropyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine, methyl, and ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine and ethyl. In some preferred embodiments of the present invention, in formula (I), the number of R2 is 2, and R2 is selected from fluorine and ethyl. In some particularly preferred embodiments of the present invention, in formula (I), there are two R2, and they are fluorine and ethyl, respectively.

[0107] In each of the above preferred embodiments, the preferred options for each of the substituents mentioned above can be combined with each other, and each type of combination also falls within the scope of the present invention.

[0108] In a preferred embodiment of the present invention, the compounds used as TRK inhibitor drugs and / or RET inhibitor drugs are selected from the following: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone (MDI-2) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)methanone (MDI-202) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)methanone (MDI-203) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-204) (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-205) 5-Ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-206) 5-Ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-207) 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-208) Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233) 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-210) Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-211) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxycyclobutyl)methanone (MDI-213) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)methanone (MDI-214), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)methanone (MDI-215) (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228) 5-Ethyl-2-fluoro-4-(3-(5-(4-hydroxycyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-217) 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218) 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-219) 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-220) 5-Ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-221) 4-(3-(5-(cyclopentatyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-224) 5-Ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-225) 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-226) 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one (MDI-227) 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one (MDI-228) 2-Cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-229) 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one (MDI-230) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231) N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236) Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-237) Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-239) (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-240) Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-242) (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-243) (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245) 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-246) 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247) 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248) 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)pyrrolidine-3-carbonitrile (MDI-250) 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-251) Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-252) Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-253) (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-255) 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile (MDI-256) 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257) N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-258) N-Cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-259) N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-260) (s)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-262) (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-263)

[0109] In the most preferred embodiment of the invention, the compound used is selected from the following: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201) [ka] Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233) [ka] (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228) [ka] 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218) [ka] N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245) [ka] 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247) [ka] 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248) [ka] Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-253) [ka] 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257) [ka]

[0110] For the sake of brevity, reference below to a "compound of formula (G)" or "compound of formula (G)" or "compound of the invention" also includes any optical isomer, geometric isomer, tautomer or isomeric mixture of a compound of formula (G); reference below to a "compound of formula (G')" or "compound of formula (G')" or "compound of the invention" also includes any optical isomer, geometric isomer, tautomer or isomeric mixture of a compound of formula (G'); and reference below to a "compound of formula (I)" or "compound of formula (I)" or "compound of the invention" also includes any optical isomer, geometric isomer, tautomer or isomeric mixture of a compound of formula (I).

[0111] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may have an R or S configuration, and the various isomers formed thereby are optical isomers. Optical isomers include all diastereomers, enantiomers, meso isomers, racemates, and mixtures thereof. For example, optical isomers can be isolated using chiral columns or chiral synthesis.

[0112] The term "geometric isomer" means that when a double bond is present in a compound, the compound may exist as a cis-isomer, a trans-isomer, an E-isomer, or a Z-isomer. Geometric isomers include the forms of cis-isomers, trans-isomers, E-isomers, Z-isomers, or mixtures thereof.

[0113] The term "tautomer" refers to an isomer resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art will appreciate that tautomers may transition between each other and reach equilibrium and coexist in a certain state. A "compound represented by formula (G)" as described herein also includes any tautomer of a compound of formula (G), a "compound represented by formula (G')" as described herein also includes any tautomer of a compound of formula (G'), and a "compound represented by formula (I)" as described herein also includes any tautomer of a compound of formula (I).

[0114] Unless otherwise specified, when this specification refers to a "compound represented by formula (G)" or a "compound of formula (G)" or a "compound of the present invention", it also includes an isotopically labeled compound in which any atom of the compound is substituted with an isotopic atom thereof; when this specification refers to a "compound represented by formula (G')" or a "compound of formula (G')" or a "compound of the present invention", it also includes an isotopically labeled compound in which any atom of the compound is substituted with an isotopic atom thereof; and when this specification refers to a "compound represented by formula (I)" or a "compound of formula (I)" or a "compound of the present invention", it also includes an isotopically labeled compound in which any atom of the compound is substituted with an isotopic atom thereof.

[0115] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compounds of formula (G) in which one or more atoms are replaced by an atom having the same atomic number as the atom normally found in nature but a different atomic mass or mass number. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compounds of formula (G') in which one or more atoms are replaced by an atom having the same atomic number as the atom normally found in nature but a different atomic mass or mass number. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compounds of formula (I) in which one or more atoms are replaced by an atom having the same atomic number as the atom normally found in nature but a different atomic mass or mass number.

[0116] Illustrative examples of isotopes suitable for inclusion in compounds of the present invention include, for example: 2 H(D), and 3 isotopes of hydrogen such as H(T), 11 C. 13 C. 14 isotopes of carbon, such as C, 36 isotopes of chlorine such as Cl, 18 fluorine isotopes such as F, 123 I, 125 isotopes of iodine, such as I, 13 N, 15 isotopes of nitrogen, such as N, 15 O. 17 O. 18 isotopes of oxygen, such as O, and 35 This includes isotopes of sulfur such as S.

[0117] Some isotopically labeled compounds of formula (G) (e.g., those containing a radioisotope) can be used in drug and / or substrate tissue distribution studies, some isotopically labeled compounds of formula (G') (e.g., those containing a radioisotope) can be used in drug and / or substrate tissue distribution studies, and some isotopically labeled compounds of formula (I) (e.g., those containing a radioisotope) can be used in drug and / or substrate tissue distribution studies. In view of ease of introduction and convenient means of detection, the radioisotope deuterium (i.e., 2 H) and carbon-14 (i.e.14 C) is particularly useful for this purpose.

[0118] Deuterium (i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some cases because they may offer therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

[0119] Positron-emitting isotopes ( 11 C. 18 F, 15 O and 13 Substitution with hydroxyl groups (such as N) can be used in Positron Emission Tomography (PET) studies to detect substrate receptor occupancy.

[0120] Isotopically labeled compounds of formula (G) can generally be prepared by conventional techniques known to those skilled in the art, or in a manner similar to that described in the Examples and Preparations herein, by substituting a suitable isotopically labeled reagent for the previously used non-labeled reagent. Isotopically labeled compounds of formula (G') can generally be prepared by conventional techniques known to those skilled in the art, or in a manner similar to that described in the Examples and Preparations herein, by substituting a suitable isotopically labeled reagent for the previously used non-labeled reagent. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or in a manner similar to that described in the Examples and Preparations herein, by substituting a suitable isotopically labeled reagent for the previously used non-labeled reagent.

[0121] The compound of formula (G) may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and / or a base addition salt of the compound of formula (G). Unless otherwise specified, the term "pharmaceutically acceptable salt" as used herein includes an acid addition salt or a base addition salt that may appear in the compound of formula (G). The compound of formula (G') may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and / or a base addition salt of the compound of formula (G'). Unless otherwise specified, the term "pharmaceutically acceptable salt" as used herein includes an acid addition salt or a base addition salt that may appear in the compound of formula (G'). The compound of formula (I) may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and / or a base addition salt of the compound of formula (I). Unless otherwise specified, the term "pharmaceutically acceptable salt" as used herein includes an acid addition salt or a base addition salt that may appear in the compound of formula (I).

[0122] Pharmaceutically acceptable salts of the compounds of formula (G), formula (G'), and formula (I) include the acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylaminesulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide. Examples of suitable base addition salts include, but are not limited to, nitrate, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene, 2-naphthalenesulfonate, nicotinate, nitrate, whey, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, gluconate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tributylamine, and zinc salts. Hemisalts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0123] Some compounds of the present invention may exist in unsolvated and solvated forms, including hydrated forms. In general, compounds of formula (G), compounds of formula (G') and compounds of formula (I) may exist in solvated or unsolvated forms, both of which are included within the scope of the present invention.

[0124] Some compounds of the present invention may exist in different crystalline or amorphous forms, and compounds of formula (G), compounds of formula (G') and compounds of formula (I) are all included within the scope of the present invention, regardless of their form.

[0125] To avoid ambiguity, the following definitions are provided for terms used herein. Unless otherwise specified, the following terms have the following meanings as used herein:

[0126] The term "pharmaceutically acceptable" means that the corresponding compound, carrier, or molecule is suitable for administration to humans. Preferably, the term refers to those approved for mammals, preferably humans, by any national regulatory body, such as CFDA (China), EMEA (Europe), FDA (USA), etc.

[0127] The term "prodrug" refers to a derivative that is converted into the compound of the present invention in vivo by a reaction such as oxidation, reduction, or hydrolysis under physiological conditions with enzymes, gastric acid, etc., each of which is catalyzed by an enzyme.

[0128] By "metabolites" is meant all molecules derived in a cell or organism, preferably a human, from any compound of the invention.

[0129] The term "hydroxy" means --OH.

[0130] The term "halogen" or "halo" means -F, -Cl, -Br, or -I.

[0131] The term "cyano" means -CN.

[0132] In the present invention, when a plurality of certain substituents are present, each substituent is selected independently from each other, that is, these substituents may be the same or different. For example, when there are two, three, or four R1s, these R1s may be the same or different. For example, when there are two, three, or four R2s, these R2s may be the same or different. For example, when R1 and R2 are both -N(R9)(R 10 ), then R9 and R 10 can be selected independently, i.e., R in R and R in R can be the same or different, and R in R 10 and R in R2 10 may be the same or different. For example, when there are two R1 and both R1 are -N(R9)(R 10 ), then R9 and R 10 can be selected separately, that is, R9 in the first R1 and R9 in the second R1 can be the same or different, and R 10 and R in the second R1 10 may be the same or different. The above description applies to R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 Suitable for.

[0133] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a group are separately replaced with the corresponding number of substituents.

[0134] As used herein, the term "separately" means that when the number of substituents is more than one, the substituents may be the same or different.

[0135] As used herein, the terms "optionally" or "optionally" indicate that the event described herein may or may not occur. For example, when a group is "optionally substituted," this indicates that the group may be unsubstituted or substituted.

[0136] As used herein, the term "heteroatom" refers to any atom selected from oxygen (O), nitrogen (N), or sulfur (O). m where m can be 0, 1, or 2, i.e., a sulfur atom S, a sulfoxide SO, or a sulfonyl S(O)2.

[0137] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, alkyl has 1-8, or 1-6, or 1-3 carbon atoms. For example, "C 1-8 The term "alkyl" means a straight or branched chain group having 1-8 carbon atoms. 1-8 The term "alkyl" is defined as "C 1-6 The terms "alkyl," "C1-C3 alkyl," and "C1-C4 alkyl" include. Illustrative examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like. An alkyl can be optionally substituted with one or more (e.g., 1-5) suitable substituents.

[0138] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, an alkenyl has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms. For example, "C 2-8The term "alkenyl" means a straight or branched chain unsaturated group (having at least one carbon-carbon double bond) having 2-8 carbon atoms. The double bond may or may not be a point of attachment to another group. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. Alkenyl may be substituted with one or more (e.g., 1-5) suitable substituents. When a compound of formula (I) contains an alkenyl, the alkenyl may exist as a pure E form, a pure Z form, or any mixture thereof.

[0139] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, alkynyl has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms. For example, "C 2-8 The term "alkynyl" means a straight or branched chain unsaturated group (having at least one carbon-carbon triple bond) having 2-8 carbon atoms. The triple bond may or may not be a point of attachment to another group. Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like. Alkynyl may be optionally substituted with one or more (e.g., 1-5) suitable substituents.

[0140] As used herein, "C 3-7 The term "cycloalkyl" means a cycloalkyl having 3-7 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Cycloalkyl may be optionally substituted with one or more suitable substituents.

[0141] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl having m ring-forming carbon atoms and (nm) ring-forming heteroatoms, wherein the heteroatoms are selected from O, S, and N. For example, 3-7 membered heterocycloalkyls include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine, oxepane, thiepane, and azepane. Heterocycloalkyls may be optionally substituted with one or more suitable substituents.

[0142] As used herein, "C 5-7 The term "aryl" refers to an aryl having an aromatic ring containing 5-7 carbon atoms, preferably phenyl.

[0143] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming the aromatic ring, wherein the heteroatoms are selected from O, S, and N. For example, 5-7 membered heteroaryls include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, and pyridine. Heteroaryls may be substituted with one or more suitable substituents.

[0144] As used herein, "C 7-11 The term "bicycloaryl" means a bicycloaryl having 7-11 carbon atoms, for example, naphthalene, indene, etc. Bicycloaryl may be optionally substituted with one or more suitable substituents.

[0145] As used herein, the term "n-membered bicyclic heteroaryl" refers to a bicyclic heteroaryl having m carbon atoms forming an aromatic bicycle and (nm) heteroatoms forming an aromatic bicycle, said heteroatoms being selected from O, S, and N. For example, 7-11 membered bicycloheteroaryls include, but are not limited to, quinoline, isoquinoline, benzothiazole, etc. Bicycloheteroaryls may be optionally substituted with one or more suitable substituents.

[0146] As used herein, the term "11-15 membered tricyclo" includes, but is not limited to, acridine and the like. The 11-15 membered tricyclic group may be optionally substituted with one or more suitable substituents.

[0147] As used herein, the term "halogenated alkyl" refers to an alkyl having one or more halogen substituents (at most a fully halogenated alkyl, i.e., each hydrogen atom of the alkyl is replaced with a halogen atom). For example, "C 1-6 The term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1-6 It means alkyl (up to fully haloalkyl, i.e., each hydrogen atom of the alkyl is replaced with a halogen atom). Another example is "C 1-4 The term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1-4 It refers to alkyl (at most fluorohaloalkyl, i.e., each hydrogen atom of the alkyl is replaced with a halogen atom), and "C 1-3 The term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1-3The term "Ci_2 haloalkyl" refers to a Ci_2 alkyl (i.e., methyl or ethyl) having one or more halogen substituents (i.e., at most fulhaloalkyl, i.e., each hydrogen atom of the alkyl is replaced with a halogen atom). As yet another example, the term "Ci haloalkyl" refers to a methyl having one, two, or three halogen substituents. Examples of halogenated alkyls include CF3, C2F5, CHF2, CH2F, CH2CF3, and CH2Cl.

[0148] As used herein, the term "alkoxy" refers to an alkyl attached to an oxygen atom with a single bond. The point of attachment of the alkoxy to the molecule is through the oxygen atom. Alkoxy includes alkyl-O-. 1-6 The term "alkoxy" means a straight or branched chain alkoxy containing 1-6 carbon atoms. 1-6 The term "alkoxy" is defined as "C 1-3 The term "alkoxy" includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxybutoxy, hexyloxy, and the like. Alkoxy may be optionally substituted with one or more suitable substituents.

[0149] Numerical ranges herein relating to the number of substituents, carbon atoms, and ring atoms refer to the recitation of all integers within the range, one by one, and the ranges are merely a shorthand notation. For example, "1-4 substituents" refers to 1, 2, 3, or 4 substituents; "1-3 substituents" refers to 1, 2, or 3 substituents; "3-12 membered ring" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring; "3-14 membered ring" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered ring; "3-8 membered ring" refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered ring; "1-12 carbon atoms" or C 1-12 " represents one (C1), two (C2), three (C3), four (C4), five (C5), six (C6), seven (C7), eight (C8), nine (C9), ten (C10), eleven (C11), or twelve carbon atoms (C12); "1-6 carbon atoms" or "C 1-6 " means one (C1), two (C2), three (C3), four (C4), five (C5), or six carbon atoms (C6); "1-4 carbon atoms" or "C 1-4 " represents one (C1), two (C2), three (C3), or four carbon atoms (C4), "2-6 carbon atoms" or "C 2-6 " represents two (C2), three (C3), four (C4), five (C5), or six carbon atoms (C6); "C3-8" refers to three (C3), four (C4), five (C5), six (C6), seven (C7), or eight carbon atoms (C8); "3-8 ring atoms" refers to 3, 4, 5, 6, 7, or 8 ring atoms.

[0150] Thus, any numerical range relating to the number of substituents, the number of carbon atoms, or the number of ring atoms also covers any one of its subranges, and each subrange is also considered to be disclosed herein.

[0151] The compound of formula (G), compound of formula (G') or compound of formula (I) used in the present invention are known compounds and can be synthesized by various methods well known to those skilled in the art of organic synthesis, such as the method disclosed in Chinese Patent CN111606908B.

[0152] As will be understood by those skilled in the art, the compounds of formula (G), (G'), or (I) used in the present invention can be referred to as "TRK inhibitors and / or RET inhibitors," and can be TRK inhibitors, TRK inhibitors, or TRK / RET dual inhibitors. At the same time, according to the disclosure of Chinese Patent CN111606908B, these compounds can also be JAK inhibitors. Therefore, the compounds of formula (G), (G'), or (I) used in the present invention can act as JAK / TRK / RET multiple inhibitors, i.e., JAK / TRK dual inhibitors, JAK / RET dual inhibitors, TRK / RET dual inhibitors, or JAK / TRK / RET triple inhibitors. Because multiple inhibitors simultaneously inhibit multiple disease targets, the compounds used in the present invention are more effective than conventional single-target inhibitors in treating some diseases (as shown in the Examples below). Therefore, the compound of formula (G), the compound of formula (G'), or the compound of formula (I) used in the present invention preferably acts as a JAK / TRK / RET multiple inhibitor. In a particularly preferred embodiment, the compound of formula (G), the compound of formula (G'), or the compound of formula (I) used in the present invention acts as a JAK / TRK dual inhibitor, and among them, some particularly preferred compounds can act as Pan-JAK / Pan-TRK dual inhibitors (i.e., simultaneously inhibit all members of the JAK kinase family and the TRK kinase family), which provides extremely effective results in the treatment of autoimmune diseases, skin diseases such as pruritus, and diseases such as diabetic foot.

[0153] In a second aspect, the present invention provides a TRK inhibitor pharmaceutical composition, which comprises a compound of formula (G), a compound of formula (G'), or a compound of formula (I) above or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0154] In a third aspect, the present invention provides a RET inhibitor pharmaceutical composition, which contains the compound of formula (G), the compound of formula (G'), or the compound of formula (I) above or an isotopically labeled compound thereof, or a mixture of optical isomers, geometric isomers, tautomers or isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0155] The pharmaceutical composition of the present invention can be prepared, as needed, into a dosage form suitable for oral, topical (including, but not limited to, overcoat, spray, etc.), parenteral (including subcutaneous, intramuscular, cutaneous, and intravenous), bronchial, or nasal administration. Among these, the pharmaceutical composition of the present invention is preferably prepared into a dosage form (preparation) suitable for oral or topical administration. More preferably, the pharmaceutical composition of the present invention is prepared into a dosage form (preparation) suitable for oral administration.

[0156] When a solid vehicle is used, the formulation may be placed in a hard gel capsule in powder or granular form, or prepared in the form of a tablet or pill. Solid carriers may contain conventional excipients such as binders, fillers, sheet-forming lubricants, disintegrants, and wetting agents. Tablets may be coated, if necessary, by conventional techniques. When a liquid vehicle is used, the formulation may be in the form of a syrup, emulsion, cream, soft gel capsule, sterile injectable carrier, aqueous or non-aqueous liquid suspension, or a dry product to be reconstituted with water or other suitable carrier before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, flavorings, and / or coloring agents. For parenteral administration, the carrier usually comprises, at least in large part, sterile water, although saline solutions, glucose solutions, and the like may also be used. Injectable suspensions may also be used, in which case conventional suspending agents may be used. Conventional preservatives, buffers, and the like may also be added to parenteral dosage forms. Pharmaceutical compositions are prepared by conventional techniques appropriate to the desired formulation containing appropriate amounts of the active ingredient, i.e., a compound of formula (G), a compound of formula (G'), or a compound of formula (I) of the present invention.

[0157] Compositions suitable for parenteral injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, and solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

[0158] These compositions may contain various excipients, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents (e.g., parahydroxybenzoates, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents, such as sugars and sodium chloride, may also be included. Absorption delaying agents (e.g., aluminum monostearate and gels) can be used to prolong the absorption of injectable pharmaceutical dosage forms.

[0159] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), and (a) fillers or fillers (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (e.g., carboxymethylcellulose, alginate esters, gels, polyvinylpyrrolidone, sucrose, and gum arabic), (c) humectants (e.g., glycerin), (d) disintegrants (e.g., agar-agar, calcium carbonate, potato starch, and the like). starch or tapioca starch, alginic acid, synthetic silicate esters, sodium carbonate), (e) solution retardants (e.g., paraffin), (f) absorption accelerators (e.g., quaternary ammonium compounds), (g) wetting agents (e.g., hexadecane alcohol and glyceryl monostearate), (h) adsorbents (e.g., kaolin and granulated earth), and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

[0160] Similar solid compositions may also be employed as fillers in soft and hard-filled gel capsules using, for example, lactose, high molecular weight polyethylene glycols, and the like as excipients.

[0161] Solid dosage forms (e.g., tablets, dragees, capsules, pills, and granules) can be prepared with coatings and shells (e.g., enteric coatings and others known in the art). These may contain light-blocking agents, and may be of a composition that releases the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Embedding compositions include, for example, polymeric substances, waxes, etc. The active ingredient may also be microencapsulated, if appropriate, with one or more of the above-mentioned excipients.

[0162] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain an inert diluent (e.g., water or other solvent), a solubilizer and emulsifier (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylbenzylammonium), oil (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof, commonly used in the art.

[0163] Besides these inert diluents, compositions can further include, for example, wetting agents, emulsifying and suspending agents, flavoring agents, and perfuming agents.

[0164] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline fibers, aluminum hydroxide, soil removers, agar-agar and aubergine gum, or mixtures thereof.

[0165] Dosage forms for topical administration of the compounds of the present invention include pastes, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any necessary preservatives, buffers, or propellants. Ophthalmic formulations, eye drops, powders, and solutions are also included within the scope of the present invention.

[0166] The topical formulations of the compounds of the present invention can be prepared in the form of water-in-oil (W / O) or oil-in-water (O / W) emulsions, in the form of multiple emulsions such as water-in-oil-in-water (W / O / W) or water-in-oil-in-water (O / W / O) emulsions, or in the form of aqueous or lipodispersions, gels or aerosols.

[0167] The topical formulation of the compound of the present invention may contain additives and formulation aids such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilizers, dyes, fragrances, and preservatives. Suitable emulsifiers include stearic acid, triethanolamine, and PEG-40 stearate. Suitable thickeners include glyceryl monostearate and PEG 600. Preservatives include propyl parahydroxybenzoate, chlorocresol, and the like. Suitable spreading agents include dimethylpolysiloxane and polydimethylcyclosiloxane. Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.

[0168] The topical dosage form of the compound of the present invention may include creams, lotions, gels, emulsions, microemulsions, sprays, skin patches, etc., and may be administered topically to treat skin diseases such as atopic dermatitis, skin side effects caused by EGFR inhibitors, acne, eczema, psoriasis, scleroderma, pruritus, vitiligo, hair loss, etc. In particular, the topical dosage form of the compound of the present invention is a paste that may be administered topically to treat skin diseases such as atopic dermatitis, skin side effects caused by EGFR inhibitors, acne, eczema, psoriasis, scleroderma, pruritus, vitiligo, hair loss, etc.

[0169] In the pharmaceutical compositions and dosage forms, the amount of the compound of formula (G), the compound of formula (G'), or the compound of formula (I) can be appropriately determined as needed by those skilled in the art. For example, the compound of formula (G), the compound of formula (G'), or the compound of formula (I) can be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.

[0170] In a fourth aspect, the present invention provides a method for treating a disease or condition associated with TRK or RET, the method comprising administering a therapeutically effective amount of the compound of formula (G), the compound of formula (G'), or the compound of formula (I), or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the composition described above, to a patient in need thereof. The patient is preferably a mammal, more preferably a human patient. The administration route may be oral administration, topical administration (including, but not limited to, overcoat, spray, etc.), parenteral gastrointestinal administration (including subcutaneous, intramuscular, cutaneous, and intravenous), bronchial administration, or nasal administration. Among these, oral administration or topical administration is preferred, and oral administration is more preferred.

[0171] As used herein, "TRK- or RET-associated diseases or conditions" include, but are not limited to:

[0172] Arthritis, including rheumatoid arthritis, juvenile arthritis and psoriatic arthritis Single-organ or single-cell autoimmune diseases, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, pernicious anemia, autoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpers' disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Glaves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis, and membranous glomerular disease, those related to systemic autoimmune diseases (e.g., systemic lupus erythema, autoimmune diseases or conditions, including rheumatoid arthritis, dry arthritis, Rheumatica syndrome, Leiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and decubitus ulcers) and other O-cell (humoral) or T-cell autoimmune diseases (including Myristylosis syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia (alopecia skin), type 1 diabetes or juvenile diabetes or thyroiditis, Cancers or tumors, including gastrointestinal / gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumors and squamous cell carcinoma), breast and breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative diseases, proliferative diabetic retinopathy or diseases associated with angiogenesis (including solid tumors); diabetes, including type 1 diabetes or diabetes with diabetic complications; Ocular diseases, conditions or conditions, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including shellfish digestive disease-related uveitis and phacoemulsification), keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophia, vitiligo, ocular pemphigus, moire ulcers, scleritis, Griffith's eye disease, Vo>Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), bullae, iridocyclitis, nodular disease, endocrine eye disease, sympathetic ophthalmia, allergic conjunctivitis or ocular neovascularization, intestinal inflammation, allergies or conditions, including Crohn's disease and / or ulcerative colitis, inflammatory bowel disease, chyle, proctitis, eosinophilic gastroenteritis or hypertrophy; Neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases due to cerebral ischemia or traumatic injury, stroke, glutamate neurotoxicity or hypoxia, ischemia / reperfusion injury in stroke, myocardial ischemia, renal ischemia, cardiac stroke, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation, Skin diseases, conditions or symptoms, including atopic dermatitis, skin side effects from EGFR inhibitors, acne, eczema, psoriasis, scleroderma, pruritus or other pruritic conditions, vitiligo, hair loss (alopecia areata), allergic reactions, including mammalian allergic dermatitis (including equine allergic diseases, e.g., jack itch), summer eczema, sweet itch, emphysema, inflammatory airway disease, recurrent airway obstruction, airway hyperresponsiveness, or chronic obstructive pulmonary disease; Asthma and other obstructive airways diseases, including chronic or persistent asthma, late stage asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, Transplant rejection, including pancreatic islet transplant rejection, bone marrow transplant rejection, graft versus host disease, organ and cell transplant rejection (e.g., bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine or trachea) or xenotransplantation.

[0173] It has been discovered that the compounds of formula (G), formula (G') or formula (I) described in the present application are particularly suitable for the treatment of a disease or condition selected from arthritis, autoimmune diseases or conditions, cancer or tumors, diabetes, diabetic slow wound healing, eye diseases, diseases or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or conditions, allergies, asthma and other obstructive airways diseases.

[0174] Animal model experiments have revealed that the compounds of formula (G), formula (G') or formula (I) are most suitable for treating diseases such as pruritus, psoriasis, atopic dermatitis, acne, vitiligo, alopecia areata, asthma, rhinitis, edema, cervicitis, pneumonia, etc. These compounds can also be used to treat diseases such as allergic conjunctivitis, cancer (tumor), diabetic slow wound healing, diabetic foot, etc.

[0175] In some particularly preferred embodiments, the compounds of formula (G), formula (G') or formula (I) above can be used as JAK / ubiquitous TRK inhibitors, particularly ubiquitous JAK / ubiquitous TRK inhibitors or ubiquitous JAK / ubiquitous TRK / RET inhibitors.

[0176] In some particularly preferred embodiments, the compounds of Formula (G), Formula (G'), or Formula (I), as described above, can be used to treat autoimmune diseases, chronic wound healing, and diabetic complications, such as arthritis, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions, or conditions, allergies, asthma and other obstructive airway diseases, transplant rejection, pressure ulcers, diabetic slow wound healing, eye diseases, conditions, or conditions, etc. In some most preferred embodiments, the compounds of Formula (G), Formula (G'), or Formula (I), as described above, can be used to treat a disease or condition selected from pruritus, psoriasis, atopic dermatitis, skin side effects from EGFR inhibitors, acne, vitiligo, alopecia areata, asthma, rhinitis, tegafnia, cervicitis, pneumonia, pressure ulcers, diabetic slow wound healing, diabetic foot, diabetic retinopathy, etc.

[0177] In a fifth aspect, the present invention provides the compound of formula (G), the compound of formula (G'), the compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, for use as a TRK inhibitor and / or RET inhibitor, or as a drug for treating a disease or condition associated with TRK or RET. Here, the definitions and preferred options of the substituents in the compound of formula (G), the compound of formula (G'), or the compound of formula (I) are as described above, and the disease or condition associated with TRK or RET are also as described above.

[0178] Preferably, the present invention provides the following embodiments:

[0179] 1. In the manufacture of a TRK inhibitor drug and / or a RET inhibitor drug, a compound of formula (G): [ka] or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, L is C=O, O=S=O, CH2 or a bond; X1 is N or CR 14 and X2 is N or CR 15 and X3 is N or CR 16 and R 14 , R 15 , R 16 are H, -OH, -SH, -CN, halogens, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7Aryl, 5-7 membered heteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein each independently selected from -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl and 3- to 7-membered heterocycloalkyl are halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 alkyl)2, -N(C 1-4 alkyl)(C(=O)C 1-4 alkyl), C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents selected from haloalkoxy; R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -SR 12 , -OR 12 , -CN, halogen, -NO2, -SF5, -SC 1-4 alkyl, C alkyl or C cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and R 13 is substituted with 0, 1, 2, 3, or 4 R1, where R 17 , R 18 are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and -OH, -CN, -SH, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12and optionally substituted with one or more substituents each independently selected from the group consisting of: 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 or R 17 , R 18 form a 3-14 membered ring together with the N atom to which they are attached, The number of R2 is 0, 1, 2, 3, or 4, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, or -SC. 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein said -SC is selected from 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 Bicycloalkyl, 5-11 membered bicycloheteroalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein said -SC is selected from 1-4 Alkyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl is optionally substituted with 1, 2, 3, or 4 R4; R3 and R4 are H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R5)(R6), -N(R 11 )(C(=O)R 12 ), -CON(R7)(R8), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein each C is independently selected from 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-6 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 and R5, R6, R7, R8, R9, R 10 , R 11 , R 12 are each independently H or C 1-6 Alkyl, C1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each member within the group is selected from the group consisting of halogen, —CF3, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy.

[0180] 2. The use of embodiment 1, wherein all H are each independently optionally substituted with D.

[0181] 3. The use according to embodiment 1 or 2, wherein only one of X1, X2, X3 is N.

[0182] 4. The use according to embodiment 1 or 2, wherein only two of X1, X2, X3 are N.

[0183] 5. The use according to embodiment 1 or 2, wherein X1, X2, and X3 are identical.

[0184] 6.X1 is CR 14 and X2 is CR 15 ,X3 is CR 16 and R 14 , R 15 , R 16 The use according to embodiment 5, wherein

[0185] 7.R 14 , R 15 , R 16 H, -OH, -SH, -CN, halogen, -NO2, C 1-6 The use according to embodiment 6, wherein the alkyl is selected from alkyl.

[0186] 8.R 14 , R 15 , R 16 are H, -OH, C 1-6 The use according to embodiment 7, wherein the alkyl is selected from alkyl.

[0187] 9. The use of embodiment 7, wherein X1, X2, and X3 are all CH.

[0188] 10. The use according to embodiment 5, wherein X1, X2, and X3 are all N.

[0189] 11. The use according to any one of embodiments 1 to 10, wherein L is C=O, O=S=O, or CH2.

[0190] 12.R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 Alkyl, C 1-6 Alkyl or C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and R 13is substituted with 0, 1, 2, 3, or 4 R1, where R 17 , R 18 are separately, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 The use according to any one of embodiments 1 to 10, wherein the aryl is selected from aryl, 5-7 membered heteroaryl and is substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5.

[0191] 13.R 13 is H, -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, -SC 1-4 alkyl, C alkyl or C cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C 5-11 bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and R 13 is substituted with 0, 1, 2, 3, or 4 R1, where R 17 , R 18 are H, C separately. 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 The use according to any one of embodiments 1 to 10, wherein the aryl is selected from aryl, 5-7 membered heteroaryl, and is optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5.

[0192] 14.R 13 is H, -N(R 17 )(R 18 ), C 1-6Alkoxy, C alkyl or C cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5- to 7-membered heteroaryl, and R 13 The use according to any one of embodiments 1 to 10, wherein is substituted with 0, 1, 2, 3, or 4 R1.

[0193] 15.R 13 is -N(R 17 )(R 18 ), C 1-6 alkoxy, C alkyl or C cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and R 13 The use according to any one of embodiments 1 to 10, wherein is substituted with 0, 1, 2, or 3 R1.

[0194] 16.R 17 , R 18 are H, C separately. 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 The use according to any one of embodiments 1 to 10, wherein the heterocycloalkyl is selected from heterocycloalkyl and is optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5.

[0195] 17.R 17 , R 18 The use according to any one of embodiments 1 to 10, wherein together with the N atom to which they are attached, form a 4-10 membered ring.

[0196] 18.L is C=O and R 13 -N(R 17 )(R 18 ), C 1-6 Alkoxy, -OH, -SH, -CN, halogen, -NO2, -SF5, or -SC 1-4 alkyl, and R 13 is substituted with 0, 1, 2, 3, or 4 R1, where R 17 , R 18 is H, C 1-6 Alkyl, C1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, and optionally substituted with one or more of -OH, -CN, -SH, halogen, -NO2, -SF5, or R 17 , R 18 The use according to any one of embodiments 1 to 10, wherein together with the N atom to which they are attached, form a 3-14 membered ring.

[0197] 19. There are 1, 2, or 3 R2, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl and 4-10 membered heterocycloalkyl are halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 The use of any one of embodiments 1 to 10, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0198] 20. One, two, or three R2 are present, and R2 is halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl, and C 3-6 Cycloalkyl is a group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 The use of any one of embodiments 1 to 10, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0199] 21. One or two R2 are present, and R2 is halogen, C 1-6 The use according to embodiment 15, wherein the alkyl is selected from alkyl.

[0200] 22.R 13 is substituted with 0 or 1 R1, where R1 is halogen, -OH, -CN, C 1-6 Alkyl, 5-7 membered heterocycloalkyl, C 3-7 cycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with 1, 2, or 3 R3, wherein the 5-7 membered heterocycloalkyl, C 3-7 Cycloalkyl can have 1, 2, 3, or 4 C 1-3 The use according to any one of embodiments 1 to 10, optionally substituted with alkyl.

[0201] 23. The compound is a compound of formula (I): [ka] or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, L is C=O, O=S=O, CH2 or a bond; X is CH or N; Ring A is C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, The number of R1 is 0, 1, 2, 3, or 4, and R1 is H, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7- to 11-membered bicycloheteroaryl, wherein 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 The alkoxy is optionally substituted with 1, 2, 3, or 4 R3, and 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicycloaryl, 7-11 membered bicycloheteroaryl is optionally substituted with 1, 2, 3, or 4 R4; The number of R2 is 0, 1, 2, 3, or 4, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein C is selected from 1-6 Alkyl, C 3-7Cycloalkyl and 4-10 membered heterocycloalkyl are substituted with halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R3 is halogen, cyano, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -N(R5)(R6), -CON(R7)(R8), or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4; R4 is halogen, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -NH, -NHCH, or -N(CH); R5, R6, R7, and R8 each independently represent hydrogen or C 1-4 is alkyl, R9 is H, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-7 cycloalkyl; R 10 is H or C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each option within the group is selected from the group consisting of -OH, -NH, -NH(CH), -N(CH), -CN, 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy; R 11 is H, C 1-4 Alkyl, and C 3-7 cycloalkyl; R 12 is C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each member within the group is selected from the group consisting of halogen, —CF3, —CN, —OH, —NH2, —NH(CH3), —N(CH3)2, oxo, —SC 1-4 Alkyl, C 1-4 Alkyl, C 1-4Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, and C 1-4 The use of embodiment 1, optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0202] 24. The use according to embodiment 23, wherein L is C=O, O=S=O, or CH2.

[0203] 25. The use according to embodiment 23, wherein X is CH.

[0204] 26. Ring A is C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 26. The use according to any one of embodiments 23 to 25, wherein the aryl is aryl, 5-7 membered heteroaryl.

[0205] 27. The use according to any one of embodiments 23 to 25, wherein ring A is a 5-6 membered heteroaryl or phenyl.

[0206] 28. There are 0 or 1 R1, and R1 is C 1-6 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with one or two R3, and the 5-7 membered heterocycloalkyl is optionally substituted with one, two, three, or four C 1-3 The use according to any one of embodiments 23 to 25, optionally substituted with alkyl.

[0207] 29. One or two R2 are present, and R2 is halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl and C 3-6 Cycloalkyl is a group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4Haloalkyl, C 1-4 Alkoxy, and C 1-4 The use of any one of embodiments 23 to 25, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0208] 30. L is C=O or O=S=O, X is CH; Ring A is a 5-7 membered heteroaryl or C 5-7 is aryl, The number of R1 is 0, 1, 2, 3, or 4, and R1 is C 1-8 alkyl, 3- to 7-membered heterocycloalkyl, wherein said C 1-8 the alkyl is optionally substituted with 1, 2, 3, or 4 R3, and said 3- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4; The number of R2 is 1, 2, or 3, and R2 is H, halogen, -OH, -NO2, -CN, -SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-N(R9)(R 10 ), -C(=O)-R 12 , -C(=O)-OR 12 , -OC(=O)R 12 , -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 wherein C is selected from 1-6 Alkyl, C 3-7 Cycloalkyl and 4-10 membered heterocycloalkyl are substituted with halogen, -CN, -OH, C 1-4Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -N(R9)(R 10 ), -N(R 11 )(C(=O)R 12 ), -C(=O)-OR 12 , -C(=O)H, -C(=O)R 12 , -C(=O)-N(R9)(R 10 ), -N(R 11 )(S(=O)2R 12 ), -S(=O)2-N(R9)(R 10 ), -SR 12 , and -OR 12 each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R3 is halogen, cyano, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -N(R5)(R6), -CON(R7)(R8), or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R4; R4 is halogen, C 1-3 Alkyl, Hydroxyl, C 1-6 alkoxy, -NH, -NHCH, or -N(CH); R5, R6, R7, and R8 each independently represent hydrogen or C 1-4 is alkyl, R9 is H, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-7 cycloalkyl; R 10 is H or C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each option within the group is selected from the group consisting of -OH, -NH, -NH(CH), -N(CH), -CN, 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy; R 11 is H, C 1-4 Alkyl, and C 3-7 cycloalkyl; R 12 is C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 alkyl-, where each member within the group is selected from the group consisting of halogen, —CF3, —CN, —OH, —NH2, —NH(CH3), —N(CH3)2, oxo, —SC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, and C 1-4 The use of any one of embodiments 23 to 25, optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0209] 31. The use according to embodiment 30, wherein ring A is a 5-6 membered heteroaryl or phenyl.

[0210] 32. There are 0 or 1 R1, and R1 is C 1-6 alkyl, 5-7 membered heterocycloalkyl, wherein said C 1-6 The alkyl is optionally substituted with one or two R1, and the 5-7 membered heterocycloalkyl is optionally substituted with one, two, three, or four C 1-3 The use according to embodiment 30, optionally substituted with alkyl.

[0211] 33. One or two R2 are present, and R2 is halogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein said C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally substituted with halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 The use of embodiment 30, wherein the aryl group is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

[0212] 34. The compound is (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone (MDI-2), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)methanone (MDI-202), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)methanone (MDI-203), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-204), (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-205), 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-206), 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-207), 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-208), Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233), 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-210), Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-211), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxycyclobutyl)methanone (MDI-213), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)methanone (MDI-214), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)methanone (MDI-215), (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228), 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxycyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-217), 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218), 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-219), 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-220), 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-221), 4-(3-(5-(cyclopentatyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-224), 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-225), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-226), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one (MDI-227), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one (MDI-228), 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-229), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one (MDI-230), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231), N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236), Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-237), cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-239), (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-240), Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-242), (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-243), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-246), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)pyrrolidine-3-carbonitrile (MDI-250), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-251), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate methyl (MDI-252), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate ethyl (MDI-253), (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-255), 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile (MDI-256), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257), N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-258), N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-259), N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-260), (s)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-262), (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-263) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt, prodrug, or metabolite of any of the above compounds.

[0213] 35. The compound is (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201) [ka] Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233) [ka] (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228) [ka] 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218) [ka] N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236) [ka] (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245) [ka] 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247) [ka] 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248) [ka] Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-253) [ka] 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257) [ka] or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt, prodrug, or metabolite of any of the above compounds.

[0214] 36. The use according to any one of embodiments 1 to 35, wherein the compound is used as a JAK / TRK dual inhibitor (preferably a pan-JAK / pan-TRK dual inhibitor), or a JAK / TRK / RET multiple inhibitor (preferably a pan-JAK / pan-TRK / RET multiple inhibitor).

[0215] 37. A pharmaceutical composition of a TRK inhibitor and / or a RET inhibitor, comprising a compound as defined in any one of claims 1 to 35 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0216] 38. The pharmaceutical composition according to embodiment 37, which is prepared as an oral dosage form or an external dosage form suitable for topical administration.

[0217] 39. The pharmaceutical composition according to embodiment 37, which is manufactured as a JAK / TRK dual inhibitor drug (preferably used as a pan-JAK / pan-TRK dual inhibitor drug), or a JAK / TRK / RET multiple inhibitor drug (preferably prepared as a pan-JAK / pan-TRK / RET multiple inhibitor drug).

[0218] 40. Use of a compound as defined in any one of embodiments 1 to 35 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition as defined in embodiment 37 or 38 or 39, in the manufacture of a medicament for the treatment and / or prevention of a disease or condition associated with TRK and / or RET.

[0219] 41. The use according to embodiment 40, wherein the disease or condition associated with TRK and / or RET is selected from arthritis, autoimmune diseases or conditions, cancer or tumors, diabetes and diabetic complications, slow wound healing (due to diabetes), eye diseases, diseases or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or conditions, allergies, asthma and other obstructive airway diseases, transplant rejection.

[0220] 42. The use of embodiment 40, wherein the disease or condition associated with TRK and / or RET is selected from pruritus, psoriasis, atopic dermatitis, skin side effects caused by EGFR inhibitors, acne, vitiligo, alopecia areata, asthma, rhinitis, hemorrhoids, cervicitis, pneumonia, slow diabetic wound healing, diabetic foot, diabetic retinopathy, cancer (tumor), and pressure ulcers.

[0221] The present invention will now be further described and illustrated with reference to the drawings and specific examples. [Brief explanation of the drawings]

[0222] [Figure 1] Figure 1 shows the results of IL-5 ELISA in lung lavage fluid from an egg white protein-induced mouse asthma model. Data are expressed as mean ± SEM (*p<0.05, **p<0.01, ***p<0.001 vs. vehicle control, one-way ANOVA, Bonferroni's multiple comparison test). [Figure 2] Figure 2 shows the results of inflammatory cell counts in lung lavage fluid from an egg white protein-induced mouse asthma model. Data are expressed as mean ± SEM (*p<0.05, **p<0.01, ***p<0.001 vs. vehicle control, one-way ANOVA, Bonferroni's multiple comparison test). [Figure 3] Figure 3 shows the results of serum IL-5 ELISA in an egg white protein-induced mouse asthma model. Data are expressed as mean ± SEM (*p<0.05, **p<0.01, ***p<0.001 vs. vehicle control, one-way ANOVA, Bonferroni's multiple comparison test). [Figure 4] Figure 4 shows representative images of lung histopathological staining from an egg white protein-induced mouse asthma model. [Figure 5] Figure 5 shows the results of lung histopathology scoring in the egg white protein-induced mouse asthma model. Data are expressed as mean ± SEM (*p<0.05, **p<0.01, ***p<0.001 vs. vehicle control group, One-way ANOVA, Bonferroni's multiple comparison test). [Figure 6] FIG. 6 shows the drug intervention scoring results (*, p<0.05) for male mice in a mouse model of allergic rhinitis. [Figure 7] FIG. 7 shows the results of drug intervention scoring in female mice in a mouse model of allergic rhinitis (*, p<0.05). [Figure 8] FIG. 8 shows the results of HE staining of sections from each group of mice of different genders in a mouse model of allergic rhinitis. [Figure 9] FIG. 9 shows the detection of IL-4 content in the serum of male mice in a mouse model of allergic rhinitis (*, p<0.05). [Figure 10] FIG. 10 shows the detection of IL-4 content in the serum of female mice in a mouse model of allergic rhinitis (*, p<0.05). [Figure 11] FIG. 11 shows the results of HE staining of lung tissues from each group in a rat animal model of chronic obstructive pulmonary disease. [Figure 12] FIG. 12 shows changes in IL-β expression levels in serum and lavage fluid in a rat animal model of chronic obstructive pulmonary disease. [Figure 13] FIG. 13 shows the effect of external hemorrhoid modeling in rats and the effect of a positive control drug. [Figure 14] FIG. 14 shows the HE staining scores of the pathological sections of each group in the rat external hemorrhoid model. [Figure 15] FIG. 15 shows the detection of TNF-α expression levels in samples from each group in a rat external hemorrhoid model. [Figure 16-1] FIG. 16 shows the effect of drugs on vulvar inflammation in rats with phenol-induced cervicitis. [Figure 16-2] Same as above [Figure 17] FIG. 17 shows the effect of drugs on erythema symptoms in rats with phenol-induced cervicitis. [Figure 18] FIG. 18 shows the effect of drugs on the edema symptoms in rats with phenol-induced cervicitis. [Figure 19] FIG. 19 shows the effect of drugs on secretory symptoms in rats with phenol-induced cervicitis. [Figure 20] FIG. 20 shows the effect of drugs on cervical index in rats with phenol-induced cervicitis. [Figure 21] FIG. 21 shows the results of vaginal HE staining in rats with phenol-induced cervicitis. [Figure 22] FIG. 22 shows the results of scoring mice for skin redness, bleeding, hair growth, and scaling in an atopic dermatitis / pruritus mouse model. [Figure 23] FIG. 23 shows the area under the curve (AUC) of the scores for skin redness, bleeding, hair loss, and scaling in mice in a mouse model of atopic dermatitis / pruritus. [Figure 24] FIG. 24 shows the results of an HE staining experiment (×400) on a mouse model of atopic dermatitis / pruritus. [Figure 25] FIG. 25 shows the results of a toluidine blue staining experiment on a mouse model of atopic dermatitis / pruritus (×400). [Figure 26] FIG. 26 shows the effect of drugs on serum IL-4 in mice with atopic dermatitis / pruritus (*compared with normal group, p<0.05). [Figure 27] FIG. 27 shows the effect of drugs on serum IL-13 in mice with atopic dermatitis / pruritus (*compared with normal group, p<0.05). [Figure 28] FIG. 28 shows the effect of drugs on serum IFN-γ in mice with atopic dermatitis / pruritus (*compared with normal group, p<0.05). [Figure 29]FIG. 29 shows the effect of drugs on serum TNF-α in mice with atopic dermatitis / pruritus (*compared with normal group, p<0.05). [Figure 30] FIG. 30 shows the effect of the score on the area of skin hair depigmentation in vitiligo mice caused by drugs (administration site, skin hair depigmentation site). [Figure 31] FIG. 31 shows the effect of drug on the scoring of the area of depigmented skin hair in vitiligo mice (non-administered ears, non-medicated areas on the trunk, and tails). [Figure 32] FIG. 32 shows the results of HE staining of vitiligo mice. [Figure 33] FIG. 33 shows the effect of drugs on serum TNF-α in vitiligo mice (*compared to blank control group, p<0.01; #compared to model group, p<0.01). [Figure 34] FIG. 34 shows the effect of drugs on serum IL6 in vitiligo mice (*compared to blank control group, p<0.01; #compared to model group, p<0.01). [Figure 35] FIG. 35 shows a comparison of the area under the hair growth score curve in mice with alopecia areata. [Figure 36] FIG. 36 shows hair growth in mice with alopecia areata (day 21). [Figure 37] FIG. 37 shows hair growth in female alopecia areata mice. [Figure 38] FIG. 38 shows the hair growth status of male mice with alopecia areata. [Figure 39] FIG. 39 shows skin thickness scores of mice with imiquimod-induced psoriasis. [Figure 40] FIG. 40 shows the clinical scores of mice with imiquimod-induced psoriasis. [Figure 41] FIG. 41 shows the AUC of skin thickness scores in mice with imiquimod-induced psoriasis (*p<0.05, **p<0.01, ****p<0.0001 vs. vehicle control group, One-way ANOVA). [Figure 42] FIG. 42 shows the AUC of clinical scores in mice with imiquimod-induced psoriasis (***p<0.001, ****p<0.0001 vs. vehicle control group, One-way ANOVA). [Figure 43] FIG. 43 shows the spleen weights of mice with imiquimod-induced psoriasis at the end of the experiment (***p<0.001, ****p<0.0001 vs. vehicle control group, One-way ANOVA). [Figure 44] FIG. 44 shows the results of pathological evaluation of psoriatic mice (****p<0.0001 vs. vehicle control group, One-way ANOVA). [Figure 45] FIG. 45 shows the results of detecting the cytokine TNF-α in psoriatic mice (*p<0.05 vs. solvent control group, One-way ANOVA). [Figure 46] Figure 46 shows the effect of the drug on the ear weight of acne rabbits (##, p<0.01 compared to the blank control, *, p<0.05 compared to the model (solvent) group). [Figure 47] FIG. 47 shows the pathology of ear tissue from acne rabbits. [Figure 48] FIG. 48 shows the effect of the drug on the diameter of the sebaceous gland in the ear tissue (##, p<0.01 compared to the blank control, *, p<0.05 compared to the model (solvent) group). [Figure 49] Figure 49 shows the effect of the drug on the ear tissue hair follicle area of acne rabbits (###, compared to blank control, p<0.01; #, compared to blank control, p<0.05; **, compared to model (solvent) group, p<0.01; *, compared to model (solvent) group, p<0.05). [Figure 50] FIG. 50 shows the effect of the drug on serum IL-1α in acne rabbits (##, compared to blank control, p<0.01; **, compared to model (solvent) group, p<0.01). [Figure 51] FIG. 51 shows the effect of the drug on serum IL-6 in acne rabbits (## compared to blank control, p<0.01; ** compared to model (vehicle) group, p<0.01). [Figure 52] FIG. 52 shows the effect of drugs on serum DHT in acne rabbits. [Figure 53A] FIG. 53 shows the experimental process and results of the effect of compounds on in vitro adipocyte lipolysis. [Figure 53B]Same as above [Figure 54] FIG. 54 shows the results of HE staining of unwounded mouse skin and wounded tissue. [Figure 55] FIG. 55 shows the results of experiments in which compounds promote epithelial healing in wounds. [Example]

[0223] In order to clarify the objectives, technical solutions, and beneficial technical effects of the present invention, the following embodiments of the present invention will be described in more detail in combination with examples. However, it should be understood that the examples of the present invention are merely for the purpose of illustrating the present invention and are not intended to limit the present invention, and the examples of the present invention are not limited to the examples set forth in the specification. In the examples, any reagents or equipment whose specific origin is not specified are ordinary reagents or equipment in chemical or biological laboratories, and any operations for which specific experimental or operating conditions are not specified in the examples are performed under ordinary conditions well known to those skilled in the art or under conditions recommended by material suppliers or equipment manufacturers.

[0224] Example 1: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone (MDI-2) [ka]

[0225] The product was synthesized according to the method described in Example 1 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0226] 1 H NMR(400MHz,MeOD-d4)δ8.67(s,1H),8.28(dd,J=8.0Hz,J=4.0Hz,1H),8.21(s,1H),7.40(s,1H),7.18(dd,J=8.0Hz,J=4.0Hz,1H),6.96 -6.89(m,2H),5.14(s,2H),4.82(s,2H),3.76-3.73(m,4H),2.58(dd,J=12.0Hz,J=8.0Hz,2H),1.76-1.66(m,6H),1.10(t,J=8.0Hz,3H).

[0227] Example 2: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201) [ka]

[0228] It was synthesized according to the method described in Example 2 of Chinese Patent CN111606908B, specifically as follows:

[0229] Synthetic route of MDI-201 [ka]

[0230] Synthesis method Intermediate MDI-201-1: Synthesis of methyl 5-morpholinepyrazine-2-carboxylate Methyl 5-chloropyrazine-2-carboxylate (1.5 g, 8.7 mmol) was dissolved in 10 ml of DMF, and N,N-diisopropylethylamine (3.0 ml, 17.4 mmol) and morpholine (0.91 g, 10.4 mmol) were added. The mixture was stirred at room temperature overnight, and water was added under vigorous stirring. The precipitated solid was filtered, washed with water, and dried to obtain intermediate MDI-201-1 in a yield of 72.2%.

[0231] Intermediate MDI-201-2: Synthesis of 5-morpholinepyrazine-2-carboxylic acid Intermediate MDI-201-1 (1.4 g, 6.27 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of water, and lithium hydroxide (0.32 g, 7.53 mmol) was added. The mixture was allowed to react at room temperature for 4 hours, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The pH was adjusted to 4 with 1N HCl. The precipitated solid was filtered, washed with water, and dried to obtain intermediate MDI-201-2 in a yield of 99.1%.

[0232] 1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.04(s,1H),3.88-3.86(m,4H),3.80-3.77(m,4H).

[0233] Synthesis of Intermediate MDI-201-3: (2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl))ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)methanone

[0234] Intermediate MDI-201-2 (27.4 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF, and HATU (67.8 mg, 0.18 mmol) was added, followed by reaction at room temperature for 10 minutes. Intermediate 2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl ester (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated. The trifluoroacetic acid was washed with dichloromethane three times, dissolved in DMF, and slowly added to the previous reaction solution. The mixture was allowed to react at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain intermediate MDI-201-3 in a yield of 47.8%.

[0235] 1H NMR(400MHz,CDCl3)δ8.91(d,J=8.0Hz,1H),8.44-8.36(m,1H),8.10(d,J=8. 0Hz,1H),7.80(s,1H),7.46-7.41(m,1H),5.96(s,2H),5.74(d,J=4.0Hz,2H), 5.27(s,1H),5.19(s,1H),5.00(s,1H),4.92(s,1H),3.90-3.88(m,4H),3.75- 3.72(m,4H),3.64-3.58(m,4H),0.96-0.89(m,4H),0.03(s,9H),0.02(s,9H).

[0236] Synthesis of Intermediate MDI-201-4: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)(5-morpholinopyrazin-2-yl)methanone

[0237] Intermediate MDI-201-3 (43.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol), and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml), purged with nitrogen gas three times, heated to 100 °C, reacted overnight, cooled to room temperature, added with water, and extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain intermediate MDI-201-4 in 40.9% yield.

[0238] 1H NMR(400MHz,CDCl3)δ8.91(dd,J=4.0Hz,J=4.0Hz,1H),8.52(dd,J=8.0Hz,J=16.0Hz,1H),8.10(dd,J=8.0Hz,J=4. 0Hz,1H),7.49(s,1H),7.27(s,1H),7.20(d,J=8.0Hz,1H),7.06(d,J=12.0Hz,1H),6.00(s,2H),5.79(d,J=4.0Hz, 2H),5.35(s,2H),5.29(s,1H),5.20(s,1H),5.02(s,1H),4.94(s,1H),3.91-3.86(m,6H),3.76-3.72(m,4H),3.65 -3.61(m,4H),2.58(t,J=8.0Hz,2H),1.10-1.03(m,3H),0.95-0.91(m,6H),0.06(s,9H),0.04(s,9H),0.03(s,9H).

[0239] Synthesis of MDI-201: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone

[0240] Intermediate MDI-201-4 (22.0 mg, 0.02 mmol) was dissolved in methanol (4 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was heated to 50°C for 6 hours. The mixture was then concentrated. The solid was dissolved in 1 ml of methanol, 2 ml of concentrated aqueous ammonia was added, the mixture was concentrated, and the aqueous ammonia was washed with methanol three times. The mixture was then purified using a preparative plate to obtain 8.0 mg of the final product, with a yield of 61.9%.

[0241] 1H NMR(400MHz,DMSO-d6)δ13.35(s,1H),9.89(s,1H),8.66(d,J=4.0Hz,1H),8.38-8.33(m,2H),7.42(s,1H),7.15(d,J=8.0Hz,1H),7.06(d,J=12.0Hz, 1H),6.95(d,J=8.0Hz,1H),5.05(s,2H),4.72(s,2H),3.76-3.74(m,4H),3 .71-3.68(m,4H),2.52(dd,J=12.0Hz,J=4.0Hz,2H),1.05(t,J=8.0Hz,3H).

[0242] Example 3: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)methanone (MDI-202) [ka]

[0243] The product was synthesized according to the method described in Example 3 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0244] 1 H NMR(400MHz,DMSO-d6)δ13.33(s,1H),12.87(s,1H),9.89(s,1H),8.35(d,J=8.0Hz,2H),7.94(s,1H),7.42(s,1H),7.15(d,J=8.0Hz, 1H),7.06(d,J=12.0Hz,1H),6.95(d,J=12.0Hz,1H),4.89(s,2H),4.67(s,2H),3.92(s,3H),2.51-2.48(m,2H),1.05(t,J=8.0Hz,3H).

[0245] Example 4: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)methanone (MDI-203) [ka]

[0246] MDI-203 may be named 5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidine-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol, and was synthesized according to the method described in Example 4 of Chinese Patent CN111606908B. The resulting product has the following hydrogen nuclear magnetic resonance spectrum data:

[0247] 1 H NMR(400MHz,DMSO-d6)δ13.35(s,1H),9.87(s,1H),9.24(s,1H),8.32(d,J=8.0Hz,1H) ,7.42(s,1H),7.22(d,J=8.0Hz,1H),7.03(d,J=12.0Hz,1H),6.96(d,J=12.0Hz,1H),4 0.80 (s, 2H), 4.48 (s, 2H), 3.04-3.01 (m, 2H), 2.79 (s, 3H), 2.55-2.51 (m, 2H), 2.05-1.99 (m, 3H), 1.85-1.78 (m, 2H), 1.01-0.98 (m, 3H). The two H signals are covered by the water peak (δ = 3.37).

[0248] Example 5: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-204) [ka]

[0249] MDI-204 may be named 5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidine-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol, and was synthesized according to the method described in Example 5 of Chinese Patent CN111606908B. The resulting product has the following hydrogen nuclear magnetic resonance spectrum data:

[0250] 1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),12.79(d,J=16.0Hz,1H),9.85(s,1H),8.62(s,1H),8.36(s,1H),8.34-8.30(m,1H),7.40(s,1H),7.14-7.10 (m,1H),7.03(d,J=12.0Hz,1H),6.92(d,J=12.0Hz,1H),5.08-4.65(m,4H ),2.55-2.49(m,6H),2.24(s,3H),2.03-1.97(m,4H),1.04-1.02(m,3H).

[0251] Example 6: (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-205) [ka]

[0252] MDI-205 may be named 3-ethyl-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol, and was synthesized according to the method described in Example 6 of Chinese Patent CN111606908B. The resulting product has the following hydrogen nuclear magnetic resonance spectrum data:

[0253] 1 H NMR(400MHz,MeOD-d4)δ8.72(d,J=4.0Hz,1H),8.28(dd,J=4.0Hz,J=8.0Hz,2H),7 .40(s,1H),7.18(dd,J=4.0Hz,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.80(d,J=4. 0Hz,1H),6.72-6.69(m,1H),5.17(s,2H),4.85(s,2H),3.83-3.81(m,4H),2.67-2 .64(m,4H),2.60(dd,J=4.0Hz,J=8.0Hz,2H),2.43(s,3H),1.10(t,J=8.0Hz,3H).

[0254] Example 7: 5-Ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-206) [ka]

[0255] The product was synthesized according to the method described in Example 7 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0256] 1 H NMR(400MHz,MeOD-d4)δ8.22(d,J=8.0Hz,1H),7.98-7.96(m,2H),7.69-7.65(m,3H),7.41(s,1H),7.16(d,J =8.0Hz,1H),6.96-6.89(m,2H),4.61-4.52(m,4H),2.57(dd,J=16.0Hz,J=8.0Hz,2H),1.08(t,J=8.0Hz,3H).

[0257] Example 8: 5-Ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-207) [ka]

[0258] The product was synthesized according to the method described in Example 8 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0259] 1 H NMR(400MHz,MeOD-d4)δ8.80(d,J=4.0Hz,1H),8.65(dd,J=4.0Hz,J=4.0Hz,1H),8.56(d,J=4.0Hz,1H),8.26(dd,J=4.0Hz,J=4.0Hz,1H),7.41(d,J=4 .0Hz,1H),7.17(dd,J=12.0Hz,J=4.0Hz,1H),6.91-6.89(m,2H),4.30(s,2 H),4.07(s,4H),2.56(dd,J=8.0Hz,J=16.0Hz,2H),1.07(t,J=8.0Hz,3H).

[0260] Example 9: 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-208) [ka]

[0261] The product was synthesized according to the method described in Example 9 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0262] 1 H NMR(400MHz,MeOD-d4)δ8.27(dd,J=4.0Hz,J=8.0Hz,1H),7.42(s,1H),7.17(dd,J=4.0Hz,J=8.0Hz,1H),6.97-6.89 (m,2H),4.02(s,4H),2.80(d,J=8.0Hz,2H),2.59-2.53(m,2H),1.10(m,4H),0.66-0.61(m,2H),0.30-0.27(m,2H).

[0263] Example 10: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233) [ka]

[0264] It was synthesized according to the method described in Example 10 of Chinese Patent CN111606908B (in CN111606908B, the compound is numbered MDI-209, and in this application, the compound is numbered MDI-1233), specifically as follows:

[0265] Synthetic route of MDI-1233 [ka]

[0266] Synthesis method Synthesis of Intermediate MDI-1233-1: (2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(cyclopropyl)methanone

[0267] Intermediate tert-butyl 2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, the mixture was stirred at room temperature for 30 minutes, concentrated, and trifluoromethane was added. The fluoroacetic acid was washed three times and dissolved in 5 ml of DCM. Triethylamine (24.3 mg, 0.24 mmol) was then added to the system, the temperature was lowered to 0°C, cyclopropylformyl chloride (18.8 mg, 0.18 mmol) was slowly added dropwise, and after the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 1-2 hours. The reaction was then stopped, and the system was quenched by adding water, followed by separation. The organic phase was dried over sodium sulfate and concentrated by column chromatography to obtain compound MDI-1233 in a yield of 45%.

[0268] 1 H NMR(400MHz,CDCl3)δ8.36(dd,J=17.8Hz,J=8.6Hz,1H),7.80-7.79(m,1H),7.41(d,J=8.6Hz,1H),5.97-5.92(m,2H),5.71(d,J=2.4 Hz,2H),4.96-4.66(m,4H),3.62-3.54(m,4H),1.78-1.67(m,1H),1.10-1.07(m,2H),0.94-0.84(m,6H),-0.05(s,9H),-0.08(s,9H).

[0269] Intermediate MDI-1233-2: Synthesis of cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone

[0270] Intermediate MDI-1233-1 (50.5 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl2 (5.9 mg, 0.008 mmol), and potassium phosphate (50.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml), purged with nitrogen gas three times, heated to 100 °C, reacted overnight, cooled to room temperature, added water, and extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain intermediate MDI-1233-2 in 76.1% yield.

[0271] 1 H NMR(400MHz,CDCl3)δ8.50-8.43(m,1H),7.46-7.45(m,1H),7.25-7.22(m,1H),7.16( d,J=8.0Hz,1H),7.02(d,J=12.0Hz,1H),5.99-5.94(m,2H),5.76(s,2H),5.32(s,2H) ,4.98-4.67(m,4H),3.88-3.84(m,2H),3.64-3.55(m,4H),2.57-2.51(m,2H),1.79-1 .68(m,1H),1.07-1.02(m,6H),0.95-0.87(m,5H),0.03(s,9H),-0.06--0.08(m,18H).

[0272] Synthesis of compound MDI-1233: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone

[0273] Intermediate MDI-1233 (50 mg, 0.06 mmol) was dissolved in methanol (4 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was heated to 50°C for 6 hours. The mixture was then concentrated. The solid was dissolved in 1 ml of methanol, 2 ml of concentrated aqueous ammonia was added, and the mixture was concentrated. The aqueous ammonia was washed with methanol three times, concentrated, and separated to obtain 10.0 mg of the final product, with a yield of 38.1%.

[0274] 1 H NMR(400MHz,MeOD-d4)δ8.28(d,J=8.0Hz,1H),7.43(s,1H),7.18(dd,J=8.4Hz,J=1.4Hz,1H),6.98(d,J=12.0Hz,1H),6.92(d,J=12.0 Hz,1H),4.95(s,2H),4.65(s,2H),2.59-2.53(m,2H),1.98-1.89(m,1H),1.08(t,J=8.0Hz,3H),1.02-1.00(m,2H),0.98-0.92(m,2H).

[0275] Example 11: 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-210) [ka]

[0276] The product was synthesized according to the method described in Example 11 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0277] 1 H NMR(400MHz,MeOD-d4)δ8.27(dd,J=4.0Hz,J=8.0Hz,1H),7.42(s,1H),7.17(dd,J=4.0Hz,J=8.0Hz,1H),6.97-6.89(m,2H),3.98( s,4H),3.00(d,J=8.0Hz,2H),2.72-2.68(m,1H),2.59-2.53(m,2H),2.21-2.18(m,2H),1.89-1.85(m,4H),1.07(t,J=8.0Hz,3H).

[0278] Example 12: Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-211) [ka]

[0279] The product was synthesized according to the method described in Example 12 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0280] 1 H NMR(400MHz,MeOD-d4)δ8.27(d,J=8.0Hz,1H),7.43(s,1H),7.17(dd,J=8.4,1.4Hz,1H),6.93(dd,J=20.0Hz,J=12.0Hz,2H),4.68- 4.63(m,4H),3.54-3.46(m,1H),2.57-2.53(m,2H),2.43-2.26(m,4H),2.16-2.04(m,1H),1.98-1.89(m,1H),1.08(t,J=8.0Hz,3H).

[0281] Example 13: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxycyclobutyl)methanone (MDI-213) [ka]

[0282] The product was synthesized according to the method described in Example 13 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0283] 1 H NMR(400MHz,MeOD-d4)δ8.28(dd,J=4.0Hz,J=8.0Hz,1H),7.43-7.42(m,1H),7.19(dd,J=4.0Hz,J=8.0Hz,1H),6.97-6.89(m ,2H),4.72-4.62(m,4H),4.23-4.20(m,1H),2.95-2.91(m,1H),2.63-2.53(m,4H),2.26-2.18(m,2H),1.10(t,J=8.0Hz,3H).

[0284] Example 14: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)methanone (MDI-214) [ka]

[0285] The product was synthesized according to the method described in Example 14 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0286] 1 H NMR(400MHz,MeOD-d4)δ9.48(dd,J=2.3,J=1.3Hz,1H),9.42(dd,J=5.2,J=1.3Hz,1H),8.26(s,1H),8.02(dd,J=5.3,J=2.2Hz,1H),7.43(d,J =1.1Hz,1H),7.17(d,J=8.2Hz,1H),6.93(dd,J=19.7,J=10.4Hz,2H),4.90(s,2H),4.73(s,2H),2.55(q,J=7.5Hz,2H),1.08(t,J=7.5Hz,3H).

[0287] Example 15: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)methanone (MDI-215) [ka]

[0288] The product was synthesized according to the method described in Example 15 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0289] 1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),12.83(d,J=33.0Hz,1H),9.85(s,1H),9.3 9(dd,J=5.0Hz,J=1.7Hz,1H),8.37-8.31(m,1H),8.07(s,1H),7.92(dd,J=8.5Hz, J=5.0Hz,1H),7.40(s,1H),7.13(d,J=8.1Hz,1H),7.03(d,J=11.9Hz,1H),6.92( d,J=9.1Hz,1H),4.84-4.45(m,4H),2.49(q,J=7.5Hz,2H),1.02(t,J=7.5Hz,3H).

[0290] Example 16: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228) [ka]

[0291] It was synthesized according to the method described in Example 16 of Chinese Patent CN111606908B (in CN111606908B, the compound is numbered MDI-216, and in this application, the compound is numbered MDI-1228), and the specific process is as follows:

[0292] Synthetic route of MDI-1228 [ka]

[0293] Synthesis method Synthesis of Intermediate MDI-1228-1: 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

[0294] tert-Butyl 2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate (500 mg, 0.75 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (401 mg, 1.13 mmol), Pd(dppf)Cl2 (75 mg, 0.075 mmol), and potassium phosphate (495 mg , 2.25mmol) was dissolved in 1,3-dioxane (30ml) and water (6ml), purged with nitrogen gas three times, heated to 100°C, reacted for 16 hours, cooled to room temperature, added water, extracted twice with ethyl acetate, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, purified through a silica gel column, the purified product was dissolved in 25ml of dichloromethane, added dropwise with 5ml of trifluoroacetic acid, stirred at room temperature for 30 minutes, concentrated, washed three times with dichloromethane to remove trifluoroacetic acid, concentrated, and purified through a silica gel column to obtain 210mg of intermediate MDI-1228-1, the yield was 39.2%.

[0295] 1 H NMR(400MHz,CDCl3)δ8.48(d,J=8.3Hz,1H),7.52(d,J=7.4Hz,1H),7.49-7.37 (m,5H),7.25(d,J=8.4Hz,1H),7.23-6.96(m,2H),5.93(s,2H),5.77(s,2H),5 .23(s,2H),4.21(d,J=35.1Hz,4H),3.66-3.52(m,4H),2.54(q,J=7.6Hz,2H), 1.05(t,J=7.5Hz,3H),0.95-0.89(m,4H),0.02(s,9H),-0.05(d,J=3.4Hz,9H).

[0296] Synthesis of Intermediate MDI-1228-2: (S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-(benzyloxy)pyrrolidin-1-yl)methanone

[0297] Triphosgene (25.8 mg, 0.09 mmol) was dissolved in 5 ml of tetrahydrofuran, and a solution of intermediate MDI-1228 (80 mg, 0.09 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C. The mixture was stirred at room temperature for 10 minutes. A solution of (S)-3-(benzyloxy)pyrrolidine (31.9 mg, 0.18 mmol) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 5 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 71 mg of intermediate MDI-1228-2, with a yield of 86.1%.

[0298] 1 H NMR(400MHz,CDCl3)δ8.46(d,J=8.3Hz,1H),7.53-7.51(m,2H),7.47-7.42(m,3H),7.39-7.29(m,6H),7.2 4(dd,J=8.4Hz,J=4.0Hz,1H),7.07-6.97(m,2H),5.95(s,2H),5.77(s,2H),5.23(s,2H),4.92-4.88(m,2H) ),4.76-4.69(m,2H),4.60(s,2H),4.23(s,1H),3.76-3.70(m,2H),3.66-3.58(m,6H),2.54(q,J=7.5Hz,2 H),2.15-2.13(m,1H),2.06-2.02(m,1H),1.05(t,J=7.5Hz,3H),0.95-0.91(m,4H),-0.01--0.11(m,18H).

[0299] Synthesis of compound MDI-1228: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0300] Intermediate MDI-1228-2 (83 mg, 0.11 mmol) was dissolved in methanol (10 ml), 10 mg of Pd / C was added, concentrated hydrochloric acid (5 ml) was added dropwise, and the mixture was heated to 50°C and reacted for 6 hours. The mixture was then filtered, concentrated, washed with methanol three times to remove the hydrochloric acid, concentrated, dissolved in methanol, added with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 8 mg of the final product, with a yield of 15.2%.

[0301] 1 H NMR(400MHz,MeOD-d4)δ8.27(d,J=8.4Hz,1H),7.43(d,J=1.0Hz,1H),7.17(d,J=8.4Hz,1H),6.97-6.90(m,2H),4.81-4.61(m, 4H),4.46-4.44(m,1H),3.79-3.69(m,2H),3.50-3.43(m,2H),2.56(q,J=7.5Hz,2H),2.09-1.99(m,2H),1.08(t,J=7.5Hz,3H).

[0302] Example 17: 5-Ethyl-2-fluoro-4-(3-(5-(4-hydroxycyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-217) [ka]

[0303] The product was synthesized according to the method described in Example 17 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0304] 1H NMR(400MHz,MeOD-d4)δ8.27(dd,J=4.0Hz,J=8.0Hz,1H),7.43-7.42(m,1H),7.19(dd,J=4.0Hz,J=8.0Hz,1H),6.96-6.88(m,2H),3.98(s,4H),3 .93(m,1H),2.74-2.72(m,1H),2.58(q,J=8.0Hz,2H),2.04-2.05(m,1H) ,1.90-1.80(m,5H),1.64-1.62(m,2H),1.10(t,J=8.0Hz,J=16.0Hz,3H).

[0305] Example 18: 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218) [ka]

[0306] It was synthesized according to the method described in Example 18 of Chinese Patent CN111606908B, specifically as follows:

[0307] Synthetic route of MDI-218 [ka]

[0308] Synthesis method Intermediate MDI-218-1: Synthesis of 6-bromo-3-(5-(cyclopropylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0309] Tert-butyl 2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formate (100 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 30 minutes, concentrated, quenched with sodium bicarbonate, extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting compound was dissolved in 5 ml of DCM and Et3N (0.08 ml, 0.59 mmol), cooled to 0°C, and cyclopropylsulfonyl chloride (22.4 mg, 0.16 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 2 hours. Water was added to quench the reaction, and the mixture was extracted twice with DCM. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain intermediate MDI-218-1 in a yield of 36.0%.

[0310] 1 H NMR(400MHz,CDCl3)δ8.37(d,J=8.0Hz,1H),7.80(d,J=4.0Hz,1H),7.43(d,J=8.0Hz,1H),5.91(s,2H),5.73(s,2H),4.75-4.74(m,2H), 4.66-4.65(m,2H),3.63-3.58(m,4H),2.50-2.44(m,1H),1.33-1.31(m,2H),1.06-1.02(m,2H),0.96-0.91(m,4H),0.00--0.05(m,18H).

[0311] Synthesis of Intermediate MDI-218-2: 3-(5-cyclopropylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0312] Intermediate MDI-218-1 (36.0 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (25.5 mg, 0.06 mmol), Pd(dppf)Cl2 (3.9 mg, 0.005 mmol), and potassium phosphate (34.2 mg, 0.16 mmol) were dissolved in 1,4-dioxane (6 ml) and water (1 ml), purged with nitrogen gas three times, heated to 100 °C, reacted overnight, cooled to room temperature, added water, extracted twice with ethyl acetate, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain intermediate MDI-218-2 in 70.0% yield.

[0313] 1 H NMR(400MHz,CDCl3)δ8.47(d,J=8.0Hz,1H),7.48(s,1H),7.26(d,J=7.9Hz,1H), 7.18(d,J=8.0Hz,1H),7.04(d,J=12.0Hz,1H),5.95(s,2H),5.78(s,2H),5.34(s, 2H),4.76(s,2H),4.68(s,2H),3.88(t,J=8.0Hz,2H),3.68-3.57(m,4H),2.56(q ,J=7.6Hz,2H),2.24(t,J=7.7Hz,1H),1.12-0.86(m,13H),-0.01--0.06(m,27H).

[0314] Synthesis of compound MDI-218: 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

[0315] Intermediate MDI-218-2 (36.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was heated to 50°C for 6 hours. The mixture was then concentrated. The solid was dissolved in 1 ml of methanol, adjusted to pH 8-9 with sodium bicarbonate solution, and extracted four times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and purified using a preparative plate to obtain 16 mg of the final product, with a yield of 81.4%.

[0316] 1 H NMR(400MHz,MeOD-d4)δ8.27(d,J=8.0Hz,1H),7.43(s,1H),7.18(dd,J=8.0Hz,J=4.0Hz,1H),6.93(dd,J=20. 0Hz,J=12.0Hz,2H),4.65(s,4H),2.76-2.69(m,1H),2.60-2.51(m,2H),1.20-1.18(m,2H),1.10-1.06(m,5H).

[0317] Example 19: 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-219) [ka]

[0318] The product was synthesized according to the method described in Example 19 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0319] 1 H NMR(400MHz,MeOD-d4)δ8.26(d,J=8.0Hz,1H),7.43(s,1H),7.17(dd,J=8.4Hz,J=1.4Hz,1H),6.93(dd,J=20.0Hz,J=12.0 Hz,2H),4.60(s,4H),4.26-4.18(m,1H),2.68-2.52(m,4H),2.40-2.31(m,2H),2.13-2.02(m,2H),1.08(t,J=7.5Hz,3H).

[0320] Example 20: 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-220) [ka]

[0321] The product was synthesized according to the method described in Example 20 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0322] 1 H NMR(400MHz,MeOD-d4)δ8.27(dd,J=8.0Hz,J=4.0Hz,1H),7.43(s,1H),7.17(dd,J=8.0Hz,J=1.4Hz,1H),6.93(dd,J=20.0Hz,J=12.0Hz, 2H),4.65(s,4H),3.91-3.83(m,1H),2.58-2.52(m,2H),2.13-2.03(m,4H),1.89-1.78(m,2H),1.75-1.64(m,2H),1.08(t,J=8.0Hz,3H).

[0323] Example 21: 5-Ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-221) [ka]

[0324] The product was synthesized according to the method described in Example 21 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0325] 1 H NMR(400MHz,MeOD-d4)δ8.25(d,J=8.0Hz,1H),7.68(s,1H),7.56(s,1H),7.42(s,1H),7.16(dd,J=8.4Hz,J=1.4Hz, 1H),6.93(dd,J=20.0Hz,J=12.0Hz,2H),4.03-3.96(m,6H),3.92(s,3H),2.58-2.53(m,2H),1.08(t,J=8.0Hz,3H).

[0326] Example 22: 4-(3-(5-(cyclopentatyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-224) [ka]

[0327] The product was synthesized according to the method described in Example 22 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0328] 1 H NMR(400MHz,MeOD-d4)δ8.26(d,J=8.0Hz,1H),7.42(s,1H),7.17(d,J=8.0Hz,1H),6.93(dd,J=20.0Hz,J=12.0Hz,2H),4.05-3.9 4(m,4H),3.27-3.25(m,1H),2.59-2.54(m,2H),2.08-2.01(m,2H),1.87-1.79(m,2H),1.73-1.56(m,4H),1.08(t,J=8.0Hz,3H).

[0329] Example 23: 5-Ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-225) [ka]

[0330] The product was synthesized according to the method described in Example 23 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0331] 1 H NMR(400MHz,MeOD-d4)δ8.26(dd,J=12.0Hz,J=4.0Hz,1H),7.42(s,1H),7.16(dd,J=8.0Hz,J=4.0Hz,1H),6.93(dd,J=20.0Hz,J=12.0Hz,2H ),4.07-3.99(m,6H),3.52-3.49(m,2H),2.95-2.90(m,1H),2.58-2.53(m,2H),2.00-1.97(m,2H),1.69-1.59(m,2H),1.08(t,J=8.0Hz,3H).

[0332] Example 24: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-226) [ka]

[0333] The product was synthesized according to the method described in Example 24 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0334] 1 H NMR (400MHz, methanol-d4) δ8.28(d,J=8Hz,1H),7.43(s,1H),7.18(d,J=8Hz,1H),6.94(dd,J=22 ,10Hz,2H),4.79(s,2H),4.65(s,2H),2.59-2.53(m,2H),2.23(s,3H),1.08(t,J=7.5Hz,3H).

[0335] Example 25: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one (MDI-227) [ka]

[0336] The product was synthesized according to the method described in Example 25 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0337] 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),12.80(s,1H),9.85(s,1H),8.33(d,J=8Hz,1H),7.40(s,1H),7.12(d,J=8Hz,1H),7.03(d,J =12Hz,1H),6.92(d,J=12Hz,1H),4.73-4.58(m,2H),4.50-4.42(m,2H),2.50-2.47(m,2H),2.43-2.37(m,2H),1.08-1.01(m,6H).

[0338] Example 26: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one (MDI-228) [ka]

[0339] The product was synthesized according to the method described in Example 26 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0340] 1 H NMR(400MHz,MeOD-d4)δ8.26(d,J=8.0Hz,1H),7.43(s,1H),7.17(d,J=8Hz,1H),6.93(dd,J=20,12Hz,2H ),4.83-4.59(m,4H),2.94-2.90(m,1H),2.58-2.52(m,2H),1.22(d,J=8.0Hz,6H),1.08(t,J=8.0Hz,3H).

[0341] Example 27: 2-Cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-229) [ka]

[0342] The product was synthesized according to the method described in Example 27 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0343] 1 H NMR(400MHz,MeOD-d4)δ8.29(d,J=8.0Hz,1H),7.43(s,1H),7.19-7.17(m,1H),6.98-6.90(m,2H),4.73-4.61(m,4H) ,2.59-2.53(m,2H),2.46(d,J=8.0Hz,2H),1.17(m,1H),1.08(t,J=8.0Hz,3H),0.64-0.59(m,2H),0.30-0.26(m,2H).

[0344] Example 28: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one (MDI-230) [ka]

[0345] The product was synthesized according to the method described in Example 28 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0346] 1 H NMR(400MHz,MeOD-d4)δ8.29-8.26(m,1H),7.43(s,1H),7.19-7.16(m,1H),6.97-6.89(m,2H) ,4.75-4.70(m,4H),2.56(q,J=7.5Hz,2H),2.36(m,2H),2.29-2.20(m,1H),1.10-1.05(m,9H).

[0347] Example 29: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231) [ka]

[0348] It was synthesized according to the method described in Example 29 of Chinese Patent CN111606908B, specifically as follows:

[0349] Synthetic route of MDI-231 [ka]

[0350] Synthesis method Synthesis of Intermediate MDI-231-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone

[0351] Dissolve triphosgene (64.4 mg, 0.21 mmol) in 15 ml of dichloromethane and heat at 0°C to obtain the intermediate A solution of 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (150 mg, 0.21 mmol) in dichloromethane (5 ml) was added dropwise, triethylamine (63.6 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of pyrrolidine (29.8 mg, 0.42 mmol) in dichloromethane was added, and the mixture was stirred at room temperature for 10 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 140 mg of the intermediate MDI-231-1 was obtained with a yield of 82.4%.

[0352] 1 H NMR(400MHz,CDCl3)δ8.48(d,J=8Hz,1H),7.53-7.38(m,6H),7.22(d,J=8Hz,1H), 7.03(d,J=12Hz,1H),6.95(d,J=8Hz,1H),5.96(s,2H),5.77(s,2H),5.23(s,2H),4 .81(s,2H),4.67(s,2H),3.66-3.59(m,4H),3.53-3.51(m,4H),2.56-2.52(m,2H) ,1.93-1.88(m,4H),1.03(t,J=8Hz,3H),0.93-0.87(m,4H),-0.05--0.09(m,18H).

[0353] Synthesis of compound MDI-231: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone

[0354] Intermediate MDI-231-1 (140 mg, 0.173 mmol) was dissolved in methanol (6 ml), 15 mg of Pd / C was added, concentrated hydrochloric acid (3 ml) was added dropwise, and the mixture was heated to 50°C for 6 hours. The mixture was then filtered, concentrated, washed with methanol three times to remove the hydrochloric acid, concentrated, dissolved in methanol, added with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 21 mg of the final product, with a yield of 26.3%.

[0355] 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),12.69(s,1H),9.83(s,1H),8.31(d,J=8Hz,1H),7.39(s,1H),7.11(d,J=8Hz,1H),7.02(d,J=12Hz,1H) ),6.91(d,J=12Hz,1H),4.57-4.56(m,2H),4.49-4.48(m,2H),3.32-3.31(m,4H),2.48-2.44(m,2H),1.85-1.79(m,4H),1.02(t,J=7Hz,3H).

[0356] Example 30: N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288) [ka]

[0357] Synthetic route of MDI-1288 [ka]

[0358] Specific synthesis method Synthesis of compound MDI-1288-2: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1-((2-trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)(3-hydroxyazetidin-1-yl)methanone

[0359] MDI-1288-1 (prepared according to the synthesis method of MDI-231 using appropriate starting materials, 51.00 g, 66.49 mmol) was dissolved in 500 ml of tetrahydrofuran, 7 g of palladium carbon was added, hydrogen gas was replaced, and the mixture was reacted at 40°C for 16 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain a total of 44.10 g of MDI-1288-I07, with a yield of 97.8%.

[0360] Synthesis of compound MDI-1288: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxyazetidin-1-yl)methanone

[0361] MDI-1288-I07 (44.10 g, 65.01 mmol) was dissolved in 240 ml of methanol, 120 ml of concentrated hydrochloric acid was added, and the mixture was allowed to react overnight at 50°C. After the reaction was complete, the reaction solution was filtered, and the filter cake was dried in a drying cabinet at 50°C to obtain 29.8 g. After slurrying in 150 ml of methanol for 0.5 hours, 27.2 g of crude hydrochloride was obtained, which was then purified by recrystallization.

[0362] 1 H NMR(400MHz,DMSO-d6)δ14.25(s,1H),9.90(s,1H),8.43(d,J=8.4Hz,1H),7.56(s, 1H),7.27(dd,J=8.5,1.4Hz,1H),7.04(d,J=11.8Hz,1H),6.97(d,J=9.1Hz,1H),6.7 1(s,1H),4.59(s,4H),3.83-3.78(m,1H),3.68(dd,J=11.2,4.2Hz,1H),3.54(dd,J =11.2,6.0Hz,1H),3.28-3.15(m,2H),2.48(q,J=7.5Hz,2H),1.02(t,J=7.5Hz,3H).

[0363] Example 31: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233) [ka]

[0364] It was synthesized according to the method described in Example 31 of Chinese Patent CN111606908B, specifically as follows:

[0365] Synthetic route of MDI-233 [ka]

[0366] Synthesis method Synthesis of Intermediate MDI-233-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone

[0367] Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml of tetrahydrofuran and the resulting intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.182 mmol) was added at 0°C. A solution of 100 mmol of methyl 2,4-dichlorobenzoate (2.2 mmol) in tetrahydrofuran (5 ml) was added dropwise, triethylamine (55.2 mg, 0.550 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of piperidine hydrochloride (44.4 mg, 0.364 mmol) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 10 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 100 mg of intermediate MDI-233-1, with a yield of 66.6%.

[0368] 1H NMR(400MHz,CDCl3)δ8.44(d,J=8.3Hz,1H),7.50-7.48(m,2H),7.44-7.35(m,4 H),7.23-7.20(m,1H),7.04-6.94(m,2H),5.93(s,2H),5.74(s,2H),5.20(s,2H) ,4.69(d,J=54.8Hz,4H),3.64-3.56(m,4H),3.31(s,4H),2.54(q,J=7.5Hz,2H), 1.64(s,6H),1.03(t,J=7.5Hz,3H),0.93-0.86(m,4H),-0.07(d,J=2.7Hz,18H).

[0369] Synthesis of compound MDI-233: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone

[0370] Intermediate MDI-233-1 (100 mg, 0.121 mmol) was dissolved in methanol (6 ml), 10 mg of 10% Pd / C was added, concentrated hydrochloric acid (3 ml) was added dropwise, and the mixture was heated to 50°C and reacted for 6 hours. The mixture was then filtered, concentrated, washed with methanol three times to remove the hydrochloric acid, concentrated, dissolved in methanol, added with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 33 mg of the final product, with a yield of 57.3%.

[0371] 1 H NMR(400MHz,MeOD-d4)δ8.25(d,J=8.4Hz,1H),7.40(s,1H),7.16-7.14(m,1H),6.95-6.87(m,2H),4. 83-4.65(m,4H),3.35-3.33(m,4H),2.54(q,J=7.5Hz,2H),1.67-1.65(m,6H),1.06(t,J=7.5Hz,3H).

[0372] Example 32: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234) [ka]

[0373] It was synthesized according to the method described in Example 32 of Chinese Patent CN111606908B, specifically as follows:

[0374] Synthetic route of MDI-234 [ka]

[0375] Synthesis method Synthesis of Intermediate MDI-234-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone

[0376] Dissolve triphosgene (54.1 mg, 0.182 mmol) in 5 ml of tetrahydrofuran and heat at 0°C to obtain the intermediate A solution of 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) was added dropwise, triethylamine (55.1 mg, 0.546 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of morpholine (31.7 mg, 0.364 mmol) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 10 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 120 mg of the intermediate MDI-234-1 was obtained with a yield of 79.7%.

[0377] 1H NMR(400MHz,CDCl3)δ8.45(d,J=8.3Hz,1H),7.53-7.51(m,2H),7.47-7.35(m,4H),7.26 -7.23(m,1H),7.06-6.97(m,2H),5.96(s,2H),5.77(s,2H),5.23(s,2H),4.68(d,J=54. 8Hz,4H),3.80-3.78(m,3H),3.67-3.59(m,4H),3.43-3.40(m,3H),3.27-3.21(m,6H),2 .54(q,J=7.5Hz,2H),1.05(t,J=7.5Hz,3H),0.96-0.89(m,4H),-0.04(d,J=2.7Hz,18H).

[0378] Synthesis of compound MDI-234: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone

[0379] Intermediate MDI-234-1 (120 mg, 0.145 mmol) was dissolved in methanol (6 ml), 12 mg of 10% Pd / C was added, concentrated hydrochloric acid (3 ml) was added dropwise, and the mixture was heated to 50°C and reacted for 6 hours. The mixture was then filtered, concentrated, washed with methanol three times to remove the hydrochloric acid, concentrated, dissolved in methanol, added with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 42 mg of the final product, with a yield of 60.9%.

[0380] 1 H NMR(400MHz,MeOD-d4)δ8.28(d,J=8.4Hz,1H),7.43(s,1H),7.19-7.16(m,1H),6.97-6.90(m,2H),4. 71-4.66(m,4H),3.78-3.75(m,4H),3.41-3.39(m,4H),2.54(q,J=7.5Hz,2H),1.06(t,J=7.5Hz,3H).

[0381] Example 33: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235) [ka]

[0382] It was synthesized according to the method described in Example 33 of Chinese Patent CN111606908B, specifically as follows:

[0383] Synthetic route of MDI-235 [ka]

[0384] Synthesis method Synthesis of Intermediate MDI-235-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone

[0385] Dissolve triphosgene (8.3 mg, 0.028 mmol) in 5 ml of tetrahydrofuran and heat at 0°C to obtain the intermediate A solution of 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (20 mg, 0.028 mmol) in tetrahydrofuran (5 ml) was added dropwise, triethylamine (8.5 mg, 0.084 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of 1-methylpiperazine (5.60 mg, 0.056 mmol) in tetrahydrofuran was added, and the mixture was stirred at room temperature for 10 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 20 mg of the intermediate MDI-235-1 was obtained with a yield of 85.1%.

[0386] 1H NMR(400MHz,CDCl3)δ8.44(d,J=8.3Hz,1H),7.50-7.48(m,2H),7.44-7.33(m,4H ),7.23-7.21(m,1H),7.04-6.94(m,2H),5.93(s,2H),5.75(s,2H),5.20(s,2H), 4.70(d,J=54.8Hz,4H),3.64-3.56(m,4H),3.43-3.41(m,4H),2.56-2.49(m,6H) ,2.34(s,3H),1.03(t,J=7.5Hz,3H),0.93-0.86(m,4H),-0.07(d,J=2.7Hz,18H).

[0387] Synthesis of compound MDI-235: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone

[0388] Intermediate MDI-235-1 (20 mg, 0.024 mmol) was dissolved in methanol (6 ml), 5 mg of Pd / C was added, concentrated hydrochloric acid (3 ml) was added dropwise, and the mixture was heated to 50°C for 6 hours. The mixture was then filtered, concentrated, washed with methanol three times to remove the hydrochloric acid, concentrated, dissolved in methanol, added with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 3 mg of the final product, with a yield of 14.8%.

[0389] 1 H NMR(400MHz,MeOD-d4)δ8.25(d,J=8.4Hz,1H),7.40(s,1H),7.16-7.14(m,1H),6.95-6.87(m,2H ),4.83-4.66(m,4H),3.44-3.41(m,4H),2.56-2.51(m,6H),2.35(s,3H),1.06(t,J=7.5Hz,3H).

[0390] Example 34: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236) [ka]

[0391] It was synthesized according to the method described in Example 34 of Chinese Patent CN111606908B, specifically as follows:

[0392] Synthetic route of MDI-236 [ka]

[0393] Synthesis method Synthesis of Intermediate MDI-236-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone

[0394] Dissolve triphosgene (54.07 mg, 0.182 mmol) in 15 ml of dichloromethane and heat at 0°C to obtain the intermediate A solution of 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.182 mmol) in dichloromethane (5 ml) was added dropwise, triethylamine (55.2 mg, 0.55 mmol) was added, and the mixture was stirred for 5 minutes. A solution of ethylpiperazine (41.5 mg, 0.364 mmol) in dichloromethane was added, and the mixture was stirred at room temperature for 10 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 100 mg of the intermediate. MDI-236-1 was obtained with a yield of 64.3%.

[0395] 1H NMR(400MHz,CDCl3)δ8.44(d,J=8Hz,1H),8.28(s,1H),7.50-7.33(m,5H),7.22( d,J=8Hz,1H),7.03(d,J=12Hz,1H),6.95(d,J=8Hz,1H),5.93(s,2H),5.74(s,2H) ),5.20(s,2H),4.77(s,2H),4.63(s,2H),3.63-3.61(m,4H),3.43-3.42(m,4H), 2.53-2.46(m,8H),1.03(t,J=6Hz,3H),0.93-0.86(m,7H),-0.06--0.08(m,18H).

[0396] Synthesis of compound MDI-236: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone

[0397] Intermediate MDI-236-1 (100 mg, 0.117 mmol) was dissolved in methanol (10 ml), 10 mg of Pd / C was added, concentrated hydrochloric acid (5 ml) was added dropwise, and the mixture was heated to 50°C for 6 hours. The mixture was then filtered, concentrated, washed with methanol three times to remove the hydrochloric acid, concentrated, dissolved in methanol, added with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 21 mg of the final product, with a yield of 35.6%.

[0398] 1 H NMR(400MHz,MeOD-d4)δ8.27(d,J=8Hz,1H),7.43(s,1H),7.17(d,J=8Hz,1H),6.96(d,J=12Hz,1H),6.91(d,J =8Hz,1H),4.75-4.60(m,4H),3.48-3.44(m,4H),2.61-2.48(m,8H),1.17(t,J=8Hz,3H),1.08(t,J=8Hz,3H).

[0399] Example 35: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-237) [ka]

[0400] The product was synthesized according to the method described in Example 35 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0401] 1 H NMR(400MHz,DMSO)δ13.60(s,1H),12.60-12.48(m,1H),10.02(s,1H),8.53(d,J=1.6Hz,1H),7.95(s,1H),7.16(d,J=11.8Hz, 1H),6.98(d,J=9.1Hz,1H),4.91-4.41(m,4H),2.51-2.47(m,2H),1.96-1.84(m,1H),1.03(t,J=8.0Hz,3H),0.87-0.80(m,4H).

[0402] LC-MS m / z(ESI)[M+H] + :C 23 H 22 The calculated value for FN6O2 is 433.2 and the measured value is 433.2.

[0403] Example 36: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-239) [ka]

[0404] The product was synthesized according to the method described in Example 36 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0405] 1 H NMR(400MHz,MeOD)δ7.27(s,1H),6.95-6.88(m,3H),4.96(s,2H),4.66(s,2H),2.63(s, 3H),2.55(q,J=7.5Hz,2H),1.98-1.92(m,1H),1.07(t,J=7.5Hz,3H),1.04-0.92(m,4H).

[0406] Example 37: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-240) [ka]

[0407] The product was synthesized according to the method described in Example 37 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0408] 1 H NMR(400MHz,MeOD)δ7.27(s,1H),6.95-6.88(m,3H),4.85 -4.82(m,2H),4.62-4.59(m,2H),4.46-4.45(m,1H),3.79-3.69(m,2H),3.64-3.57(m,1H),3. 46-3.42(m,1H),2.61(s,3H),2.56(q,J=7.5Hz,2H),2.09-1.98(m,2H),1.07(t,J=7.5Hz,3H).

[0409] Example 38: Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-242) [ka]

[0410] The product was synthesized according to the method described in Example 38 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0411] 1 H NMR(400MHz,MeOD)δ9.61(d,J=1.0Hz,1H),7.77(d,J=1.1Hz,1H),7.16(d,J=11.6Hz,1H),6.93(d,J=8.8Hz,1H),5.07-4.88 (m,2H),4.68-4.62(m,2H),2.69-2.64(m,2H),1.98-1.89(m,1H),1.09-1.05(m,3H),1.01-0.98(m,2H),0.96-0.94(m,2H).

[0412] Example 39: (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-243) [ka]

[0413] The product was synthesized according to the method described in Example 39 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0414] 1 H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(d,J=1.0Hz,1H),7.17(d,J=8.4Hz,1H),6.98-6.90(m,2H),4.82-4.60(m,4H),4.47-4 .45(m,1H),3.79-3.70(m,2H),3.60-3.57(m,1H),3.46-3.43(m,1H),2.56(q,J=7.5Hz,2H),2.09-1.98(m,2H),1.08(t,J=7.5Hz,3H).

[0415] Example 41: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245) [ka]

[0416] It was synthesized according to the method described in Example 41 of Chinese Patent CN111606908B, specifically as follows:

[0417] Synthetic route of MDI-245 [ka]

[0418] Synthesis method Synthesis of Intermediate MDI-245-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-hydroxypiperidin-1-yl)methanone

[0419] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dry dichloromethane, and a solution of the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml) was added dropwise at 0°C. After the addition was complete, dry triethylamine (18 Add piperidin-4-ol (36.9 mg, 0.36 mmol) in dichloromethane (5 ml) slowly, stir at room temperature for 10 minutes, monitor the disappearance of the raw material by TLC, add piperidin-4-ol (36.9 mg, 0.36 mmol) in dichloromethane (5 ml), stir at room temperature for 20 minutes, quench with water, extract twice with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify with silica gel column to obtain 116 mg of intermediate MDI-245-1, yield 75.7%.

[0420] 1 H NMR(400MHz,CDCl3)δ8.46(d,J=8.3Hz,1H),7.53-7.51(m,2H),7.47-7.35(m,4H),7.25(d,J=8.4Hz ,1H),7.06-6.97(m,2H),5.96(s,2H),5.75(s,2H),5.37(s,2H),4.79-4.66(m,4H),3.95-3.92(m,1H ),3.75-3.72(m,2H),3.66-3.52(m,4H),3.12-3.07(m,2H),2.54(q,J=7.6Hz,2H),2.02-1.91(m,2H ),1.68-1.63(m,2H),1.06(t,J=7.5Hz,3H),0.99-0.89(m,4H),0.02(s,9H),-0.05(d,J=3.4Hz,9H).

[0421] Synthesis of compound MDI-245: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone

[0422] MDI-245-1 (116 mg, 0.14 mmol) was dissolved in 20 ml of methanol, 20 mg of palladium carbon was added, hydrogen gas was purged, and the mixture was reacted at 40°C for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, the concentrate was dissolved in 12 ml of methanol, 6 ml of concentrated hydrochloric acid was added, the mixture was reacted at 50°C for 7 hours, the concentrate was added, the hydrochloric acid was washed with methanol three times, the concentrate was added, the mixture was dissolved in 8 ml of methanol, 0.8 ml of aqueous ammonia was added, the concentrate was added, and the mixture was purified using a preparative plate to obtain 30 mg of the final product, with a yield of 44.4%.

[0423] 1 H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.97-6.90(m,2H),4.72-4.65(m,4H),3.88-3.82( m,1H),3.76-3.73(m,2H),3.13-3.06(m,2H),2.56(q,J=7.5Hz,2H),1.97-1.95(m,2H),1.63-1.55(m,2H),1.08(t,J=7.5Hz,3H).

[0424] Example 42: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-246) [ka]

[0425] The product was synthesized according to the method described in Example 42 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0426] 1H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.97- 6.90(m,2H),4.56(s,4H),2.84(s,3H),2.56(q,J=7.5Hz,2H),1.08(t,J=7.5Hz,3H).

[0427] Example 43: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247) [ka]

[0428] It was synthesized according to the method described in Example 43 of Chinese Patent CN111606908B, specifically as follows:

[0429] Synthetic route of MDI-247 [ka]

[0430] Synthesis method Intermediate MDI-247-1: Synthesis of 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-indazol-3-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole 5-(1H)-carboxamide

[0431] Dissolve triphosgene (22.9 mg, 0.08 mmol) in 6 ml of dry dichloromethane and heat at 0°C to obtain the intermediate A solution of 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (55 mg, 0.08 mmol) in dichloromethane (5 ml) was added dropwise. After the addition was completed, dry triethylamine (78.0 mg, 0.8 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes and the disappearance of the raw materials was monitored by TLC. Ethylamine hydrochloride (12.6 mg, 0.16 mmol) was added, the mixture was stirred at room temperature for 2 hours, water was added to quench the reaction, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 47 mg of the intermediate. MDI-247-1 was obtained with a yield of 77.7%.

[0432] 1 H NMR(400MHz,CDCl3)δ8.46(d,J=8.3Hz,1H),7.53-7.51(m,2H),7.47-7.35(m,4H),7. 25(d,J=8.4Hz,1H),7.07-6.97(m,2H),5.96(s,2H),5.78(s,2H),5.23(s,2H),4.72-4 .54(m,4H),3.65-3.58(m,4H),3.45-3.38(m,2H),2.54(q,J=7.6Hz,2H),1.18-1.14( m,3H),1.05(t,J=7.5Hz,3H),0.95-0.89(m,4H),0.02(s,9H),-0.05(d,J=3.4Hz,9H).

[0433] Synthesis of compound MDI-247: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide

[0434] MDI-247-1 (47 mg, 0.06 mmol) was dissolved in 10 ml of methanol, 8 mg of palladium carbon was added, hydrogen gas was purged, and the mixture was reacted at 40°C for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, the concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 7 hours. The concentrate was then washed with methanol three times to remove the hydrochloric acid, and the mixture was concentrated. The mixture was dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. The mixture was purified using a preparative plate to obtain 11 mg of the final product, with a yield of 42.4%.

[0435] 1 H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.98-6.90(m,2H),4 .57(s,4H),3.38-3.28(m,2H),2.56(q,J=7.5Hz,2H),1.21(t,J=7.2Hz,3H),1.08(t,J=7.5Hz,3H).

[0436] Example 44: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248) [ka]

[0437] It was synthesized according to the method described in Example 44 of Chinese Patent CN111606908B, specifically as follows:

[0438] Synthetic route of MDI-248 [ka]

[0439] Synthesis method Intermediate MDI-248-1: Synthesis of 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-indazol-3-yl)-N-(2-hydroxyethyl)1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole 5-(1H)-carboxamide

[0440] Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml of dry dichloromethane and the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (55 mg, 0.08 mmol) was added to 5 ml of dichloromethane at 0°C. After the addition, dry triethylamine (78.0 mg, 0.8 mmol) was slowly added dropwise and stirred at room temperature for 10 minutes. The disappearance of the raw material was monitored by TLC. A solution of ethanolamine (9.4 mg, 0.16 mmol) in dichloromethane (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to quench the reaction, and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over sodium sulfate, concentrated, and purified using an anhydrous silica gel column to obtain 44 mg of intermediate MDI-248-1, with a yield of 71.3%.

[0441] 1 H NMR(400MHz,CDCl3)δ8.46(d,J=8.3Hz,1H),7.73-7.51(m,2H),7.48-7.35(m ,4H),7.27-7.24(m,1H),7.07-6.97(m,2H),5.96(s,2H),5.78(s,2H),5.23(s ,2H),4.73-4.57(m,4H),3.65-3.53(m,6H),3.33-3.29(m,2H),2.54(q,J=7.6 Hz,2H),1.05(t,J=7.5Hz,3H),0.95-0.89(m,4H),0.02(s,9H),-0.05(s,9H).

[0442] Synthesis of compound MDI-248: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide

[0443] MDI-248-1 (44 mg, 0.06 mmol) was dissolved in 10 ml of methanol, 8 mg of palladium carbon was added, hydrogen gas was purged, and the mixture was reacted at 40°C for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, the concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 7 hours. The concentrate was then washed with methanol three times to remove the hydrochloric acid, and the mixture was concentrated. The mixture was then dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, the concentrate was added, and the mixture was purified using a preparative plate to obtain 14 mg of the final product, with a yield of 56.6%.

[0444] 1 H NMR(400MHz,MeOD)δ8.28(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.97-6.90(m,2H),4. 59(s,4H),3.68(t,J=5.8Hz,2H),3.40(t,J=5.8Hz,2H),2.56(q,J=7.5Hz,2H),1.08(t,J=7.5Hz,3H)

[0445] Example 46: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)pyrrolidine-3-carbonitrile (MDI-250) [ka]

[0446] The product was synthesized according to the method described in Example 46 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0447] 1H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.98-6.90(m,2H),4.70(s,4H),3.89-3.85(m, 1H),3.78-3.76(m,1H),3.70-3.59(m,2H),3.23-3.18(m,1H),2.56(q,J=7.5Hz,2H),2.42-2.19(m,2H),1.08(t,J=7.5Hz,3H).

[0448] Example 47: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-251) [ka]

[0449] The product was synthesized according to the method described in Example 47 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0450] 1 H NMR(400MHz,MeOD)δ8.28(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.97-6.90(m,2H),4.63(s,4H),4.45-4.40(m, 1H),4.03-3.94(m,2H),3.87-3.81(m,1H),3.71-3.68(m,1H),2.56(q,J=7.5Hz,2H),2.32-1.87(m,2H),1.08(t,J=7.5Hz,3H).

[0451] Example 48: Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-252) [ka]

[0452] The product was synthesized according to the method described in Example 48 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0453] 1H NMR(400MHz,MeOD)δ8.28(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.97- 6.90(m,2H),4.61(s,4H),3.83(s,3H),2.56(q,J=7.5Hz,2H),1.08(t,J=7.5Hz,3H).

[0454] Example 49: Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-253) [ka]

[0455] It was synthesized according to the method described in Example 49 of Chinese Patent CN111606908B, specifically as follows:

[0456] Synthetic route of MDI-253 [ka]

[0457] Synthesis method Intermediate MDI-253-1: Synthesis of ethyl 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)1H-indazol-3-yl)1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole 5-(1H)-carboxylate

[0458] Dissolve triphosgene (20.1 mg, 0.07 mmol) in 5 ml of dry dichloromethane and add the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (48 mg, 0.07 mmol) to a dichloromethane (5 ml) solution at 0°C. After the addition is complete, slowly add dry triethylamine (68.1 mg, 0.67 mmol) and stir at room temperature for 10 minutes. Monitor the disappearance of the raw materials by TLC. Concentrate the reaction solution, dissolve in 10 ml of ethanol, add DMAP (8.2 mg, 0.07 mmol), and react at 80 degrees for 4 hours. Add water to the reaction solution, extract twice with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify with a silica gel column to obtain 33 mg of intermediate MDI-253-1, with a yield of 62.5%.

[0459] 1 H NMR(400MHz,CDCl3)δ8.50-8.45(m,1H),7.53-7.51(m,2H),7.47-7.37(m,4H),7. 25(d,J=8.4Hz,1H),7.07-6.96(m,2H),5.96(s,2H),5.77(s,2H),5.23(s,2H),4.7 2-4.59(m,4H),4.29-4.25(m,2H),3.65-3.58(m,4H),2.54(q,J=7.6Hz,2H),1.38- 1.34(m,3H),1.05(t,J=7.5Hz,3H),0.95-0.89(m,4H),0.02(s,9H),-0.05(s,9H).

[0460] Synthesis of compound MDI-253: ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0461] MDI-253-1 (33 mg, 0.04 mmol) was dissolved in 10 ml of ethanol, 6 mg of palladium carbon was added, hydrogen gas was purged, and the mixture was reacted at 40°C for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, the concentrate was dissolved in 6 ml of ethanol, 3 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 7 hours. The concentrate was then washed with ethanol three times to remove the hydrochloric acid, and the mixture was concentrated. The mixture was then dissolved in 5 ml of ethanol, 0.5 ml of aqueous ammonia was added, the concentrate was added, and the mixture was purified using a preparative plate to obtain 10 mg of the final product, with a yield of 54.8%.

[0462] 1 H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),6.97-6.90(m,2H),4. 60(s,4H),4.26(q,J=7.1Hz,2H),2.57(q,J=7.5Hz,2H),1.36(t,J=7.1Hz,3H),1.08(t,J=7.5Hz,3H).

[0463] Example 50: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-255) [ka] The product was synthesized according to the method described in Example 50 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0464] 1 H NMR(400MHz,DMSO)δ13.61(s,1H),10.22(s,1H),8.78(d,J=8.0Hz,1H),7.71(d, J=8.0Hz,1H),7.34(d,J=12.0Hz,1H),6.97(d,J=8.0Hz,1H),4.93(d,J=4.0Hz,1 H),4.75-4.42(m,4H),4.30-4.27(m,1H),3.58-3.53(m,2H),3.41-3.40(m,1H), 3.26-3.23(m,1H),2.73-2.71(m,2H),2.01-1.79(m,2H),1.09(t,J=8.0Hz,3H).

[0465] Example 51: 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile (MDI-256) [ka]

[0466] The product was synthesized according to the method described in Example 51 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0467] 1 H NMR(400MHz,MeOD)δ8.27(d,J=8.0Hz,1H),7.43(s,1H),7.18(d,J=8.0Hz,1H),6.97(dd,J=8. 0Hz,J=20.0Hz,2H),4.77-4.70(m,4H),3.62(s,2H),2.59-2.53(m,2H),1.09(t,J=8.0Hz,3H).

[0468] Example 52: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257) [ka]

[0469] It was synthesized according to the method described in Example 52 of Chinese Patent CN111606908B, specifically as follows:

[0470] Synthetic route of MDI-257 [ka]

[0471] Synthesis method Synthesis of Intermediate MDI-257-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide

[0472] The synthesis process is similar to the synthesis method of intermediate MDI-246-1 in Chinese patent CN111606908B, except that dimethylamine hydrochloride is used instead of methylamine hydrochloride.

[0473] Synthesis of compound MDI-257: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide

[0474] Intermediate MDI-257-1 (41 mg, 0.05 mmol) was dissolved in methanol (6 ml), 8 mg of 10% Pd / C was added, the mixture was purged with hydrogen gas three times, heated to 40°C, reacted for 1 hour, filtered, concentrated, 4 ml of methanol and 1 ml of concentrated hydrochloric acid were added, heated to 50°C, reacted for 6 hours, concentrated, washed the hydrochloric acid with methanol three times, concentrated, dissolved in methanol, neutralized with 1 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 8 mg of the final product, with a yield of 35.2%.

[0475] 1 H NMR(400MHz,DMSO)δ13.28(s,1H),9.85(s,1H),8.32(d,J=8.0Hz,1H),7.40(s,1H),7.13(d,J=8.0Hz,1H),7.03(d ,J=12.0Hz,1H),6.93(d,J=12.0Hz,1H),4.54-4.53(m,4H),2.85(s,6H),2.50-2.46(m,2H),1.04(t,J=8.0Hz,3H).

[0476] Example 53: N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-258) [ka]

[0477] The product was synthesized according to the method described in Example 53 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0478] 1 H NMR(400MHz,MeOD)δ8.25(d,J=8.4Hz,1H),7.41(s,1H),7.16(d,J=8.4Hz,1H),6.91(dd,J=20. 8,10.3Hz,2H),4.61-4.54(m,4H),3.55-3.50(m,2H),2.66-2.51(m,4H),1.06(t,J=7.5Hz,3H).

[0479] Example 54: N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-259) [ka]

[0480] The product was synthesized according to the method described in Example 54 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0481] 1 H NMR(400MHz,MeOD)δ8.25(d,J=8.4Hz,1H),7.43(s,1H),7.16(dd,J=8.4,1.4Hz,1H),6.91(dd,J=20.6,10.4Hz,2H),4 .66-4.48(m,4H),2.68-2.62(m,1H),2.59-2.53(m,2H),1.08(t,J=7.5Hz,3H),0.76-0.71(m,2H),0.60-0.56(m,2H).

[0482] Example 55: N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H) -Carbonamide (MDI-260) [ka]

[0483] The product was synthesized according to the method described in Example 55 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0484] 1H NMR(400MHz,MeOD)δ8.27(d,J=8.4Hz,1H),7.43(s,1H),7.18(d,J=8.4Hz,1H),7.01-6.85(m,2H),4.57(s,4H),4.3 5-4.31(m,1H),2.59-2.53(m,2H),2.36-2.30(m,2H),2.11-2.04(m,2H),1.76-1.69(m,2H),1.08(t,J=7.5Hz,3H).

[0485] Example 57: (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-262)

[0486] The product was synthesized according to the method described in Example 57 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0487] 1 H NMR(400MHz,MeOD)δ8.28(d,J=8.0Hz,1H),7.44(s,1H),7.18(d,J=8.5Hz,1H),6.96(d,J=11.7Hz,1H),6.91(d,J=8.9Hz,1H),4.80-4 .64(m,4H),4.09-4.05(m,1H),3.26-3.22(m,2H),2.59-2.53(m,2H),2.06-1.86(m,4H),1.08(t,J=8.0Hz,3H).LC-MSm / z(ESI)[M+H] + :C 25 H 26 The calculated value for FN6O2 is 461.2 and the measured value is 461.2.

[0488] Example 58: (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-263) [ka]

[0489] The product was synthesized according to the method described in Example 58 of Chinese Patent CN111606908B, and the hydrogen nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0490] 1H NMR(400MHz,MeOD)δ8.27(d,J=8.0Hz,1H),7.44(s,1H),7.18(d,J=8.4Hz,1H),6.96(d,J=12.2Hz,1H),6.91(d,J=8.8Hz,1H),4.82- 4.60(m,4H),4.21-4.15(m,1H),3.33-3.23(m,1H),3.08-2.99(m,1H),2.59-2.53(m,2H),2.08-1.86(m,4H),1.08(t,J=8.0Hz,3H).

[0491] Example 59: Inhibitory activity test of compounds against TRKA, TRKB, and TRKC 1. Experimental materials and equipment

[0492] [Table 1]

[0493] 2. Experimental Method 2.1 Preparation of 1X kinase reaction buffer 1 volume of 5X kinase reaction buffer plus 4 volumes of water, 5 mM MgCl2, 1 mM DTT.

[0494] 2.2 Preparation of kinase and substrate Preparation of 2.5X substrate mix

[0495] [Table 2]

[0496] 2.3 Compound Inhibition Test Process 1) Compounds are diluted 4-fold with DMSO in a dilution plate, with the starting compound concentration being 1000 nM. 2) Dilute compounds 50-fold in 1X kinase reaction buffer and shake on a shaker for 20 minutes. 3) Prepare 2X TRKA with 1X enzyme reaction buffer. 4) Add 2 μl of TRKA kinase (prepared in step 3) per well to the reaction plate. 5) 1 μl of compound diluted in buffer is added to each well, the plate is sealed with a sealing film, centrifuged at 1000 g for 30 seconds, and left at room temperature for 10 minutes. 6) Prepare a 4x ATP&sub mixture with 1x enzyme reaction buffer, and add 1 μl of the 4x ATP&sub mixture to the reaction plate. 7) Seal the plate with sealing film, centrifuge at 1000 g for 30 seconds, and react at room temperature for 60 minutes. 8) Transfer 4 μL of ADP-Glo to a 384 reaction plate, centrifuge at 1000 rpm / min for 1 minute, and incubate at 25° C. for 40 minutes. 9) Transfer 8 μL of detection solution to a 384 reaction plate, centrifuge at 1000 rpm / min for 1 minute, and incubate at 25° C. for 40 minutes. 10) RLU (Relative luminescence unit) signal readings are performed using a Biotek multi-function instrument. The signal intensity represents the degree of kinase activity.

[0497] 3. Data Analysis 3.1 The calculation of the inhibition rate is as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100% Negative control: DMSO Positive control: LOXO101

[0498] 3.2 Calculate IC50 and generate compound inhibition curves. The IC50 (half inhibitory concentration) of the compound is obtained by the following nonlinear fitting equation: Data analysis is performed by Graphpad 6.0 software. Y=Bottom+(Top-Bottom) / (1+10^((Log IC50-X)*Hill Slope)) X: logarithm of compound concentration Y: Inhibition rate (%inh)

[0499] 3.3 Quality Inspection After one experimenter cleans the data, another examines it again, ensuring the accuracy of the data analysis.

[0500] Ensure experimental data: Z factor > 0.5, S / B > 2, and positive control IC50 is within 3 times the historical average.

[0501] 4. Compound activity test results

[0502] [Table 3]

[0503] Example 60: Inhibitory activity test of compounds against RET kinase 1. Experimental materials and equipment

[0504] [Table 4]

[0505] 2. Experimental Method 2.1 Preparation of 1X kinase reaction buffer 1 volume of 5X kinase reaction buffer plus 4 volumes of water, 5 mM MgCl2, 1 mM DTT.

[0506] 2.2 Reaction conditions

[0507] [Table 5]

[0508] 2.3 Compound activity inhibition test process: 1) Compounds are diluted 4-fold in DMSO in a dilution plate, with the starting compound concentration being 1 uM. 2) Dilute compounds 40-fold in 1X kinase reaction buffer and shake on a shaker for 20 minutes. 3) Prepare 2.5X kinase in 1X enzyme reaction buffer. 4) Add 2 μl of kinase to each well of the reaction plate (prepared in step 3). 5) 1 μl of compound diluted in buffer is added to each well, the plate is sealed with a sealing film, centrifuged at 1000 g for 30 seconds, and left at room temperature for 10 minutes. 6) Prepare a 2.5x Tk-substrate-biotin and ATP mixture with 1x enzyme reaction buffer, and add 2 μl of the Tk-substrate-biotin / ATP mixture to the reaction plate. 7) Seal the plate with sealing film, centrifuge at 1000 g for 30 seconds, and react at room temperature for 30 minutes. 8) Prepare 5X Sa-XL665 in HTRF assay buffer (250 nM). 9) Add 5 μl of XL665 and 5 μl of Tk-antibody-cryptate to each well, centrifuge at 1000 g for 30 seconds, and allow to react at room temperature for 1 hour. 10) Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) on a Biotek.

[0509] 3. Data Analysis 3.1 Calculate the ratio (Ratio_665 / 615nm) for each well and calculate the inhibition rate as follows: Inhibition rate of compound (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100% Positive control: Pralsetinib 1000nM Negative control: 0.5% DMSO

[0510] 3.2 Calculate IC50 and generate compound inhibition curves. The IC50 (half inhibitory concentration) of the compound is obtained by the following nonlinear fitting equation: Data analysis is performed by Graphpad 6.0 software. Y=Bottom+(Top-Bottom) / (1+10^((Log IC50-X)*Hill Slope)) X: logarithm of compound concentration Y: Inhibition rate (%inh)

[0511] 3.3 Quality Inspection After one experimenter cleans the data, another examines it again, ensuring the accuracy of the data analysis.

[0512] Ensure experimental data: Z factor > 0.5, S / B > 2, and positive control IC50 is within 3 times the historical average.

[0513] 4. Compound activity test results

[0514] [Table 6]

[0515] Example 61: Therapeutic effects of compounds on egg white protein-induced mouse asthma model 1. Materials and methods

[0516] Experimental materials and reagents Egg white protein (OVA): Sigma-A5243 Aluminum adjuvant: Sigma-239186 Diff Quick: National Pharmaceutical Group, 100092680 Hematoxylin: HONGQUAN BIO, HQ60002 Eosin: HONGQUAN BIO, HQ60001 Interleukin 5 (IL-5) Elisa Kit: BIOSWAMP-DRE30011 IgE Elisa kit: BIOSWAMP-DRE30653 Phosphate buffer solution (PBS): Solarbio-P1022 Tween 80: Solarbio-LA7760

[0517] Experimental equipment Electronic balance: Wuxin Weighing Apparatus Co., Ltd., Model No. MAX-A3003 Microplate reader: Finland (Labsystems Mμltiskan MS), model number 352 Plate washer: Finland (Thermo Labsystems), model number AC8 Centrifuge: High-speed microcentrifuge, model number TGL-16 Pipette: Gilson P-type pipette (Pipetman), model number F123601 Incubator: Watertight constant temperature incubator, model number BPN-190RHP Microscope: OLYMPUS, model number CX41 Constant temperature oven: Shanghai Hengyi Scientific Instruments, model number DHG-9140 Paraffin sectioning machine: Leica, model number SQ2125 Extender: Leica, model number PPTHK-21B Water bath pot: Leica, model number HI1210 Atomizer: Jiangsu Yu Yuebu Medical, model number 403M

[0518] experimental animals 7-8 week old female Balb / c mice were purchased from Changzhou Cavens Co., Ltd., China, with the animal certification number 202005500. The mice were kept in the animal room of the Shanghai Medical University, Shanghai, China, under the following conditions: SPF grade, temperature 22-24℃, humidity 40%-70%, light exposure 7:00-19:00, 3 mice per cage, and free access to food and water.

[0519] Fauna composition After the animals arrived, they were allowed to adapt for 7 days and then randomly divided into 8 groups according to their weight, with 8 animals in each group. The details are shown in the table below.

[0520] [Table 7]

[0521] Preparation of reagents Preparation of the immunization preparation: Weigh out an appropriate amount of OVA and add an appropriate amount of PBS to a final concentration of 0.1 mg / ml. Add an equal volume of aluminum adjuvant, mix evenly, and leave at 4°C. Use immediately after preparation. Preparation of sensitizer (5% OVA): Weigh out an appropriate amount of OVA and add an appropriate amount of PBS to make the final concentration 5%. Mix evenly and leave at 4°C as a reserve. Use immediately after preparation. Preparation of the vehicle: Add 200 μl of Tween 80 to 100 ml of saline and mix thoroughly. Leave at 4°C for future use. Preparation of compound MDI-1288 solution: Weigh out the appropriate amount of MDI-1288 and solvent and dissolve it to a final concentration of 1.2 mg / ml. Mix evenly and leave at 4 degrees for storage. Prepare once every 3 days. Preparation of compound MDI-1228 solution: Weigh out the appropriate amount of MDI-1228 and solvent and dissolve it to a final concentration of 1.2 mg / ml. Mix evenly and leave at 4°C for storage. Prepare once every 3 days. Preparation of compound MDI-1233 solution: Weigh out the appropriate amount of MDI-1233 and solvent and dissolve to a final concentration of 0.4, 1.2, and 4 mg / ml. Mix evenly and leave at 4°C for storage. Prepare once every 3 days.

[0522] Building the model Immunization: On days 0, 7, 14, and 21, Group 1 is injected intraperitoneally with 200 μl of PBS, and Groups 2-8 are injected intraperitoneally with 200 μl (10 μg) of OVA / aluminum adjuvant emulsion.

[0523] Sensitization: On days 28-32, animals in Group 1 were nebulized with PBS for 20 minutes in a nebulizer, and animals in Groups 2-8 were nebulized with 5% OVA for 20 minutes in a nebulizer, and then removed from the nebulizer at 12:30 pm every day.

[0524] Administration: The drug was administered twice daily at 9:00 AM and 5:00 PM via nasal instillation. Dexamethasone (Dex) was administered intragastrically once daily at 9:00 AM.

[0525] Evaluation indicators Serum IgE: Animals are euthanized with carbon dioxide and then bled via the orbit, and plasma is collected and stored at -40°C for use in detecting plasma IgE.

[0526] Bronchoalveolar lavage fluid (BALF) cell count: Weigh out an appropriate amount of fetal bovine serum and dissolve it in PBS to a final concentration of 1%. After collecting blood from the orbit, open the trachea, replace the 1 ml syringe needle with a mouse intragastric needle, and aspirate 0.8 ml of lavage fluid into the syringe, washing the lungs a total of three times. Collect the lavage fluid and centrifuge it at 1,000 rpm for 10 minutes. Collect the supernatant and store it at -40°C. Add 1 ml of PBS to the cells to resuspend them and count them. Take 100 μl of the centrifuged spread sheet and stain it with Diff Quick to record the number of eosinophils, basophils, lymphocytes, and macrophages.

[0527] Lung lavage fluid IL-5: Lung lavage fluid is collected and IL-5 is detected.

[0528] Lung tissue pathology: Lung tissue was fixed with formaldehyde, and after 24 hours, sections were embedded and stained with HE staining. The infiltration of inflammatory cells was observed and scored. The pathological evaluation criteria were as follows: A) 0 points: No lymphocytic infiltration B) 1 point: slight lymphocytic infiltration C) 2 points: small amount of lymphocyte infiltration D) 3 points: Moderate lymphocytic infiltration E) 4 points: Severe lymphocytic infiltration

[0529] Once the scores are completed, they are calculated and analyzed.

[0530] 2. Experimental Results Lung lavage fluid IL-5 The experimental results are shown in Figure 1. The normal group animals had low IL-5 expression levels in lung lavage fluid. Compared with the normal group, the IL-5 expression levels in lung lavage fluid of the vehicle group animals were significantly elevated (p<0.001). Compared with the model group (i.e., the vehicle group), the positive control dexamethasone significantly reduced IL-5 expression (p<0.001). Compounds MDI-1228 and MDI-1288 also significantly reduced IL-5 expression (p<0.001). Compared with the positive control, compounds MDI-1228 and MDI-1288 had weaker ability to reduce IL-5 expression. Compared with the model group, all three dose groups of compound MDI-1233 were able to reduce IL-5 expression, with a significant difference between the 3mpk and 10mpk groups (p<0.001). Compared with compounds MDI-1228 and MDI-1288, compound MDI-1233 at 3 mpk has an IL-5 reducing ability that is almost consistent with compounds MDI-1228 and MDI-1288. Compared with the positive control dexamethasone, compound MDI-1233 at 10 mpk has an IL-5 reducing ability that is almost consistent with positive control dexamethasone. The lung lavage IL-5 detection data show that each MDI-1233 administration group can reduce IL-5 expression levels and that there is a dose effect.

[0531] Lung lavage fluid inflammatory cell count The experimental results are shown in Figure 2. The normal group animals had a relatively low number of inflammatory cells in the lung lavage fluid. Compared with the normal group, the number of inflammatory cells in the lung lavage fluid of the vehicle group animals was significantly increased (p<0.001). Compared with the model group (i.e., the vehicle group), the positive control dexamethasone was able to significantly reduce the number of inflammatory cells (p<0.001). Compounds MDI-1228 and MDI-1288 were also able to significantly reduce the number of inflammatory cells (p<0.001). Compared with the positive control, compounds MDI-1228 and MDI-1288 had a weaker ability to reduce the number of inflammatory cells. Compared with the model group, all three dose groups of compound MDI-1233 were able to reduce the number of inflammatory cells, with a significant difference between the 3mpk and 10mpk groups (p<0.001). Compared with compounds MDI-1228 and MDI-1288, compound MDI-1233 at 3 mpk has the ability to reduce inflammatory cell counts almost identical to compounds MDI-1228 and MDI-1288. Compared with the positive control dexamethasone, compound MDI-1233 at 10 mpk has the ability to reduce inflammatory cell counts almost identical to positive control dexamethasone. Lung lavage inflammatory cell count detection data show that each MDI-1233 administration group can reduce inflammatory cell counts and there is a dose effect.

[0532] Serum IgE The experimental results are shown in Figure 3. The normal group animals had relatively low serum IgE expression levels. Compared with the normal group, the vehicle group animals had significantly elevated serum IgE expression levels (p<0.001). Compared with the model group, the positive control dexamethasone significantly reduced IgE expression (p<0.001). Compounds MDI-1228 and MDI-1288 also significantly reduced IgE expression (p<0.001). Compared with the positive control, compounds MDI-1228 and MDI-1288 had weaker ability to reduce IgE expression. Compared with the model group, all three dose groups of compound MDI-1233 were able to reduce IgE expression, with a significant difference between the 3mpk and 10mpk groups (p<0.001). Compared to compounds MDI-1228 and MDI-1288, compound MDI-1233 at 3 mpk has an IgE-reducing ability that is almost identical to compounds MDI-1228 and MDI-1288. Compared to the positive control dexamethasone, compound MDI-1233 at 10 mpk has an IgE-reducing ability that is almost identical to positive control dexamethasone. Serum IgE detection data show that each MDI-1233 administration group reduces IgE expression levels and there is a dose effect.

[0533] Pathological examination The experimental results are shown in Figure 4. Pathological staining of the normal group animals showed no abnormalities. Compared with the normal group, the pulmonary inflammatory cell infiltration of the vehicle group animals was significantly elevated (p<0.001). Compared with the model group, the positive control dexamethasone significantly reduced pulmonary inflammatory cell infiltration (p<0.001). Compounds MDI-1228 and MDI-1288 also significantly reduced pulmonary inflammatory cell infiltration (p<0.001). Compared with the positive control, compounds MDI-1228 and MDI-1288 had a weaker ability to reduce pulmonary inflammatory cell infiltration. Compared with the model group, all three dose groups of compound MDI-1233 were able to reduce pulmonary inflammatory cell infiltration, with a significant difference between the 3mpk and 10mpk groups (p<0.001). Compared with compounds MDI-1228 and MDI-1288, compound MDI-1233 at 3mpk has the ability to reduce pulmonary inflammatory cell infiltration, which is almost consistent with compounds MDI-1228 and MDI-1288. Compared with the positive control dexamethasone, compound MDI-1233 at 10mpk has the ability to reduce pulmonary inflammatory cell infiltration, which is almost consistent with the positive control dexamethasone. Pathological results show that each MDI-1233 administration group can reduce pulmonary inflammatory cell infiltration, and there is a dose effect.

[0534] The results of the pathological evaluation experiment of lung tissue are shown in Figure 5. As can be seen from the results, compound MDI-1233 has a good therapeutic effect on the asthma animal model, and the effect is dose-dependent, while MDI-1228 and MDI-1288 also have a relatively consistent therapeutic effect.

[0535] Example 62: Inhibitory effect of test compounds on allergic rhinitis in mice 1. Materials and methods Main Reagents

[0536] (1) Preparation of 0.2% Tween 80: Take 1 ml of TW80 + 499 ml of physiological saline.

[0537] (2) Preparation of 0.05 mg / ml egg white protein suspension (sensitization): 1) Take 10 mg of OVA + 10 ml of saline. 2) After shaking the above 2 ml of 10 mg / 10 ml egg white protein solution and 38 ml of physiological saline solution uniformly, add 200 mg of aluminum hydroxide.

[0538] (3) Preparation of MDI-1233: 1) 1 mg / kg MDI-1233: C = (1 mg / kg × 25 g × 10-3 kg) ÷ (20 × 10-3 ml) = 1.25 mg / ml, 0.3 ml of 10 mg / kg MDI-1233 suspension + 2.7 ml of 0.2% TW80 was taken and shaken uniformly. 2) 3 mg / kg MDI-1233: C = (3 mg / kg × 25 g × 10-3 kg) ÷ (20 × 10-3 ml) = 3.75 mg / ml, 0.9 ml of 10 mg / kg MDI-1233 suspension + 2.1 ml of 0.2% TW80 was taken and shaken uniformly. 3) 10 mg / kg MDI-1233: C = (10 mg / kg × 25 g × 10-3 kg) ÷ (20 × 10-3 ml) = 12.5 mg / ml, 56.25 mg of MDI-1233 + 4.5 ml of 0.2% TW80 was taken and shaken uniformly.

[0539] (4) Preparation of MDI-1228: C=(3mg / kg×25g×10-3kg)÷(20×10-3ml)=3.75mg / ml 11.25 mg of MDI-1228 and 3.54 ml of saline were weighed and mixed evenly by shaking.

[0540] (5) Preparation of MDI-1288: C=(3mg / kg×25g×10-3kg)÷(20×10-3ml)=3.75mg / ml 11.2 mg of MDI-1288 and 2.98 ml of physiological saline were weighed and mixed evenly by shaking.

[0541] (6) Preparation of 10% OVA: 12 mg of OVA and 1.2 ml of saline were taken and shaken to mix evenly.

[0542] Equipment and instruments

[0543]

Table 8

[0544] animal Female and male BALB / C mice aged 42 - 49 days (manufacturer: Changsheng Biotechnology, license number: SCXK(Therapy)2015 - 0001), breeding conditions: normal feed breeding, temperature 20 - 26°C, humidity 40% - 70%.

[0545] Fauna composition and modeling 1. Blank control group (without treatment) 2. Allergic rhinitis group (solvent treatment: physiological saline containing 0.2% Tween80) 3. Allergic rhinitis + compound MDI - 1233: 1 mg / kg 4. Allergic rhinitis + compound MDI - 1233: 3 mg / kg 5. Allergic rhinitis + compound MDI - 1233: 10 mg / kg 6. Allergic rhinitis + compound MDI - 1228: 3 mg / kg 7. Allergic rhinitis + compound MDI - 1288: 3 mg / kg 8. Allergic rhinitis + positive control group (fluticasone propionate, GSK, E88D)

[0546] To prepare the mouse AR model, BALB / c mice were sensitized and challenged with egg white protein (OVA) to mimic the acute symptoms caused by contact with an allergen through natural inoculation. Experimental animals were weighed and separated into males and females. Sensitization was performed on days 1, 5, 9, and 12, and challenge was performed once daily for 7 consecutive days from day 13 onward. After the final challenge, the mice's behavior was observed and scored. Sensitization was performed by intraperitoneally injecting 200 μl of a 50 μg / ml OVA (Sigma, A5503-1G) suspension (500 μg of egg white protein and 50 mg of Al(OH)3 (CAS 21645-51-2) in 10 ml of saline, pH 7.4). The stimulation method was to prepare a pH 7.4 OVA (10 mg / ml) saline solution and instill 10 μl into each nostril of each mouse using a microsyringe. Within 30 minutes, the mice were monitored for the number of times they scratched their noses, sneezed, and ran their noses. On day 12, the mice were stimulated once with 10% OVA (PBS was used as a control). The mice were scored according to the table below, and a total score was calculated using the superposition method. A total score of 5 or more was considered successful, and subsequent experiments were performed after the modeling was successful.

[0547] [Table 9]

[0548] Administration method Compound administration and stimulation began on the 13th day of modeling. The compound administration method was to calculate the nasal dose of compound based on mouse body weight according to the needs of each group. Compounds MDI-1233, MDI-1228, and MDI-1288 were dissolved in saline containing 0.2% Tween 80 at specific concentrations. Administration was performed 30 minutes before stimulation and twice daily. For the positive control treatment, nasal administration (10 μl / side) was performed once 30 minutes before nasal OVA stimulation and twice daily. 30 minutes after the second drug administration, mice were stimulated with 10% OVA. The amount of nasal discharge, sneezing, and nose scratching were observed, recorded, and scored within 30 minutes after each stimulation. The control group received nasal saline.

[0549] Sample collection After the rhinitis modeling was completed and the scores stabilized, each group was anesthetized and sacrificed on the 20th day after the scores were completed. Samples were collected, and peripheral serum (whole blood was collected, left at room temperature for 1 hour, then centrifuged to collect the supernatant) was extracted for ELISA detection. Nasal mucosa was extracted and stained with HE (fixed in 10% formalin). After rinsing the nasal cavity, the supernatant was extracted for ELISA detection.

[0550] Pathological examination (1) HE staining: The tissue was removed and washed in running water for several hours, dehydrated in 70%, 80%, and 90% ethanol solutions, and then placed in a 100% xylene / 100% mixture for 15 minutes, followed by xylene I for 15 minutes and xylene II for 15 minutes (until transparent). The tissue was then placed in a 50% xylene / paraffin mixture for 15 minutes, followed by paraffin I and paraffin II for 50-60 minutes to permeate the wax. Paraffin sections were embedded and cut. The paraffin sections were stretched, baked, dewaxed, and hydrated. The sections were placed in distilled water, stained in hematoxylin solution for 3 minutes, differentiated in hydrochloric acid-ethanol differentiation solution for 15 seconds, rinsed briefly, restored the blue color for 15 seconds in blue recovery solution, rinsed in running water, stained with eosin for 3 minutes, rinsed in running water, dehydrated, cleared, sealed, and examined under a microscope.

[0551] (2) ELISA detection: The kit uses a double-antibody, one-step sandwich enzyme-linked immunosorbent assay (ELISA). The specimen, standard, and HRP-labeled detection antibody were sequentially added to micropores pre-coated with mouse analyte capture antibodies, incubated, and thoroughly washed. Color development occurred with the substrate TMB, which was converted to blue by the catalytic action of peroxidase and finally converted to yellow by the action of acid. The color intensity correlated positively with the concentration of the analyte in the sample. The absorbance (OD450 value) was measured at a wavelength of 450 nm using a microplate reader, and the sample concentration was calculated.

[0552] 2. Experimental Results Animal modeling results The animal modeling was divided into a preliminary experiment and a main experiment. In the preliminary experiment, the success of the rhinitis model was determined by behavioral observation and scoring after nasal OVA instillation and HE staining of pathological sections. A total of 10 mice were used in the preliminary experiment, and the detection rate after nasal instillation was only 30% on day 15. The positive rates on days 19 and 20 were 90% and 80%, respectively.

[0553] To verify the reliability of the modeling, pathological sections and HE staining were performed on the nasal mucosa of mice classified as positive. The results showed that the nasal mucosa of the blank control group was densely packed, while the nasal mucosa of the model group had already lost its nasal mucosa, indicating significant inflammation.

[0554] Results after drug intervention in a rhinitis model This experiment was divided into eight groups. Except for the blank group, all other groups underwent rhinitis modeling. Compound MDI-1233 was administered at doses of 1 mg / kg, 3 mg / kg, and 10 mg / kg, respectively. Compound MDI-1228 was administered at doses of 3 mg / kg, and MDI-1288 was administered at doses of 3 mg / kg. The positive control drug was fluticasone propionate. After a 7-day treatment period, the animals' behaviors were scored at scheduled times and statistically analyzed (Figures 6 and 7). After compound treatment in male mice, the positive rhinitis score tended to decrease. The positive rhinitis score was significantly lower than in the model group (p<0.05). After compound treatment in female mice, the positive rhinitis score was also significantly lower (p<0.05). Statistical analysis showed that both the compound treatment group and the positive control drug group had a significant effect on suppressing rhinitis behavior in the experimental animals. The overall results show that MDI-1233 at a dose of 10mg / Kg was proven to have inhibitory effects in male mouse rhinitis models by analyzing behavioral scores, compound MDI-1228 failed to significantly inhibit the allergic response in male mice, and MDI-1288 at a dose of 3mg / Kg was proven to have inhibitory effects in both male and female mouse rhinitis models by analyzing behavioral scores.

[0555] Pathological section analysis After compound treatment, samples were taken and sectioned in each group. After HE staining, random field observation and recording were performed to analyze the changes in the nasal mucosa pathology. The results are shown in Figure 8. The results clearly show that the nasal mucosa structure of both males and females in the blank group was uniform, with dense cilia, significant cup-shaped cells, and no significant inflammatory cell infiltration (Figures 8A and 8H). The rhinitis group had lost cilia, a disrupted nasal mucosa structure, edema, bleeding symptoms in the submucosa, and significant inflammatory cell infiltration (Figures 8B and 8I). The compound MDI-1288 treatment group had a basically normal nasal mucosa structure, significant ciliary structure, and some samples showed nasal submucosal bleeding and ciliary shedding, significant cup-shaped cells, and a decrease in inflammatory cells (Figures 8C and 8J). In the 1 mg / kg and 3 mg / kg MDI-1233 treatment groups, bleeding still occurred under the nasal mucosa, inflammatory cell infiltration, cilia shedding in the nasal mucosa, no significant cup-shaped cells, and edema symptoms were improved (Figures 8D, 8E, 8K, and 8L). In the 10 mg / kg compound treatment group, the nasal mucosa structure was basically clear, some cilia were formed in clusters or inverted cilia, some cilia were significantly shedding, edema symptoms were significantly improved, cup-shaped cells were present, and inflammatory cell infiltration was also observed (Figures 8F and 8M). In the positive control drug group, bleeding occurred under the nasal mucosa, no obvious edema symptoms were observed, cilia were formed in clusters, some cilia were shedding, cup-shaped cells were evident, and inflammatory cell infiltration was still observed (Figures 8G and 8N). Judging from the overall section results, the pathological findings in both male and female rhinitis mice reached pathological indicators, primarily reflected in nasal mucosal fibrous shedding and inflammatory cell infiltration. After compound intervention, the pathological symptoms of the nasal mucosa gradually improved. The nasal mucosal structure was essentially normal, with clear ciliary structures. Some samples still exhibited submucosal bleeding and cilia shedding, while cup-shaped cells were evident and inflammatory cells were reduced. The positive control drug, fluticasone propionate, also inhibited the progression of rhinitis and promoted ciliary repair in the nasal mucosa. Judging from the characteristics of the pathological sections, the group pretreated with 10 mg / kg MDI-1233 demonstrated a relatively significant effect on nasal mucosal ciliary repair, with clear cilia, but inflammatory cell infiltration was still present.However, after administering MDI-1288 to the rhinitis model, its therapeutic effect approached that of the positive control drug, fluticasone propionate, which also inhibited the progression of rhinitis and promoted ciliary repair in the nasal mucosa.

[0556] ELISA detection Pathological sections were used to examine the repair status of nasal mucosa and ciliary damage in each group of experimental animals, and ELISA was used to examine serum and nasal wash fluid samples from the test animals. The main indicators were inflammatory factors IL-4 and IL-17, type II interferon IFN-γ, and immunoglobulin IgE, respectively. Changes in serum IL-4 expression levels tended to be relatively consistent between male and female groups (Figures 9 and 10). In the rhinitis modeling module, serum IL-4 levels were detected to be approximately two-fold higher than in the blank control group. After treatment with the positive control drug, the levels fell to a level similar to that of the blank group. In the test drug groups, serum IL-4 levels tended to decrease significantly, demonstrating a correlation with drug dose.

[0557] Example 63: Measurement of the therapeutic effect of compounds on a rat animal model of chronic obstructive pulmonary disease 1. Materials and methods

[0558] experimental animals Healthy 6-8 week old SD rats (manufacturer: Hunan SJA Laboratory Animal Co., Ltd., license number: SCXK(Xiang)2019-0004), half male and half female, were housed under normal conditions (fed on normal diet, temperature 20-26°C, humidity 40%-70%).

[0559] Fauna composition and modeling (1) Blank control group (7 animals) (2) COPD group + vehicle group (vehicle: 0.2% Tween 80 / physiological saline buffer) (8 animals) (3) COPD + positive control drug (levetiracetam) group (8 animals) (4) COPD+ compound MDI-1233 (1 mg / kg) dose group (8 animals) (5) COPD+ compound MDI-1233 (3mg / kg) dose group (8 animals) (6) COPD+ compound MDI-1233 (10mg / kg) dose group (8 animals)

[0560] Experimental environment: Temperature 20℃-26℃, humidity 40%-70%

[0561] Rats were adapted for 7 days to establish a chronic obstructive pulmonary disease model and then treated with different drugs.

[0562] Modeling: On days 1 and 14, rats were anesthetized with an intraperitoneal injection of 10% chloral hydrate, followed by intratracheal intubation and intratracheal injection of 200 μg / 200 μL of LPS. After completion, the rats were rotated upright for 10–20 seconds to ensure uniform distribution of LPS in the lungs. From days 2–13 and 15–28, a smoke chamber (80 cm x 60 cm x 50 cm) was sealed with homemade organic glass and rats were exposed to 15 cigarettes per day for 30 minutes each day.

[0563] Animal administration Nasal administration began in each group on the 29th day after smoking, and each group received continuous administration twice a day for a total of 30 days.

[0564] Methods: The blank control group (no treatment) was not treated with any medication; the COPD group (saline) was modeled and then administered saline nasally; the compound MDI-1233 group was modeled and then administered the corresponding dose of the compound; and the positive control drug group was administered nasally at a dose of 0.1 mg / kg / day twice a day.

[0565] During this period, the rats were weighed once a week and their general behavior such as eating, coughing, and activity was observed.

[0566] Animal sampling After treatment, rats were anesthetized with an intraperitoneal injection of 10% chloral hydrate. The chest was opened, the trachea and lungs were exposed, and approximately 5 mL of blood was drawn from the heart. The blood was centrifuged at 3500 r / min for 10 minutes, and serum was collected and stored at -20°C. The right main bronchus was ligated, and the left lung was punctured at the umbilical cord with a trocar. 2 mL of saline was lavaged into the left lung, followed by slow retraction, recovering approximately 1.5 mL of fluid each time. This lavage was repeated three times. The lavage solution was mixed evenly and centrifuged at 1000 r / min at 4°C for 10 minutes. The supernatant was collected and stored at -20°C. The right middle lobe of the lung was immersed in 4% polyacetal solution for 72 hours and embedded in conventional paraffin. The lung pathology of rats in each group was examined by HE staining.

[0567] HE staining Lung tissue from the animals was excised, fixed in 10% neutral formalin buffer, dehydrated, and embedded in paraffin. Histological sections were stained with hematoxylin (AR11800-1, BOSTER), eosin (AR11800-2, BOSTER), Superclean high-grade sealant (YZB, BASO), and Scott Blue solution (G1865, Solarbio). A pharmaceutical refrigerator (BYC-310, BIOBASE), a microscope (CX41 OLYMPUS), a sectioning machine (BQ-318D, BONA), and an electric heating and drying cabinet (DHG-9070A, SHANGHAI YIHENG) were used. The tissue was removed and washed in running water for several hours, then dehydrated in 70%, 80%, and 90% ethanol solutions. Then, the tissue was placed in a 1:1 mixture of pure alcohol and xylene for 15 minutes, followed by xylene I for 15 minutes and xylene II for 15 minutes (until clear). The tissue was then placed in a 50% xylene and paraffin mixture for 15 minutes, followed by paraffin I and paraffin II for 50-60 minutes to permeate the wax. The tissue was then embedded in paraffin and sectioned. The paraffin sections were baked, dewaxed, and hydrated. The sections were placed in distilled water, stained in hematoxylin solution for 3 minutes, differentiated in hydrochloric acid-ethanol differentiation solution for 15 seconds, rinsed briefly, restored the blue color for 15 seconds in blue recovery solution, rinsed in running water, stained with eosin for 3 minutes, rinsed in running water, dehydrated, cleared, sealed, and examined under a microscope.

[0568] ELISA detection ELISA detects the content of inflammatory factors TNF-α, IL-1β, IL-6, and IL-8 in serum and bronchoalveolar lavage fluid.

[0569] Main equipment and instruments

[0570] [Table 10]

[0571] 2. Experimental Results Modeling chronic obstructive pulmonary disease in rats On days 1 and 14, rats were intubated and injected with LPS into the trachea. From days 2 to 13 and from days 15 to 28, the rats were placed in a self-made organic glass sealed smoke chamber and allowed to inhale cigarette smoke continuously for 30 minutes each day to model chronic obstructive pulmonary disease. Lung tissue staining revealed that large numbers of inflammatory cells adhered to the bronchial walls of the model group, and the epithelium of the tracheal adhesive membrane was necrotic, desquamated, and disorganized, with significant proliferation of cup-shaped cells and glands, indicating that the modeling was successful.

[0572] HE staining After 30 days of administration, the lung tissue morphology and inflammatory cell infiltration status of the rats in each group were observed under an optical microscope (shown in Figure 11). The rats in the normal control group showed no thickening of the bronchial wall, no obvious inflammatory cell infiltration, intact alveolar structure, and no cilia loss. The rats in the COPD model group showed a large number of inflammatory cell infiltrations in the bronchial wall and around the blood vessels, with a large number of epithelial cells falling off, cilia collapsed, the gas duct wall ruptured, obvious thickening, narrowed lumen, and ruptured and fused alveoli. The rats in the positive control drug group showed mild localized deformation of the tracheal lumen, and mild duct wall damage. The tracheal lumen of rats administered MDI-1233 showed reduced deformation and inflammatory cell infiltration compared with the COPD model group. With increasing drug concentration, the lumen showed reduced deformation and a gradual decrease in inflammatory cells. The high-dose MDI-1233 group showed the best effect, but was slightly inferior to the positive control group.

[0573] ELISA detection Based on the pathogenic mechanisms of COPD development in vivo, such as oxidative stress and inflammatory responses, the study primarily used inflammatory chemokine...

Claims

1. In the manufacture of a TRK inhibitor drug and / or a RET inhibitor drug, a compound of formula (G): 【Chemical 1】 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, L is C=O, O=S=O, CH ２ or a bond, X １ is N or CR １４ and X ２ is N or CR １５ and X ３ is N or CR １６ and R １４ , R １５ , R １６ is H, -OH, -SH, -CN, halogen, -NO ２ , -SF ５ , -SC １－４ Alkyl, C １－６ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－６ Alkoxy, C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-N(R ９ ) (R １０ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ wherein -SC is independently selected from １－４ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl and 3- to 7-membered heterocycloalkyl include halogen, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C ３－７ Cycloalkyl, C １－４ Hydroxyalkyl, —S—C １－４ Alkyl, —C(═O)H, —C(═O)—C １－４ Alkyl, —C(═O)—O—C １－４ Alkyl, —C(═O)—NH ２ , -C(=O)-N(C １－４ alkyl) ２ , -N(C １－４ alkyl)(C(=O)C １－４ alkyl), C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents selected from haloalkoxy; R １３ is H, -N(R １７ ) (R １８ ), C １－６ Alkoxy, -SR １２ , -OR １２ , -CN, halogen, -NO ２ , -SF ５ , -SC １－４ Alkyl, C １－６ Alkyl, C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C ５－１１ bicycloalkyl, or 5- to 11-membered bicycloheteroalkyl, and R １３ is 0, 1, 2, 3, or 4 R １ where R １７ , R １８ is H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ３－７ Heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C ５－１１ bicycloalkyl, 5- to 11-membered bicycloheteroalkyl, and —OH, —CN, —SH, halogen, —NO ２ , -SF ５ , -SC １－４ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, 4-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-N(R ９ ) (R １０ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ and optionally substituted with one or more substituents each independently selected from the group consisting of: １－４ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, 4-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, —CN, —OH, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ cycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-OR １２ , -C(=O)H, -C(=O)R １２ , -C(=O)-N(R ９ ) (R １０ ), -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ or R １７ , R １８ form a 3-14 membered ring together with the N atom to which they are attached, R ２ The number of is 0, 1, 2, 3, or 4, and R ２ is H, halogen, -OH, -NO ２ , -CN, -SF ５ , -SH, -SC １－４ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, 4-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-N(R ９ ) (R １０ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ wherein said -SC is selected from １－４ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, 4-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, —CN, —OH, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ cycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-OR １２ , -C(=O)H, -C(=O)R １２ , -C(=O)-N(R ９ ) (R １０ ), -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R １ is H, halogen, -OH, -NO ２ , -CN, -SF ５ , -SH, -SC １－４ Alkyl, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Alkoxy, C ３－７ cycloalkyl, 3-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C ５－１１ Bicycloalkyl, 5-11 membered bicycloheteroalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-N(R ９ ) (R １０ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ wherein said -SC is selected from １－４ Alkyl, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Alkoxy is one, two, three, or four R ３ and optionally substituted with C ３－７ cycloalkyl, 3-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl can have 1, 2, 3, or 4 R ４ optionally replaced by R ３ , R ４ are respectively H, halogen, —OH, —NO ２ , -CN, -SF ５ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, -N(R ５ ) (R ６ ), -N(R １１ ) (C(=O)R １２ ), -CON(R ７ ) (R ８ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ wherein said C １－６ Alkyl, C ３－７ cycloalkyl, 3-10 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl and 7-11 membered bicycloheteroaryl are substituted with halogen, —CN, —OH, C １－４ Alkyl, C １－６ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ cycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-OR １２ , -C(=O)H, -C(=O)R １２ , -C(=O)-N(R ９ ) (R １０ ), -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ and R is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ are each independently H or C １－６ Alkyl, C １－４ Haloalkyl, C ３－７ cycloalkyl, 4-14 membered heterocycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, (C ３－７ cycloalkyl)-C １－４ Alkyl-, (4- to 10-membered heterocycloalkyl)-C １－４ Alkyl-, (C ６－１０ aryl)-C １－４ Alkyl- and (5-10 membered heteroaryl)-C １－４ alkyl-, where each member within the group is selected from the group consisting of halogen, —CF ３ , —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN, oxo, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C １－４ Hydroxyalkyl, —S—C １－４ Alkyl, —C(═O)H, —C(═O)—C １－４ Alkyl, —C(═O)—O—C １－４ Alkyl, —C(═O)—NH ２ , -C(=O)-N(C １－４ alkyl) ２ , C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ Optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy.

2. 2. The use according to claim 1, wherein all H are each independently optionally substituted with D.

3. X １ , X ２ , X ３ The use according to claim 1 or 2, wherein only one of

4. X １ , X ２ , X ３ The use according to claim 1 or 2, wherein only two of

5. X １ , X ２ , X ３ The use according to claim 1 or 2, wherein

6. X １ is CR １４ and X ２ is CR １５ and X ３ is CR １６ and R １４ , R １５ , R １６ The use according to claim 5, wherein

7. R １４ , R １５ , R １６ is H, -OH, -SH, -CN, halogen, -NO ２ , C １－６ 7. The use according to claim 6, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

8. R １４ , R １５ , R １６ is H, -OH, C １－６ 8. The use according to claim 7, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

9. X １ , X ２ , X ３ and (b) are CH.

10. X １ , X ２ , X ３ and each of the following is N:

11. L is C=O, O=S=O, or CH ２ The use according to any one of claims 1 to 10, wherein

12. R １３ is H, -N(R １７ ) (R １８ ), C １－６ Alkoxy, -OH, -SH, -CN, halogen, -NO ２ , -SF ５ , -SC １－４ Alkyl, C １－６ Alkyl, C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo, C ５－１１ bicycloalkyl, or 5- to 11-membered bicycloheteroalkyl; R １３ is 0, 1, 2, 3, or 4 R １ where R １７ , R １８ is H, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, C ３－７ Heterocycloalkyl, C ５－７ aryl, 5- to 7-membered heteroaryl, and one or more of —OH, —CN, —SH, halogen, —NO ２ , -SF ５ 11. The use according to any one of claims 1 to 10, optionally substituted with

13. R １３ is H, -N(R １７ ) (R １８ ), C １－６ Alkoxy, -OH, -SH, -CN, halogen, -NO ２ , -SF ５ , -SC １－４ Alkyl, C １－６ Alkyl, C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ bicycloaryl, 7-11 membered bicycloheteroaryl, or 11-15 membered tricyclo, R １３ is 0, 1, 2, 3, or 4 R １ 11. The use according to any one of claims 1 to 10, wherein said compound is substituted with

14. R １３ is H, -N(R １７ ) (R １８ ), C １－６ Alkoxy, C １－６ Alkyl, C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ aryl, or 5-7 membered heteroaryl; R １３ is 0, 1, 2, 3, or 4 R １ 11. The use according to any one of claims 1 to 10, wherein said compound is substituted with

15. R １３ is -N(R １７ ) (R １８ ), C １－６ Alkoxy, C １－６ Alkyl, C ３－７ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; R １３ is 0, 1, 2, or 3 R １ 11. The use according to any one of claims 1 to 10, wherein said compound is substituted with

16. R １７ , R １８ are H, C separately. １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ heterocycloalkyl and one or more of -OH, -CN, -SH, halogen, -NO ２ , -SF ５ 11. The use according to any one of claims 1 to 10, optionally substituted with

17. R １７ , R １８ The use according to any one of claims 1 to 10, wherein together with the N atom to which they are attached form a 4-10 membered ring.

18. L is C=O and R １３ -N (R １７ ) (R １８ ), C １－６ Alkoxy, -OH, -SH, -CN, halogen, -NO ２ , -SF ５ , or -S-C １－４ alkyl, and R １３ 0, 1, 2, 3, or 4 R １ where R １７ , R １８ is H, C １－６ Alkyl, C １－６ Alkoxy, C ３－７ Cycloalkyl, C ３－７ Heterocycloalkyl, C ５－７ aryl, 5- to 7-membered heteroaryl, and one or more of —OH, —CN, —SH, halogen, —NO ２ , -SF ５ or optionally substituted with R １７ , R １８ The use according to any one of claims 1 to 10, wherein together with the N atom to which they are attached, form a 3-14 membered ring.

19. 1, 2, or 3 R ２ exists and R ２ is H, halogen, -OH, -NO ２ , -CN, -SF ５ , -SH, -SC １－４ Alkyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 4- to 10-membered heterocycloalkyl, wherein said —S—C １－４ Alkyl, C １－６ Alkyl, C ３－７ Cycloalkyl and 4-10 membered heterocycloalkyl are halogen, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ 11. The use of any one of claims 1 to 10, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

20. 1, 2, or 3 R ２ exists and R ２ is a halogen, C １－６ Alkyl, and C ３－６ cycloalkyl, wherein said C １－６ Alkyl, and C ３－６ Cycloalkyl is a halogen, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ 11. The use of any one of claims 1 to 10, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

21. 1 or 2 R ２ exists and R ２ is a halogen, C １－６ 16. The use according to claim 15, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

22. R １３ is 0 or 1 R １ and R １ is halogen, -OH, -CN, C １－６ Alkyl, 5-7 membered heterocycloalkyl, C ３－７ cycloalkyl, wherein said C １－６ Alkyl is one, two, or three R ３ wherein said 5-7 membered heterocycloalkyl, C ３－７ Cycloalkyl can have 1, 2, 3, or 4 C １－３ 11. The use according to any one of claims 1 to 10, optionally substituted with alkyl.

23. The compound is a compound of formula (I): 【Chemistry 2】 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, L is C=O, O=S=O, CH ２ or a bond, X is CH or N; Ring A is C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ bicycloaryl, 7-11 membered bicycloheteroaryl, 11-15 membered tricyclo; R １ The number of is 0, 1, 2, 3, or 4, and R １ is H, halogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Alkoxy, C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ bicycloaryl, 7- to 11-membered bicycloheteroaryl, wherein said C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Alkoxy is one, two, three, or four R ３ and optionally substituted with C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ Aryl, 5-7 membered heteroaryl, C ７－１１ Bicycloaryl, 7-11 membered bicycloheteroaryl can have 1, 2, 3, or 4 R ４ optionally replaced by R ２ The number of is 0, 1, 2, 3, or 4, and R ２ is H, halogen, -OH, -NO ２ , -CN, -SF ５ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 4-10 membered heterocycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-N(R ９ ) (R １０ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ wherein said C １－６ Alkyl, C ３－７ Cycloalkyl and 4-10 membered heterocycloalkyl include halogen, —CN, —OH, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ cycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-OR １２ , -C(=O)H, -C(=O)R １２ , -C(=O)-N(R ９ ) (R １０ ), -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R ３ is halogen, cyano, C １－３ Alkyl, hydroxyl, C １－６ Alkoxy, —N(R ５ ) (R ６ ), -CON(R ７ ) (R ８ ), or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is selected from 1, 2, 3 or 4 R ４ optionally replaced by R ４ is a halogen, C １－３ Alkyl, hydroxyl, C １－６ Alkoxy, —NH ２ , -NHCH ３ , or -N(CH ３ ) ２ is selected from R ５ , R ６ , R ７ , R ８ are each independently hydrogen or C １－４ is alkyl, R ９ is H, C １－４ Alkyl, C １－４ haloalkyl, or C ３－７ cycloalkyl; R １０ is H or C １－４ Alkyl, C １－４ Haloalkyl, C ３－７ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, (C ３－７ cycloalkyl)-C １－４ Alkyl-, (4- to 10-membered heterocycloalkyl)-C １－４ Alkyl-, (C ６－１０ aryl)-C １－４ Alkyl- and (5-10 membered heteroaryl)-C １－４ alkyl-, where each option within the group is selected from the group consisting of -OH, -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C ３－７ Cycloalkyl, C １－４ Hydroxyalkyl, —S—C １－４ Alkyl, —C(═O)H, —C(═O)—C １－４ Alkyl, —C(═O)—O—C １－４ Alkyl, —C(═O)—NH ２ , -C(=O)-N(C １－４ alkyl) ２ , C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy; R １１ is H, C １－４ Alkyl, and C ３－７ cycloalkyl; R １２ is C １－６ Alkyl, C ３－７ cycloalkyl, 4- to 14-membered heterocycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, (C ３－７ cycloalkyl)-C １－４ Alkyl-, (4- to 10-membered heterocycloalkyl)-C １－４ Alkyl-, (C ６－１０ aryl)-C １－４ Alkyl- and (5-10 membered heteroaryl)-C １－４ alkyl-, where each member within the group is selected from the group consisting of halogen, —CF ３ , -CN, -OH, -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , oxo, -S-C １－４ Alkyl, C １－４ Alkyl, C １－４ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C １－４ Alkoxy, and C １－４ 2. The use of claim 1, optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

24. L is C=O, O=S=O, or CH ２ 24. The use according to claim 23, wherein

25. 24. The use according to claim 23, wherein X is CH.

26. Ring A is C ３－７ cycloalkyl, 3-7 membered heterocycloalkyl, C ５－７ The use according to any one of claims 23 to 25, wherein the aryl is aryl or 5- to 7-membered heteroaryl.

27. 26. The use according to any one of claims 23 to 25, wherein ring A is a 5-6 membered heteroaryl or phenyl.

28. 0 or 1 R １ exists and R １ is C １－６ alkyl, 5-7 membered heterocycloalkyl, wherein said C １－６ Alkyl is one or two R ３ and said 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 C １－３ 26. The use according to any one of claims 23 to 25, optionally substituted with alkyl.

29. 1 or 2 R ２ exists and R ２ is halogen, C １－６ Alkyl, and C ３－６ cycloalkyl, wherein said C １－６ Alkyl and C ３－６ Each cycloalkyl is optionally selected from halogen, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ 26. The use of any one of claims 23 to 25, substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

30. L is C=O or O=S=O; X is CH; Ring A is a 5-7 membered heteroaryl or C ５－７ is aryl, R １ The number of is 0, 1, 2, 3, or 4, and R １ is C １－８ alkyl, 3- to 7-membered heterocycloalkyl, wherein said C １－８ Alkyl can be one, two, three, or four R ３ and said 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R ４ optionally replaced by R ２ The number of is 1, 2, or 3, and R ２ is H, halogen, -OH, -NO ２ , -CN, -SF ５ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 4-10 membered heterocycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-N(R ９ ) (R １０ ), -C(=O)-R １２ , -C(=O)-OR １２ , —OC(═O)R １２ , -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ wherein said C １－６ Alkyl, C ３－７ Cycloalkyl and 4-10 membered heterocycloalkyl include halogen, —CN, —OH, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－６ cycloalkyl, —N(R ９ ) (R １０ ), -N(R １１ ) (C(=O)R １２ ), -C(=O)-OR １２ , -C(=O)H, -C(=O)R １２ , -C(=O)-N(R ９ ) (R １０ ), -N(R １１ ) (S(=O) ２ R １２ ), -S(=O) ２ -N(R ９ ) (R １０ ), -SR １２ , and -OR １２ each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: R ３ is halogen, cyano, C １－３ Alkyl, hydroxyl, C １－６ Alkoxy, —N(R ５ ) (R ６ ), -CON(R ７ ) (R ８ ), or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is selected from 1, 2, 3, or 4 R ４ optionally replaced by R ４ is a halogen, C １－３ Alkyl, hydroxyl, C １－６ Alkoxy, —NH ２ , -NHCH ３ , or -N(CH ３ ) ２ is selected from R ５ , R ６ , R ７ , R ８ are each independently hydrogen or C １－４ is alkyl, R ９ is H, C １－４ Alkyl, C １－４ haloalkyl, or C ３－７ cycloalkyl; R １０ is H or C １－４ Alkyl, C １－４ Haloalkyl, C ３－７ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, (C ３－７ cycloalkyl)-C １－４ Alkyl-, (4- to 10-membered heterocycloalkyl)-C １－４ Alkyl-, (C ６－１０ aryl)-C １－４ Alkyl- and (5-10 membered heteroaryl)-C １－４ alkyl-, where each option within the group is selected from the group consisting of -OH, -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C ３－７ Cycloalkyl, C １－４ Hydroxyalkyl, —S—C １－４ Alkyl, —C(═O)H, —C(═O)—C １－４ Alkyl, —C(═O)—O—C １－４ Alkyl, —C(═O)—NH ２ , -C(=O)-N(C １－４ alkyl) ２ , C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of haloalkoxy; R １１ is H, C １－４ Alkyl, and C ３－７ cycloalkyl; R １２ is C １－６ Alkyl, C ３－７ cycloalkyl, 4- to 14-membered heterocycloalkyl, C ６－１０ aryl, 5-10 membered heteroaryl, (C ３－７ cycloalkyl)-C １－４ Alkyl-, (4- to 10-membered heterocycloalkyl)-C １－４ Alkyl-, (C ６－１０ aryl)-C １－４ Alkyl- and (5-10 membered heteroaryl)-C １－４ alkyl-, where each member within the group is selected from the group consisting of halogen, —CF ３ , -CN, -OH, -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , oxo, -S-C １－４ Alkyl, C １－４ Alkyl, C １－４ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C １－４ Alkoxy, and C １－４ 26. The use of any one of claims 23 to 25, optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

31. The use according to claim 30, wherein ring A is a 5-6 membered heteroaryl or phenyl.

32. 0 or 1 R １ exists and R １ is C １－６ alkyl, 5-7 membered heterocycloalkyl, wherein said C １－６ Alkyl is one or two R １ and said 5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 C １－３ 31. The use of claim 30, optionally substituted with alkyl.

33. 1 or 2 R ２ exists and R ２ is a halogen, C １－６ Alkyl, and C ３－６ cycloalkyl, wherein said C １－６ Alkyl and C ３－６ Cycloalkyl is a halogen, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN,C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ 31. The use of claim 30, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of haloalkoxy.

34. The compound is (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone (MDI-2), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)methanone (MDI-202), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)methanone (MDI-203), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-204), (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)methanone (MDI-205), 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-206), 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-207), 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-208), cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233), 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-210), cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-211), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxycyclobutyl)methanone (MDI-213), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)methanone (MDI-214), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)methanone (MDI-215), (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228), 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxycyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-217), 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218), 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-219), 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-220), 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-221), 4-(3-(5-(cyclopentatyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-224), 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-225), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-226), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one (MDI-227), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one (MDI-228), 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-229), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one (MDI-230), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231), N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236), cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-237), cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-239), (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-240), cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)methanone (MDI-242), (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-243), (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-246), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248), 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)pyrrolidine-3-carbonitrile (MDI-250), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-251), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-252), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-253), (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-255), 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile (MDI-256), 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257), N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-258), N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-259), N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-260), (s)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-262), (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (MDI-263) or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt, prodrug, or metabolite of any of the above compounds.

35. The compound is (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinopyrazin-2-yl)methanone (MDI-201) 【Chemistry 3】 Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)methanone (MDI-1233) 【Chemistry 4】 (s)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (MDI-1228) 【Chemistry 5】 4-(3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218) 【Chemistry 6】 N-(3-chloro-2-hydroxypropyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-1288) 【Chemistry 7】 (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)methanone (MDI-231) 【Chemistry 8】 (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)methanone (MDI-233) 【Chemistry 9】 (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)methanone (MDI-234) 【Chemistry 10】 (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)methanone (MDI-235) 【Chemistry 11】 (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)methanone (MDI-236) 【Chemistry 12】 (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxypiperidin-1-yl)methanone (MDI-245) 【Chemistry 13】 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-formamide (MDI-247) 【Chemistry 14】 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxyethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-formamide (MDI-248) 【Chemistry 15】 Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (MDI-253) 【Chemistry 16】 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carbonamide (MDI-257) 【Chemistry 17】 or an isotopically labeled compound, optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt, prodrug, or metabolite of any of the above compounds.

36. The use according to any one of claims 1 to 35, wherein the compound is used as a JAK / TRK dual inhibitor (preferably a pan-JAK / pan-TRK dual inhibitor) or a JAK / TRK / RET multiple inhibitor (preferably a pan-JAK / pan-TRK / RET multiple inhibitor).

37. A pharmaceutical composition of a TRK inhibitor and / or a RET inhibitor, comprising: A compound defined in any one of claims 1 to 35 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof; one or more pharmaceutically acceptable carriers, adjuvants or excipients; A pharmaceutical composition comprising:

38. 38. The pharmaceutical composition of claim 37, which is prepared as an oral dosage form or an external dosage form suitable for topical administration.

39. The pharmaceutical composition according to claim 37, which is manufactured as a JAK / TRK dual inhibitor drug (preferably used as a pan-JAK / pan-TRK dual inhibitor drug) or a JAK / TRK / RET multiple inhibitor drug (preferably prepared as a pan-JAK / pan-TRK / RET multiple inhibitor drug).

40. Use of a compound defined in any one of claims 1 to 35 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 37, 38 or 39, in the manufacture of a medicament for treating and / or preventing a disease or condition associated with TRK and / or RET.

41. 41. The use according to claim 40, wherein the disease or condition associated with TRK and / or RET is selected from arthritis, autoimmune diseases or conditions, cancer or tumors, diabetes and diabetic complications, slow wound healing (due to diabetes), eye diseases, diseases or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or conditions, allergies, asthma and other obstructive airway diseases, transplant rejection.

42. The use according to claim 40, wherein the disease or condition associated with TRK and / or RET is selected from pruritus, psoriasis, atopic dermatitis, skin side effects caused by EGFR inhibitors, acne, vitiligo, alopecia areata, asthma, rhinitis, hemorrhoids, cervicitis, pneumonia, slow wound healing due to diabetes, diabetic foot, diabetic retinopathy, cancer (tumor), and bedsore.

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