TWI786742B - Pyridone compounds and their preparation methods and applications - Google Patents

Abstract

The invention discloses a pyridone compound, a preparation method and application thereof. In particular, the present invention relates to compounds of formula I, which are useful for the treatment of diseases associated with irritable bowel syndrome (IBS) and other gastrointestinal disorders, as well as for the treatment of RET and/or TRK functional disorders or for the regulation of RET and/or TRK activity Cancer, inflammatory bowel disease, neurodegenerative disease, chronic pain, acute pain, inflammatory disease, Trypanosoma cruzi infection, diseases related to imbalances in the regulation of bone remodeling.

Description

Pyridone compounds and their preparation methods and applications

The invention belongs to the field of medicines, and in particular relates to pyridone compounds and their preparation methods and applications.

Rearrangement during transfection (RET) is a nerve growth factor receptor tyrosine kinase that plays an important role in the development of the kidney and enteric nervous system, and the maintenance of homeostasis in the nervous, endocrine, hematopoietic, and male reproductive systems. The structure of RET is divided into extracellular region, transmembrane region and intracellular kinase region. Its signaling is mediated by the binding of soluble proteins of glial cell line-derived neurotrophic factor (GDNF) and family ligands (GFL), whose ligands of the neurotrophic factor (GDNF) family do not directly bind to RET, but first Form a complex GFL–GFRα with GDNF family receptor α, and then catalyze RET homodimerization, make RET autophosphorylate in the intracellular region, and then recruit adapter proteins and pathway proteins to activate including MAPK, PI3K, JAK-STAT, PKA Various signaling pathways, including PKC, are involved in cell proliferation, nerve conduction, cell migration and cell differentiation (Alexander Drilon, Nature Reviews Clinical Oncology, 2018, 15:151–167). These transmitted messages play an important role in regulating cell survival, differentiation, proliferation, migration and chemotaxis.

RET plays an important role in the growth and survival of afferent nociceptors in the skin and intestine. RET kinase knockout mice lack enteric neurons and have other neurological abnormalities, suggesting that a functional RET kinase protein product may be required for normal nervous system development (Taraviras, S. et al., 1999, 126:2785-2797) . A high proportion of familial and sporadic RET deletion mutations has been reported in population-based studies of Hirschsprung disease patients characterized by colonic obstruction (Butler Tjaden N., et al., Transl. Res., 2013, 162:1-15).

The chromosomal rearrangement of the RET gene may lead to breakage of the RET gene. After the breakage, the 3' end of the RET gene can be fused with different genes such as KIF5B, TRIM33, CCDC6 or NCOA4 to form a fusion gene. The expressed fusion protein is continuously activated and drives Tumor occurrence. According to reports, RET gene fusions exist in about 10-20% of PTC (papillary thyroid carcinoma) patients, mainly CCDC6-RET and NCOA4-RET fusions. About 1% to 2% of patients with lung adenocarcinoma have RET fusion genes in their bodies, mainly including four types: KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, among which KIF5B-RET is the most common (Rosell R, and Karachaliou N, Lancet Oncol., 2016, 17:1623-1625).

The gene encoding RET protein is located on the long arm of human chromosome 10, and its abnormality (gene fusion, mutation, etc.) can cause a variety of diseases, including papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), Hirschsprung cancer, pulmonary Adenocarcinoma, irritable bowel syndrome, etc.

Currently, there are two RET-targeted drugs on the market, namely Loxo Oncology's LOXO-292 (selpercatinib/LY3527723) and Blurprint's BLU-667 (pralsetinib/Gavreto). These two targeted drugs have shown ideal efficacy and safety for RET fusion or mutation-positive patients, especially RET fusion-positive non-small cell lung cancer (NSCLC) and RET mutation-positive medullary thyroid. Cancer (medullary thyroid cancer, MTC).

Trks are high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members, Trk A, Trk B and Trk C. Trk A is a high-affinity receptor for nerve growth factor (hereinafter referred to as NGF), and Trk B is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin (hereinafter referred to as NT)-4/5 , Trk C is a high-affinity receptor for NT-3. All Trk receptors are highly expressed in nerve tissue and participate in the differentiation and maintenance of nerve cell function.

Trk has been reported to be involved in osteoarthritis, chronic low back pain, rheumatoid arthritis, fractures, nociceptive pain in interstitial cystitis and chronic pancreatitis, neuropathic pain, and cancer with both of the above pain types in pain. In addition, Trk receptors are expressed in cancer cells such as glioma, hepatic cholangiocarcinoma, papillary thyroid carcinoma, colon cancer, non-small cell lung cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, sarcoma and melanoblastoma, prostate and pancreatic cancer), inflammatory cells (such as mast cells and eosinophils), immunocompetent cells (such as T cells and B cells), and keratinocytes, and have been reported to be involved in cancer cell proliferation, migration, and metastasis , inflammatory diseases (such as ulcerative colitis and Crohn's disease), allergic diseases (such as asthma, rhinitis and atopic dermatitis) and other diseases (such as psoriasis).

Compounds having Trk inhibitory activity are therefore useful in the treatment of nociceptive pain, neuropathic pain and pain combining these two types of pain, cancer, inflammatory diseases, allergic diseases and psoriasis.

Irritable bowel syndrome (IBS) is a common functional disorder affecting 10-20% of individuals and is characterized by abnormal bowel movements, bloating, abdominal pain, and visceral hypersensitivity. At present, most studies believe that the cause of IBS is due to the barrier between the brain and gastrointestinal tract, the interference of intestinal microorganisms or the increase of inflammation, which affects the intestinal transmission function, resulting in diarrhea and constipation. Some patients take drugs at will, which further leads to the imbalance of intestinal flora and aggravates the disease. These studies suggest that inhibition of RET and/or TRK may be an effective strategy for the treatment of diseases associated with irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, chronic pain , acute pain, inflammatory diseases, and cancers that treat RET and/or TRK dysfunction or modulate RET and/or TRK activity.

The purpose of the present invention is to provide a RET and TRK kinase inhibitor, which can be used for the treatment of diseases related to irritable bowel syndrome (IBS), inflammatory bowel disease, other gastrointestinal disorders, neurodegenerative diseases, chronic pain, acute pain, Inflammatory diseases, and treatment of RET and/or TRK dysfunction or cancers that modulate RET and/or TRK activity.

In the first aspect of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;

In the formula,

)、C3-C6環烷基、C6-C10芳基、5-10員雜芳基、R'NH-(

)、R'R"N-(

)；Each R is independently H, halogen or selected from substituted or unsubstituted hydroxyl, amino, _C1 -C6 alkyl, R'-O-(

), C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, R'NH-(

), R'R"N-(

);

R', R" are each independently selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, Wherein, the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, C1-C6 alkyl;

Or when two R ₁ are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;

)、R₈ C(O)-(

)、R₈ S(O)₂ (

)、C1-C6烷基、C3-C6環烷基；Each R ₂ is independently H, halogen, cyano, nitro, or selected from substituted or unsubstituted hydroxyl, amino, R ₈ C(O)O-(

), R ₈ C(O)-(

), R ₈ S(O) ₂ (

), C1-C6 alkyl, C3-C6 cycloalkyl;

Or when two R ₂ are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6-C10 aryl, 5 -10-membered heteroaryl;

)、R₈ C(O)-(

)、R₈ S(O)₂ (

)、C1-C6烷基、C3-C6環烷基、3-8員環雜烷基、C6-C10芳基、5-10員雜芳基、-OR₆ (

)、-CONR₇ R'₇ (

)，其中，所述取代是指被一個或多個R_a 取代：Each R _b is independently halogen, cyano, nitro, or selected from substituted or unsubstituted amino, R ₈ C(O)O-(

), R ₈ C(O)-(

), R ₈ S(O) ₂ (

), C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR ₆ (

), -CONR ₇ R' ₇ (

), wherein the substitution refers to being substituted by one or more R _a :

)；Each R _a is independently selected from halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR ₇ R' ₇ (

);

R ₆ , R ₇ and R' ₇ are independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 members Cycloheteroalkyl;

)、R₈ S(O)₂ (

)、胺基、羥基、C1-C6烷基、3-8員雜烷基、C1-C6烷氧基、C3-C6環烷基、3-8員雜環基、C2-C6烯基、C2-C6炔基、-(L₁ )_p -OH、-(L₁ )_p -(C1-C6烷氧基)、-C(O)OR₈ (

)、-(L₁ )_p -N(R₉ )(R'₉ )(

)、-C(O)-N(R₁₀ )(R'₁₀ )(

)、-C(O)-N(R₁₁ )-(L₂ )_m -N(R'₁₁ )(R"₁₁ )(

)；R ₅ is hydrogen, cyano, halogen, nitro or substituted or unsubstituted aldehyde, R ₈ C(O)-(

), R ₈ S(O) ₂ (

), amino, hydroxyl, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C2-C6 alkenyl, C2 -C6 alkynyl, -(L ₁ ) _p -OH, -(L ₁ ) _p -(C1-C6 alkoxy), -C(O)OR ₈ (

), -(L ₁ ) _p -N(R ₉ )(R' ₉ )(

), -C(O)-N(R ₁₀ )(R' ₁₀ )(

), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ )(

);

Or when R _b and R ₅ are located at two adjacent C atoms, the C atoms connected to them are fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered cycloheteroyl, C6-C10 aryl, 5-10 member heteroaryl;

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, C1 -C6 alkyl, N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen, C1-C6 alkyl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which it is connected;

Or R' ₁₁ and R " ₁₁ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to;

)、羥基、3-8員雜烷基、3-8員雜環基、C6-C10芳基、5-10員雜芳基，其中，R₁₂ 和R'₁₂ 各自獨立地選自C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R ₉ and R' ₉ are each independently H, cyano or selected from substituted or unsubstituted aldehyde groups, C1-C6 alkyl, -NR ₁₂ R' ₁₂ (

), hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from C1-C6 Alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which they are attached;

Unless otherwise specified, the substitution refers to substitution by one or more R;

Each R is independently selected from halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

)、CO、SO₂ ；其中，R_f 和R_g 各自獨立地選自H、C1-C6烷基、鹵素、氰基、羥基、胺基；Each L ₁ and L ₂ are independently selected from: -CR _f R _g -(

), CO, SO ₂ ; wherein, R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

r is 1, 2 or 3;

m and p are each independently 1, 2, 3, 4, 5 or 6;

n is 0, 1 or 2;

n' is 0, 1, 2 or 3;

n" is 0, 1, 2 or 3.

選自

、

、

、

，其中，

為單鍵或雙鍵；q為0、1或2；X₁ 和X₂ 各自獨立地選自NH、O、S或CH₂ ；X₃ 和X₄ 各自獨立地選自N或CH；R₁ 的定義如上所述。In another preferred example,

selected from

,

,

,

,in,

is a single bond or a double bond; q is 0, 1 or 2; X ₁ and X ₂ are each independently selected from NH, O, S or CH ₂ ; X ₃ and X ₄ are each independently selected from N or CH; R ₁ is defined as above.

In another preferred example, the compound of formula I or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug has the structure shown in formula I':

In the formula,

R is selected from H, halogen, hydroxyl, amino, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, Halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH-, (C1-C6 alkyl) (C1-C6 alkyl )N-;

Each R is independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C1 _- C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkane base;

)、-CONR₇ R'₇ (

)，其中，所述C1-C6烷基任選地被一個或多個選自下組的基團取代氰基、羥基、C1-C6烷氧基、鹵代C1-C6烷氧基、-NR₇ R'₇ (

)，所述C6-C10芳基或者5-10員雜芳基任選地被一個或多個選自下組的基團取代鹵素、C1-C6烷基、鹵代C1-C6烷基；R ₃ and R ₄ are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkane Base, C6-C10 aryl, 5-10 membered heteroaryl, -OR ₆ (

), -CONR ₇ R' ₇ (

), wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from the group consisting of cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR ₇ R' ₇ (

), the C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

R ₆ , R ₇ and R' ₇ are independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 members Cycloheteroalkyl;

)、胺基、羥基、鹵素、C1-C6烷基、3-8員雜烷基、鹵代C1-C6烷基、C1-C6亞烷基-OH、-(L₁ )_p -(C1-C6烷氧基)、C1-C6烷氧基、C3-C6環烷基、C2-C6烯基、C2-C6炔基、-C(O)OR₈ (

)、-(L₁ )_p -N(R₉ )(R'₉ )(

)、 -C(O)-N(R₁₀ )(R'₁₀ )(

)、 -C(O)-N(R₁₁ )-(L₂ )_m -N(R'₁₁ )(R"₁₁ )(

)；R ₅ is selected from: hydrogen, cyano, aldehyde, R ₈ C(O)-(

), amino, hydroxyl, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkylene-OH, -(L ₁ ) _p -(C1- C6 alkoxy), C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C (O) OR ₈ (

), -(L ₁ ) _p -N(R ₉ )(R' ₉ )(

), -C(O)-N(R ₁₀ )(R' ₁₀ )(

), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ )(

);

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen or C1-C6 alkyl;

)、羥基、3-8員雜烷基、3-8員雜環基、5-10雜芳基，其中，R₁₂ 和R'₁₂ 各自獨立地選自C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R ₉ and R' ₉ are each independently selected from cyano, aldehyde, C1-C6 alkyl, -NR ₁₂ R' ₁₂ (

), hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, 5-10 heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from C1-C6 alkyl, halogenated C1- C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

)，其中，所述R_f 和R_g 各自獨立地選自H、C1-C6烷基、鹵素、氰基、羥基、胺基；L ₁ and L ₂ are each independently -CR _f R _g -(

), wherein, the R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

n is 0, 1 or 2;

m and p are each independently 1, 2, 3, 4, 5 or 6.

In another preferred example, R is selected from: _C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy;

)、C1-C6烷基、鹵代C1-C6烷基、3-8員雜烷基、-C1-C6亞烷基-OH、C2-C6烯基、C2-C6炔基、-(L₁ )_p -(C1-C6烷氧基)、-C(O)OR₈ (

)、-(L₁ )_p -N(R₉ )(R'₉ )(

)、 -C(O)-N(R₁₀ )(R'₁₀ )(

)、 -C(O)-N(R₁₁ )-(L₂ )_m -N(R'₁₁ )(R"₁₁ )(

)；R ₅ is selected from cyano group, aldehyde group, R ₈ C(O)-(

), C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L ₁ ) _p -(C1-C6 alkoxy), -C(O)OR ₈ (

), -(L ₁ ) _p -N(R ₉ )(R' ₉ )(

), -C(O)-N(R ₁₀ )(R' ₁₀ )(

), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ )(

);

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyanide, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen , C1-C6 alkyl;

)、羥基、3-8員雜烷基、3-8員雜環基、5-10雜芳基，其中，R₁₂ 和R'₁₂ 各自獨立地選自：C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R ₉ and R' ₉ are each independently selected from cyano, aldehyde, C1-C6 alkyl, -NR ₁₂ R' ₁₂ (

), hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, 5-10 heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1 -C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

)，其中，所述R_f 和R_g 各自獨立地選自H、C1-C6烷基、鹵素、氰基、羥基、胺基；L ₁ and L ₂ are each independently -CR _f R _g -(

), wherein, the R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

m and p are each independently 1, 2, 3, 4, 5 or 6;

Each R is independently selected from halogen, cyano, nitro, C1 _- C6 alkyl, halogenated C1-C6 alkyl;

R ₃ and R ₄ are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl.

In another preferred example, R ₁ is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.

)、C1-C6烷基、鹵代C1-C6烷基、3-8員雜烷基、-C1-C6亞烷基-OH、C2-C6烯基、C2-C6炔基、-(L₁ )_p -(C1-C6烷氧基)、-C(O)OR₈ (

)、-(L₁ )_p -N(R₉ )(R'₉ )(

)、-C(O)-N(R₁₀ )(R'₁₀ )(

)、 -C(O)-N(R₁₁ )-(L₂ )_m -N(R'₁₁ )(R"₁₁ )(

)；In another preferred example, R ₅ is selected from cyano, aldehyde, R ₈ C(O)-(

), C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L ₁ ) _p -(C1-C6 alkoxy), -C(O)OR ₈ (

), -(L ₁ ) _p -N(R ₉ )(R' ₉ )(

), -C(O)-N(R ₁₀ )(R' ₁₀ )(

), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ )(

);

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyanide, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen , C1-C6 alkyl;

)、羥基、3-8員雜烷基、3-8員雜環基、5-10雜芳基，其中，R₁₂ 和R'₁₂ 各自獨立地選自：C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R ₉ and R' ₉ are each independently selected from cyano, aldehyde, C1-C6 alkyl, -NR ₁₂ R' ₁₂ (

), hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, 5-10 heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1 -C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

)，其中，所述R_f 和R_g 各自獨立地選自H、C1-C6烷基、鹵素、氰基、羥基、胺基；L ₁ and L ₂ are each independently -CR _f R _g -(

), wherein, the R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

m and p are each independently 1, 2, 3, 4, 5 or 6.

In another preferred example, each R ₂ is independently selected from halogen, cyano, nitro, C1-C6 alkyl, and halogenated C1-C6 alkyl.

_In another preferred example, _R3 and R4 are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.

In another preference, the compound of formula I has a structure shown in formula I":

In the formula,

Rc is selected from substituted or unsubstituted C1-C6 alkyl, said substitution refers to being substituted by one or more groups selected from halogen, cyano, and hydroxyl;

X is selected from halogen, cyano, nitro, halogenated C1-C6 alkyl;

R ₅ is as defined above.

、

。 _In another preferred embodiment, R is selected from

,

.

)，其中，R₈ 選自甲基、乙基、異丙基、第三丁基。In another preferred embodiment, R ₅ is -C(O)OR ₈ (

), wherein, R _is selected from methyl, ethyl, isopropyl, tertiary butyl.

)，其中，p為1、2、3；R₉ 和R'₉ 的定義如上所述。In another preferred example, R ₅ is -(L ₁ ) _p -N(R ₉ )(R' ₉ ) (

), wherein, p is 1,2,3; R ₉ and R' ₉ are as defined above.

)，其中，R₁₀ 和R'₁₀ 各自獨立地選自H、甲基、乙基、異丙基、第三丁基、C3-C6環烷基（如環丙基、環丁基、環戊基、環己基）、3-6員雜環烷烴（如四氫呋喃基、四氫吡咯基、嗎啉基），或者R₁₀ 和R'₁₀ 與其連接的N原子一起形成5-6員雜環基。In another preferred embodiment, R ₅ is -C(O)-N(R ₁₀ )(R' ₁₀ )(

), wherein, R ₁₀ and R' ₁₀ are each independently selected from H, methyl, ethyl, isopropyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl), or R ₁₀ and R' ₁₀ form a 5-6 membered heterocyclic group together with the N atom to which they are attached.

)，其中，R'₁₁ 和R"₁₁ 各自獨立地選自H、甲基、乙基、異丙基、第三丁基、C3-C6環烷基（如環丙基、環丁基、環戊基、環己基）、3-6員雜環烷烴（如四氫呋喃基、四氫吡咯基、嗎啉基）。In another preferred example, R ₅ is -C(O)-NH-CH ₂ CH ₂ -N(R' ₁₁ )(R" ₁₁ )(

), wherein, R' ₁₁ and R" ₁₁ are each independently selected from H, methyl, ethyl, isopropyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).

In another preferred example, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are specific groups corresponding to specific compounds in the embodiments.

。In another preferred example, the compound is selected from

.

In another preferred example, the compound is selected from the compounds shown in the Examples.

The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug; and a pharmaceutical carrier or diluent.

In another preferred example, the pharmaceutical composition further includes one or more other therapeutic agents selected from aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrogenated Cortisone, dexamethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226 , STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR- 1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, offa Timomab, tositumomab, imomoumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (such as alectinib Dailaris, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapa Tini, dacomitinib, icotinib, canertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, ravatinib, cabozantinib, sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinostat, Dacilast, Teikedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206 , Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Ocatinib , linsitini b. BMS-754807, GSK1838705A, etc.).

In the third aspect of the present invention, there is provided a compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug in the preparation of treating irritable bowel syndrome, other intestinal-related diseases and and/or use in medicines for cancer.

In another preferred example, the pharmaceutically acceptable salts include but are not limited to the following groups: acetate, adipate, alginate, ascorbate, aspartate, benzoic acid Salt, Benzene Sulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphor Sulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, Glycerophosphate, Hemisulfate, Heptanoate, Hexanoate, Hydrochloride, Hydrobromide, Hydroiodide, Isethionate , lactate, maleate, methanesulfonate, naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate, phosphate, picrate , Pivalate, Propionate, Salicylate, Succinate, Sulfate, Sulfonate, Tartrate, Thiocyanate, Toluenesulfonate, Dodecanoate.

In another preferred example, the irritable bowel syndrome is diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, mixed irritable bowel syndrome, and unspecified irritable bowel syndrome.

In another preferred example, the other intestinal-related diseases are functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional gastroduodenal disease .

In another preferred example, the irritable bowel syndrome includes: diarrhea-dominant, constipation-dominant or alternating defecation patterns, functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome syndrome, chronic idiopathic constipation, and functional gastroduodenal disease.

In another preferred example, the cancer includes: bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, familial adenoma Sexual polypoid carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, Cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hepatocellular carcinoma , gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma.

In another preferred example, the cancer is non-small cell lung cancer, glioma, multiple myeloma, hepatobiliary liver cancer, medullary thyroid cancer, thyroid papillary tumor, neuroblastoma, colon cancer, squamous cell carcinoma of the head and neck Stem cell carcinoma, pancreatic cancer, sarcoma, melanoma, fibrosarcoma, pancreatic tumor, soft tissue sarcoma, high-solid tumor, breast tumor, or cholangiocarcinoma.

The fourth aspect of the present invention provides the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug in the preparation of treatment of neurodegenerative diseases, chronic pain, acute pain, inflammatory Use in medicine for diseases, inflammatory bowel disease, Trypanosoma cruzi infection or diseases associated with imbalances in the regulation of bone remodeling.

。The fifth aspect of the present invention provides a kind of GSK-3179106 and/or BOS-589, or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug in the preparation of treatment of neurodegenerative diseases, chronic pain, acute Use in medicine for pain, inflammatory diseases, inflammatory bowel disease, Trypanosoma cruzi infection or diseases associated with an imbalance in the regulation of bone remodeling;

.

The sixth aspect of the present invention provides the compound described in the first aspect or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug, or the pharmaceutical composition described in the second aspect in preparation for Use in a medicament for inhibiting RET kinase and/or TRK kinase activity in a cell or a subject.

In the seventh aspect of the present invention, there is provided a kind of GSK-3179106 and/or BOS-589, or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug in the preparation for inhibiting cell or subject Use in medicines for RET kinase and/or TRK kinase activity.

The eighth aspect of the present invention provides a method for treating RET and/or TRK-related diseases, the method comprising administering a therapeutically effective amount of the RET and/or TRK-related diseases to a subject identified or diagnosed as described in the first aspect The compound or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug, the pharmaceutical composition as described in the second aspect, GSK-3179106 or its pharmaceutically acceptable salt, hydrate, Solvate, isotope compound or prodrug, or BOS-589 or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug.

In the ninth aspect of the present invention, there is provided a method for inhibiting RET and/or TRK kinase activity in a cell or a subject, the method comprising contacting the cell or administering to the subject the method described in the first aspect. The compound or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug, the pharmaceutical composition described in the second aspect, GSK-3179106 or its pharmaceutically acceptable salt, hydrate, solvate , an isotope compound or a prodrug, or BOS-589 or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof.

In another preferred embodiment, the cells are mammalian cells.

In another preferred example, the subject is a mammal, preferably a human.

M               N                               AIn the tenth aspect of the present invention, there is provided a method for preparing the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof, comprising the steps of:

M N A

A                             I1) reacting the compound of formula M with the compound of formula N to obtain the compound of formula A;

A I

2) reacting the compound of formula A with an acid to obtain the compound of formula I;

Wherein, Y is selected from OH, halogen;

Other groups are as defined in the first aspect.

In the eleventh aspect of the present invention, there is provided a method for preparing a compound of formula 1-2, comprising the steps of:

Compound 1-1 is slowly added with concentrated nitric acid or fuming nitric acid for nitration under the condition of concentrated sulfuric acid to obtain compound 1-2, R _b , n" are as defined in the first aspect.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

After extensive and in-depth research, the present inventors unexpectedly discovered a class of SF5-substituted pyridone compounds that have better RET and TRK kinase inhibitory activity, and have better selectivity for VEGFR2 kinase. In addition, the compounds have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been accomplished.

the term

In the present invention, unless otherwise specified, the terms used have the usual meanings known to those skilled in the art.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (ie, C1-C6 means one to six carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, s-butyl, n-pentyl, n-hexyl, and the like base. One or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.

The term "C1-C6 alkoxy" by itself or as part of another substituent means a straight or branched or cyclic alkoxy group having 1 to 6 carbon atoms (such as C3-C6 cycloalkoxy) , representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preference is given to C1-C3 alkoxy.

The term "heteroalkyl" by itself or as part of another substituent means a group in which the carbon atoms in the alkyl group are replaced by 1, 2, 3 heteroatoms selected from N, O, S, Si or P, And wherein, nitrogen and sulfur atoms are optionally oxidized, "3-8 membered heteroalkyl" in the present invention refers to containing 1-6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms, and A group of 1 or 2 heteroatoms selected from N, O, S or P, representative examples include (but are not limited to): CH ₃ OCH ₂ -, CH ₃ SCH ₂ -, CH ₃ CH ₂ OCH ₂ -Wait.

The term "cycloalkyl" by itself or as part of another substituent refers to cyclic alkyl groups including saturated monocyclic, bicyclic or polycyclic, eg C3-C8 or C3-C12 cycloalkyl. C3-C8 cycloalkyl refers to C3, C4, C5, C6, C7, or C8 cycloalkyl. Cycloalkyl groups may also include cycloalkyl groups with structures such as spiro rings, bridged rings, and parallel rings. Representative cycloalkyl groups of the invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. It is to be understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included within the definition of "cycloalkyl".

The term "cycloheteroalkyl" by itself or as part of another substituent means having the specified number of ring vertices (or members) and having one to five heteroatoms selected from N, O, and S replacing carbons in the ring backbone respectively. atom, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized cycloalkyl ring. Cycloheteroalkyl groups are typically 4-12 membered rings. Cycloheteroalkyl groups can be monocyclic, bicyclic or polycyclic ring systems. Examples of cycloheteroalkyl groups include, but are not limited to: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, butyrolactamyl, valerolactylamide, imidazolidinonyl, hydantoinyl, dioxalactyl Cyclopentyl, phthalimino, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thio Morpholine-S, S-oxide, piperyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyranone, tetrahydrofuryl, tetrahydrothiophenyl, quinuclidinyl, and analog.

The term "alkenyl" by itself or as part of another substituent denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms (or C2-C8). For example, in the present invention, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 15 ring members , a bicyclic or tricyclic ring system (preferably a 6-10 membered aromatic ring), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "Aryl" can be substituted or unsubstituted. In certain embodiments of the invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Connecting lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom.

The term "heteroaryl" by itself or as part of another substituent refers to a heteroaromatic system containing 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5 to 10 membered ring, more preferably 5 or 6 membered, e.g. pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, triazolyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amine, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, Cycloalkylthio, oxo, carboxyl and carboxylate groups.

Preferably, each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S.

基。本發明還包括含有例如上述雜環的稠環和螺環化合物。The term "heterocycle", "heterocyclyl" or "heterocyclic group" by itself or as part of another substituent refers to a stable 3-membered, 4-membered, 5-membered, or 7-membered monocyclic or bicyclic or 7-membered membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered polycyclic heterocyclic rings, including fused, spiro and/or bridged ring structures, which are saturated, partially unsaturated or is fully unsaturated and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by fusing heterocycles with aromatic rings, such as benzene rings. A "heterocycle" can be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuryl, benzothienyl, benzoxazole benzothiazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisozozolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4a H -carbazolyl, carbolinyl, 𠳭yl, 𠳭alkenyl, cinnolinyl, decahydroquinolyl, 2 H , 6 H -1,5,2-dithia thiol, dihydrofuro[2 ,3- b ]tetrahydrofuryl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H -indazolyl, imidazopyridyl, indolenyl, indoline Indolyl, indolyl, indolyl, 3 H -indolyl, isatinoyl, isobenzofuryl, isoindolyl, isoindazolyl, isoindolinyl, isoindole Base, isoquinolyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthyl, octahydro Isoquinolyl, Odiazolyl, 1,2,3-Odiazolyl, 1,2,4-Odiazolyl, 1,2,5-Odiazolyl, 1,3,4-Odiazolyl Oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, perylenediazaphenyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, Phenenyl, phenothienyl, phenethiyl, phenetyl, phthaloyl, piperyl, piperidinyl, piperidinonyl, 4-piperidinonyl, piperonyl, pteridinyl, Purinyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl , pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinyl, 2 H -pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4 H -quinoline, quinolinyl, Quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6 H -1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thieno Thiazolyl, thienozozolyl, thienoimidazolyl, thienyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl , 1,3,4-triazolyl and 𠮿

base. The present invention also includes fused ring and spiro compounds containing, for example, the aforementioned heterocycles.

Preferably, each "3-6 membered heterocyclic group" is a 3-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S. The terms "4-8 membered heterocyclyl", "3-6 membered cycloheteroalkyl", "3-8 membered heterocyclyl", "4-8 membered cycloheteroyl", "C3-C6 cycloheteroalkyl " has a similar meaning.

The term "C4-C8 cycloalkenyl" refers to a cyclic 4-8 membered ring containing 1, 2 or 3 ethylenic bonds. In the present invention, each group in the above-mentioned alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclyl, etc. Can be substituted or unsubstituted.

)、-NR_b S(=O)₂ R_e (

)、-NR_b P(=O)₂ R_e (

)、-S(=O)₂ NR_b R_c (

)、-P(=O)₂ NR_b R_c (

)、-C(=O)OR_d (

)、-C(=O)R_a (

)、-C(=O)NR_b R_c (

)、-OC(=O)R_a (

)、-OC(=O)NR_b R_c (

)、-NR_b C(=O)OR_e (

)、-NR_d C(=O)NR_b R_c (

)、-NR_d S(=O)₂ NR_b R_c (

)、-NR_d P(=O)₂ NR_b R_c (

)、-NR_b C(=O)R_a (

)、或-NR_b P(=O)₂ R_e (

)，其中，R_a 可以獨立表示氫、氘、烷基、環烷基、烯基、炔基、雜環或芳環，R_b 、R_c 和R_d 可以獨立表示氫、氘、烷基、環烷基、雜環或芳環，或者R_b 和R_c 與N原子一起可以形成雜環；R_e 可以獨立表示氫、烷基、環烷基、烯基、炔基、雜環或芳環。上述典型的取代基，如烷基、環烷基、烯基、環烯基、炔基、雜環或芳環可以任選取代。所述取代基例如(但並不限於)：鹵素、羥基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8環烷基、3-12員雜環基、芳基、雜芳基、C1-C8醛基、C2-C10醯基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺醯基、及C1-C6脲基等。In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or _Cl3 containing alkyl), nitrile Base, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, -OR _a , -SR _a , -S (=O)R _e , -S(=O) ₂ R _e , -P(=O) ₂ R _e , -S(=O) ₂ OR _e , -P(=O) ₂ OR _e , -NR _b R _c (

), -NR _b S(=O) ₂ R _e (

), -NR _b P(=O) ₂ R _e (

), -S(=O) ₂ NR _b R _c (

), -P(=O) ₂ NR _b R _c (

), -C(=O)OR _d (

), -C(=O)R _a (

), -C(=O)NR _b R _c (

), -OC(=O)R _a (

), -OC(=O)NR _b R _c (

), -NR _b C(=O)OR _e (

), -NR _d C(=O)NR _b R _c (

), -NR _d S(=O) ₂ NR _b R _c (

), -NR _d P(=O) ₂ NR _b R _c (

), -NR _b C(=O)R _a (

), or -NR _b P(=O) ₂ R _e (

), wherein, R _a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, heterocycle or aromatic ring, or R _b and R _c together with N atoms can form a heterocycle; _Re can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring . The typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic rings may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, And C1-C6 ureido group, etc.

Unless otherwise stated, it is assumed that any heteroatom with a dissatisfied valence has sufficient hydrogen atoms to fill its valence.

When the substituent is a non-terminal substituent, it is the subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to Alkyleneoxy, etc.

The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.

The term "PMB" refers to p-methoxybenzyl.

The term "aldehyde group" has the structure -CHO.

active ingredient

As used herein, the term "compound of the present invention" or "active ingredient of the present invention" is used interchangeably and refers to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound (such as a deuterated compound) ) or prodrugs. The term also includes racemates, optical isomers.

In the present invention, the compound of formula I has the following structure:

In the formula,

R ₁ , R ₂ , R ₅ , R _b , n, r, n' and n" are as defined above.

Preferably, the compound of formula I has a structure shown in formula I':

In the formula, the definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are as above.

Preferably, in formula I and formula I', R ₁ is selected from C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.

)、-(L₁ )_p -N(R₉ )(R'₉ ) (

)、-C(O)-N(R₁₀ )(R'₁₀ )(

)、-C(O)-N(R₁₁ )-(L₂ )_m -N(R'₁₁ )(R"₁₁ )(

)；Preferably, in formula I and _formula I', R is selected from cyano, aldehyde, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkyl-OH , C2-C6 alkenyl, C2-C6 alkynyl, -C(O)OR ₈ (

), -(L ₁ ) _p -N(R ₉ )(R' ₉ ) (

), -C(O)-N(R ₁₀ )(R' ₁₀ )(

), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ )(

);

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

)、羥基、3-8員雜烷基、3-8員雜環基、5-10雜芳基，其中，R₁₂ 和R'₁₂ 各自獨立地選自：C1-C6烷基、鹵代C1-C6烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6環雜烷基；R ₉ and R' ₉ are each independently selected from: cyano, aldehyde, -NR ₁₂ R' ₁₂ (

), hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, 5-10 heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1 -C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

)，其中，所述R_f 和R_g 各自獨立地選自H、C1-C6烷基、鹵素、氰基、羥基、胺基；L ₁ and L ₂ are each independently -CR _f R _g -(

), wherein, the R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

m and p are each independently 1, 2, 3, 4, 5 or 6.

Preferably, in formula I and formula I', each R ₂ is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.

Preferably, the compound of formula I has a structure shown in formula I":

In the formula,

Rc is selected from substituted or unsubstituted C1-C6 alkyl, said substitution refers to being substituted by one or more halogen, cyano, hydroxyl;

X is selected from halogen, cyano, nitro, halogenated C1-C6 alkyl;

R ₅ is as defined above.

、

。Preferably, in _formula I, I', I", R is selected from

,

.

)，其中，R₈ 選自甲基、乙基、異丙基、第三丁基。Preferably, in formula I, I', I", R ₅ is -C(O)OR ₈ (

), wherein, R _is selected from methyl, ethyl, isopropyl, tertiary butyl.

)，其中，p為1、2、3；R₉ 和R'₉ 的定義如上所述。Preferably, in formula I, I', I", R ₅ is -(L ₁ ) _p -N(R ₉ )(R' ₉ ) (

), wherein, p is 1,2,3; R ₉ and R' ₉ are as defined above.

)，其中，R₁₀ 和R'₁₀ 各自獨立地選自H、甲基、乙基、異丙基、第三丁基、C3-C6環烷基（如環丙基、環丁基、環戊基、環己基）、3-6員雜環烷烴（如四氫呋喃基、四氫吡咯基、嗎啉基），或者R₁₀ 和R'₁₀ 與其連接的N原子一起形成5-6員雜環基。Preferably, in formula I, I', I", R ₅ is -C(O)-N(R ₁₀ )(R' ₁₀ ) (

), wherein, R ₁₀ and R' ₁₀ are each independently selected from H, methyl, ethyl, isopropyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl), or R ₁₀ and R' ₁₀ form a 5-6 membered heterocyclic group together with the N atom to which they are attached.

)，其中，R'₁₁ 和R"₁₁ 各自獨立地選自H、甲基、乙基、異丙基、第三丁基、C3-C6環烷基（如環丙基、環丁基、環戊基、環己基）、3-6員雜環烷烴（如四氫呋喃基、四氫吡咯基、嗎啉基）。Preferably, in formula I, I', I", R ₅ is -C(O)-NH-CH ₂ CH ₂ -N(R' ₁₁ )(R" ₁₁ )(

), wherein, R' ₁₁ and R" ₁₁ are each independently selected from H, methyl, ethyl, isopropyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl), 3-6 membered heterocycloalkanes (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).

Typically, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug thereof;

In the formula,

Each R1 is independently selected from the group consisting _of substituted or unsubstituted groups: H, halogen, hydroxyl, amino, C1-C6 alkyl, R'-O-, C3-C6 cycloalkyl, C6-C10 aryl , 5-10 membered heteroaryl, R'NH- or R'R"N-;

R', R" are independently selected from the following groups of substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C10 aryl, 5-10 membered Heteroaryl, the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, C1-C6 alkyl;

Or when two R ₁ are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;

Each R ₂ is independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, hydroxyl, amino, cyano, nitro, R ₈ C(O)O-, R ₈ C(O)-, R ₈ S(O) ₂ , C1-C6 alkyl, C3-C6 cycloalkyl;

Or when two R ₂ are connected to two adjacent atoms on the ring, they can be fused to form substituted or unsubstituted following groups: C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6- C10 aryl, 5-10 membered heteroaryl;

Each R _b is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amine, cyano, nitro, R ₈ C(O)O-, R ₈ C(O)-, R ₈ S(O ) ₂ , C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR ₆ , -CONR ₇ R' ₇ , Wherein, the substitution refers to being substituted by one or more R _a :

Each R _a is independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or -NR ₇ R'₇;

R ₆ , R ₇ and R' ₇ are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 members Cycloheteroalkyl;

R ₅ is selected from the group consisting of substituted or unsubstituted groups: -H, -CN, -CHO, nitro, R ₈ C(O)-, R ₈ S(O) ₂ , -NH ₂ , -OH, halogen , C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, - C(O)OR ₈ , -(L ₁ ) _p -N(R ₉ )(R' ₉ ), -C(O)-N(R ₁₀ )(R' ₁₀ ), -C(O)-N( R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ );

Or when R _b and R ₅ are located at two adjacent C atoms, the C atoms connected to them are fused to form the following groups of substituted or unsubstituted groups: C4-C8 cycloalkenyl, 4-8 membered cycloheteroyl, C6 -C10 aryl, 5-10 membered heteroaryl;

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from substituted or unsubstituted groups from the following groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution refers to being substituted by one or more groups selected from the group: halogen, Hydroxy, C1-C6 alkyl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which it is connected;

Or R' ₁₁ and R " ₁₁ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to;

R ₉ and R' ₉ are each independently selected from the following substituted or unsubstituted groups: H, -CN, -CHO, -NR ₁₂ R' ₁₂ , -OH, 3-8-membered heteroalkyl, 3-8-membered Heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy Base, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom to which they are attached;

Unless otherwise specified, the substitution refers to substitution by one or more R;

Each R is independently selected from: halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

Each L ₁ and L ₂ are independently selected from: -CR _f R _g -, CO, SO ₂ ; wherein, R _f and R _g are each independently selected from the following group: H, C1-C6 alkyl, halogen, cyano , hydroxyl, amino;

r is 1, 2 or 3;

m and p are each independently 1, 2, 3, 4, 5 or 6;

n is 0, 1 or 2;

n' is 0, 1, 2 or 3;

n" is 0, 1, 2 or 3.

部分選自：

、

、

、

，其中，

為單鍵或雙鍵；q為0、1、2；X₁ 和X₂ 各自獨立地選自：NH、O、S或CH₂ ；X₃ 和X₄ 各自獨立地選自：N或CH；R₁ 的定義如上所述。In another preferred example,

Some selected from:

,

,

,

,in,

is a single bond or a double bond; q is 0, 1, 2; X ₁ and X ₂ are each independently selected from: NH, O, S or CH ₂ ; X ₃ and X ₄ are each independently selected from: N or CH; R ₁ is defined as above.

In another preferred example, the compound of formula I or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound or prodrug has the structure shown in formula I':

In the formula,

R1 is selected from: H, halogen, hydroxyl, amino, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl , halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH- or (C1-C6 alkyl) (C1-C6 alkane Base) N-;

Each R is independently selected from: H, halogen, hydroxyl, amino, cyano, nitro, C1 _- C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 ring alkyl;

R ₃ and R ₄ are each independently selected from: H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cyclohetero Alkyl, C6-C10 aryl, 5-10 membered heteroaryl, -OR ₆ , -CONR ₇ R' ₇ , wherein the C1-C6 alkyl is optionally selected from one or more of the following group Group substitution: cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy and -NR ₇ R' ₇ , the C6-C10 aryl or 5-10 membered heteroaryl is optionally Substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

R ₆ , R ₇ and R' ₇ are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 Member cycloheteroalkyl;

R ₅ is selected from: -H, -CN, -CHO, -NH ₂ , -OH, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkyl -OH, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)OR ₈ , -(L ₁ ) _p -N(R ₉ )( R' ₉ ), -C(O)-N(R ₁₀ )(R' ₁₀ ), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ );

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

R ₉ and R' ₉ are each independently selected from: -CN, -CHO, -NR ₁₂ R' ₁₂ , -OH, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10-membered heteroaryl , wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

L ₁ and L ₂ are each independently -CR _f R _g -, wherein each of said R _f and R _g is independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

n is 0, 1 or 2;

m and p are each independently 1, 2, 3, 4, 5 or 6.

In another preferred example, R ₁ is selected from: C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.

In another preferred example, R ₅ is selected from: -CN, -CHO, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkyl-OH, C2- C6 alkenyl, C2-C6 alkynyl, -C(O)OR ₈ , -(L ₁ ) _p -N(R ₉ )(R' ₉ ), -C(O)-N(R ₁₀ )(R' ₁₀ ), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ );

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl;

Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

R ₉ and R' ₉ are each independently selected from: -CN, -CHO, -NR ₁₂ R' ₁₂ , -OH, 3-8-membered heteroalkyl, 3-8-membered heterocyclyl, 5-10-membered heteroaryl , wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl ;

Or R ₉ and R' ₉ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom they are connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, Cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

L ₁ and L ₂ are each independently -CR _f R _g -, wherein each of said R _f and R _g is independently selected from: H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino;

m and p are each independently 1, 2, 3, 4, 5 or 6.

In another preferred example, "-(L ₁ ) _p -" and "-(L ₂ ) _m -" are -CH ₂ CH ₂ -.

In another preferred example, m is 1, 2, 3 or 4.

In another preferred example, p is 1, 2, 3 or 4.

In another preferred example, each R ₂ is independently selected from: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl.

_In another preferred example, _R3 and R4 are each independently selected from: H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl.

In another preference, the compound of formula I has a structure shown in formula I":

In the formula,

Rc is selected from substituted or unsubstituted C1-C6 alkyl, said substitution refers to being substituted by one or more halogen, cyano, hydroxyl;

X is selected from: halogen, cyano, nitro, halogenated C1-C6 alkyl;

R ₅ is as defined above.

、

。 _In another preference, R is selected from:

,

.

In another preferred example, R ₅ is -C(O)OR ₈ , wherein R ₈ is selected from: methyl, ethyl, isopropyl, and tert-butyl.

In another preferred example, R ₅ is -(L ₁ ) _p -N(R ₉ )(R' ₉ ), wherein p is 1, 2, or 3; the definitions of R ₉ and R' ₉ are as above.

In another preferred example, R ₅ is -C(O)-N(R ₁₀ )(R' ₁₀ ), wherein R ₁₀ and R' ₁₀ are each independently selected from: H, methyl, ethyl, iso Propyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuryl, tetrahydropyrrolyl, Linyl), or R ₁₀ and R' ₁₀ form a 5-6 membered heterocyclic group together with the N atom to which they are attached.

In another preferred example, R ₅ is -C(O)-NH-CH ₂ CH ₂ -N(R' ₁₁ )(R" ₁₁ ), wherein R' ₁₁ and R" ₁₁ are each independently selected from: H, methyl, ethyl, isopropyl, tertiary butyl, C3-C6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3-6 membered heterocycloalkane (such as tetrahydrofuranyl, tetrahydropyrrolyl, morpholinyl).

In another preferred example, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are specific groups corresponding to specific compounds in the embodiments.

The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise stated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when a compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may be formed are contained in within the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation. The compound of the present invention may form a salt, for example, compound I reacts with a certain amount, such as an equivalent amount of acid or base, and salts it out in a medium, or freeze-dries it in an aqueous solution.

Basic moieties contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids from which salts can be formed include acetate (e.g. with acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzoate Sulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphor Sulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethane Sulfonate salt, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, isethionate (eg, 2-Hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectin salts, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoate, etc.

Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, Hipamine (salt with N,N -di(dehydroabietyl)ethylenediamine), N -methyl-D-glucosamine, N -methyl-D-glucosamide, butyl Base amines, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenyl bromides) and the like.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.

Another preferred class of salts are the salts of the compounds of the invention with bases, such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g. lower alkanolammonium salts) and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tributylamine salts, amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperamide, and lysine, respectively.

The term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a specific ratio. "Hydrate" refers to a complex formed by coordination between the compound of the present invention and water.

Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" here refers to a compound that undergoes metabolic or chemical transformation during the treatment of related diseases to produce the compound, salt, or solvate of the present invention. The compounds of the present invention include solvates, such as hydrates.

Compounds, salts or solvates of the present invention, possible tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

Stereoisomers of all compounds (for example, those due to possible asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated by the present invention. The individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (for example, as a pure or substantially pure optical isomer having a specific activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or parts thereof. The chiral center of the present invention has two configurations of S or R, which are defined by the 1974 proposal of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic forms can be resolved by physical methods such as fractional crystallization, or by derivatization into diastereoisomers, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods such as salt formation with optically active acids followed by crystallization.

The compound in the present invention, the weight content of the compound obtained by preparation, separation and purification in sequence is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the main text listed. Such "very pure" compounds of the invention are also included herein as part of the invention.

All configurational isomers of the compounds of the invention are contemplated, whether in admixture, pure or very pure form. The definitions of the compounds of the present invention include both cis ( Z ) and trans ( E ) olefinic isomers, as well as carbocyclic and heterocyclic cis and trans isomers.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Definitions of specific functional groups and chemical terms are detailed below. For purposes of this invention, the chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , 75 ^th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.

Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic spin mixtures and other mixtures. Alternatively an asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers, as well as mixtures thereof, are included in the present invention.

According to the present invention, the mixture of isomers may contain various ratios of isomers. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, readily understood by one of ordinary skill in the art, are also within the scope of the invention.

The invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs. Examples of isotopes that may be included in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as ³ H and ¹⁴ C radioactive isotopes, are useful in tissue distribution assays for drugs and substrates. Tritium, namely ³ H, and carbon-14, namely ¹⁴ C, are relatively easy to prepare and detect. is the first choice among isotopes. In addition, substitution of heavier isotopes such as deuterium, ie ² H, may be preferred in some cases due to its good metabolic stability, which has advantages in certain therapies, such as increased half-life in vivo or reduced dosage. Isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the protocols disclosed in the Examples.

If the synthesis of a specific enantiomer of a compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereoisomeric salt can be formed with a suitable optically active acid or base, and then crystallized by separation or The pure enantiomers are then obtained by separation by conventional means such as chromatography.

As described herein, the compounds of the present invention may be supplemented with any number of substituents or functional groups to extend their scope. Generally, whether the term "substitution" appears before or after the term "optional", the general formula including the substituent in the formula of the present invention means that the hydrogen radical is replaced by the specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, the substituents may be the same or different for each position. The term "substitution" as used herein includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence. Furthermore, this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted. Combinations of substituents and variables are considered by the present invention to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.

The metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, as well as the prodrugs that can be transformed into the structures of the compounds involved in the application and their pharmaceutically acceptable salts in vivo, are also included in the patent application of the application in range.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: irritable bowel syndrome and/or cancer.

The compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases. In the case of combined administration, the administration method and dosage of the original drug can be kept unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken together with one or several other drugs, the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used. Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time. When the compound of formula I is used in combination with one or several other drugs, the dosage of the compound of formula I or known drugs may be lower than that of their single administration.

Drugs or active ingredients that can be combined with the compound described in general formula (I) include but are not limited to: aminosalicylic acid preparations (such as sulfasalazine), glucocorticoids (such as hydrocortisone, Semethasone, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333 , JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, simotumumab, icomomab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR -1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), PI3K inhibitors (such as Idelaris, Dactolisib , Taselisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dac Icotinib, Icotinib, Canertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Ravatinib, Cabozantinib, Sunitinib, Donafenib, etc. ), HDAC inhibitors (such as Givinostat, Droxinostat, entinostat, dalcylast, tecdinaline, etc.), CDK inhibitors (such as palbociclib, ribociclib, Abemaciclib, Lerociclib, etc.), MEK Inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, ocatinib, linsitinib, BMS -754807, GSK1838705A, etc.) or any combination of them.

The dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled release type, sustained release type or nanometer preparation .

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moisturizers Wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or extenders, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as, Glycerin; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents such as paraffin; (f) absorption acceleration (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, stearic acid Calcium, magnesium stearate, polyethylene glycol solid, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered. For a person with a body weight of 60 kg, The daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention compounds are mixed to form a pharmaceutical composition.

The present invention also provides a treatment method, which includes the steps of: administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting RET.

Preparation

Methods of preparing compounds of Formula I are described in the following Schemes and Examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise illustrated. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products.

The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.

Usually, in the preparation process, each reaction is usually carried out in an appropriate solvent under the protection of an inert gas at a temperature of 0 to 90° C., and the reaction time is usually 2-24 hours.

Preferably, the preparation method of the compound of formula I of the present invention comprises the following steps:

(s1) Compound 1-1 is slowly added dropwise with concentrated nitric acid or fuming nitric acid under the condition of concentrated sulfuric acid for nitration reaction to obtain compound 1-2;

(s2) compound 1-2 undergoes functional group conversion and reduction steps to obtain compound I1;

(s3) Compound 2-1 reacts in an inert solvent under basic conditions to generate Compound 2-2;

(s4) compound 2-2 generates compound I2 through coupling and other reactions;

(s5) In an inert solvent, in the presence of a catalyst, the compound of formula I1 and formula I2 reacts to obtain the compound of formula 3-1;

(s6) In an inert solvent, under acidic conditions, the compound of formula 3-1 reacts to obtain the compound of formula I;

In the formula, Y is selected from OH and halogen;

R ₁ , R ₂ , R ₅ , R _b , r, n, n' and n" are as defined above.

Preferably, in steps (s3), (s5), and (s6), the inert solvent is pyridine, DMF, DMSO, triethylamine, DCM, 1,2-dichloroethane, tetrahydrofuran, 1,6- Dioxane.

Preferably, in step (s5), the catalyst is propylphosphoric anhydride (T ₃ P).

Preferably, in step (s6), the acid is TFA.

Preferably, the compounds of the present invention can be obtained by the following steps:

In the formula, the definitions of R ₁ and R ₅ are as above;

)；Preferably, R ₁ is -O-R'(

);

)、-C(O)-N(R₁₁ )-(L₂ )_m -N(R'₁₁ )(R"₁₁ )(

)。Preferably, R ₅ is selected from -C(O)-N(R ₁₀ )(R' ₁₀ )(

), -C(O)-N(R ₁₁ )-(L ₂ ) _m -N(R' ₁₁ )(R" ₁₁ )(

).

(i) under the condition of concentrated sulfuric acid, slowly add concentrated nitric acid or fuming nitric acid for nitration reaction to obtain compound 2;

(ii) Acid is converted to acyl chloride by the action of phosphide chloride or oxalyl chloride and a catalyst (for example, DMF). Under alkaline (for example, Et ₃ N, DIEA) conditions, acyl chloride and amine rapidly react to form compound 3 ;

(iii) Under acidic (for example: HCl) conditions, iron reduces the nitro group to obtain compound 4;

(iv) Under basic conditions (such as potassium carbonate), compound 5 reacts with iodoalkyl to generate compound 6;

(v) Under alkaline conditions (such as potassium hydroxide), compound 6 reacts with p-methoxyphenylcarbinol to generate compound 7;

(vi) Under basic conditions (such as cesium carbonate), compound 7 and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborine Pentan-2-yl) phenyl) methyl acetate is coupled to generate compound 8;

(vii) Under alkaline conditions (such as lithium hydroxide), compound 8 is demethylated to generate compound 9;

(viii) Under basic (for example, pyridine) and acid anhydride conditions, compound 4 and compound 9 are condensed to form an amide to generate compound 10;

(ix) Compound 10 is removed from benzyloxy group under acidic (eg TFA) conditions to finally obtain Compound 11;

In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.

In the above reaction steps, the reaction raw materials and reagents can be synthesized through commercially available or literature-reported routes.

The present invention has the following main advantages:

(1) The compound of the present invention has excellent inhibitory ability to RET kinase, and has excellent selectivity to RET kinase, and has low inhibitory activity to other kinases such as VEGFR2;

(2) The compound of the present invention has excellent inhibitory ability to TRK kinase, and has stronger inhibitory ability to mutant TRK kinase;

(3) Some compounds in the present invention have better cytostatic activity, and show better pharmacodynamic effects in the IBS model (acetic acid-induced intestinal hypersensitivity model).

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass chromatography (LC-MS).

NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the determination solvents included deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).

Liquid chromatography-mass chromatography (LC-MS) was detected using an Agilent 1260 mass spectrometer. Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100 × 3.0 mm) was used for HPLC determination, and 0.4 mm-0.5 mm was used for preparative thin-layer chromatography. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are all known and commercially available, or can be adopted or synthesized according to literatures reported in the art.

Unless otherwise specified, all reactions in the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.

The following abbreviations are used throughout this specification

THF: Tetrahydrofuran

DCM: dichloromethane

Fe: iron powder

H ₂ SO ₄ : sulfuric acid

HNO ₃ : nitric acid

SOCl ₂ : Phosphorus chloride

HCl: hydrochloric acid

_H2O : water

TEA: Triethylamine

DIEA: N , N -Diisopropylethylamine

DMF: N , N -Dimethylformamide

Cs ₂ CO ₃ : cesium carbonate

LiOH: lithium hydroxide

EA: ethyl acetate

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

T ₃ P: Propyl phosphoric anhydride

Synthesis of intermediate 1 3- nitro-5-( pentafluorothio) benzoic acid

Add 3-(pentafluorothio)benzoic acid (1.0 g, 4.03 mmol) into a single-necked flask, then slowly add concentrated sulfuric acid (12 mL), stir the mixture and cool it down to 0°C, then slowly add concentrated nitric acid (2 mL), stirred for 10 minutes, then heated to 80°C for 12 h, after the reaction was complete, cooled, the reaction solution was slowly poured into ice water, extracted with EA, the organic phase was neutralized with saturated sodium bicarbonate, dried, and filtered , and concentrated to obtain 0.9 g of 3-nitro-5-(pentafluorothio)benzoic acid.

Synthesis of intermediate 2 3- amino- N- (2-( dimethylamino) ethyl)-5-( pentafluorothio) benzamide

step 1 Synthesis of N -(2-( Dimethylamino) Ethyl)-3- Nitro-5-( Pentafluorothio) benzamide

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (0.5 g, 1.71 mmol) in SOCl ₂ (10 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete For the reaction solution, dissolve acyl chloride in DCM (15 mL), cool the mixture to 0 °C, then add triethylamine (0.52 g, 5.12 mmol), then add N , N -dimethylethylenediamine (0.23 g, 2.56 mmol), continue the reaction at 0°C for half an hour, after the reaction is complete, add water to quench the reaction, separate the liquids, concentrate the organic phase, and obtain N- (2-(dimethylamino)ethyl )-3-nitro-5-(pentafluorothio)benzamide 0.55 g, MS m/z (ESI): 363.3[M+H] ⁺ .

step 2 Synthetic 3- Amino- N -(2-( Dimethylamino) Ethyl)-5-( Pentafluorothio) benzamide

Add N- (2-(dimethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.5 g, 1.38 mmol) into methanol (10 mL), Iron powder (1.5 g) was added, and then hydrochloric acid (1 mL, 12 mol/L) was slowly added, and the mixture was stirred and reacted at 72°C for 2 hours. After monitoring the completion of the reaction, it was cooled, filtered with suction, and the reaction solution was spin-dried. Column chromatography gave 0.38 g of 3-amino- N- (2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide, MS m/z (ESI): 333.9[ M+H] ⁺ .

Synthesis of Intermediate 3 2-(4-(4- ethoxy-6-((4 -methoxybenzyl) oxy) pyridin -3 -yl)-2- fluorophenyl) acetic acid

step 1 Synthetic 5- Bromo-4- Ethoxy-2 ((4- Methoxybenzyl)oxy)pyridine

Add (4-methoxyphenyl)methanol (1.75 g , 12.7 mmol), KOH (1.2 g, 21.2 mmol) and 18-crown-6 (0.28 g, 1.06 mmol), the mixture was reacted at 120°C for 3 hours, after the reaction was complete, the reaction solution was spin-dried, and water (15 mL), and then extracted with EA (30 mL*2), the organic phase was dried, spin-dried, and column chromatographed to obtain 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy ) pyridine 3.0 g. MS m/z (ESI): 339.1 [M+H] ⁺ .

step 2 Synthetic 2- (4- (4- Ethoxy-6- ((4- Methoxybenzyl)oxy)pyridine-3- Base) -2- Fluorophenyl) methyl acetate

Under nitrogen protection, 5-bromo-4-ethoxy-2((4-methoxybenzyl)oxy)pyridine (1.9 g, 5.62 mmol), 2-(2-fluoro-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.82 g, 6.18 mmol), PdCl ₂ (dppf) (0.45 g, 0.56 mmol) and cesium carbonate (3.65 g, 11.2 mmol) were added to a one-necked bottle, then 1,4-dioxane (30 mL) and water (10 mL) were added, and the mixture was reacted at 95°C for 3 hours . After the reaction was complete, it was extracted with EA (40 mL*2), the organic phase was dried, spin-dried, and column chromatography gave 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy base) pyridin-3-yl)-2-fluorophenyl) methyl acetate 1.8 g. MS m/z (ESI): 426.3 [M+H] ⁺ .

step 3 Synthetic 2- (4- (4- Ethoxy-6- ((4- Methoxybenzyl)oxy)pyridine-3- Base) -2- Fluorophenyl)acetic acid

2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid methyl ester (2.4 g, 5.63 mmol ) was dissolved in THF (15 mL), and then an aqueous solution of lithium hydroxide (0.3 g, 12.4 mmol) was added to it, and the mixture was stirred and reacted at 60°C for 4 hours. After the reaction is complete, spin dry most of the organic phase, then adjust the pH to 7 with dilute hydrochloric acid, precipitate a white solid, filter with suction, wash the filter cake with water, and dry to obtain 2-(4-(4-ethoxy- 6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid 2.1 g, MS m/z (ESI): 412.2 [M+H] ⁺ .

Example 1 N- (2-( dimethylamino) ethyl)-3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl Synthesis of -2- fluorophenyl)acetamido-5-(pentafluorothio) benzamide

step 1 Synthetic N- (2- (Dimethylamino)ethyl)-3- (2- (4- (4- Ethoxy-6- ((4- Methoxybenzyl)oxy)pyridine-3- Base) -2- Fluorophenyl) acetamido) -5- (Pentafluorothio)benzamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.6 g, 1.45 mmol) was added into pyridine (5 mL), and then added 3-amino- N- (2-(dimethylamino)ethyl)-5-(pentafluorothio)benzamide (0.48 g, 1.75 mmol ) and T ₃ P (0.55 g, 1.75 mmol), the mixture was reacted at room temperature for 12 hours. After the reaction is complete, the reaction solution is directly spin-dried, and then column chromatography is obtained to obtain N- (2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4 -methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.82 g, MS m/z (ESI ): 727.5[M+H] ⁺ .

step 2 Synthesis of N -(2-( Dimethylamino) Ethyl)-3- (2- (4- (4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base-2- Fluorophenyl) acetamido-5-( Pentafluorothio) benzamide

N- (2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (0.82 g, 1.13 mmol) was dissolved in DCM (10 mL), then TFA (2 mL ), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl )-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl-2-fluorophenyl)acetamido-5-(pentafluoro Thio)benzamide (Compound 1 ) 0.48 g. MS m/z (ESI): 607.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 10.85 (s , 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.40 – 7.30 (m, 2H), 7.28 – 7.17 (m, 2H), 5.80 (s, 1H), 4.02 (dt, J = 6.8, 2.1 Hz, 4H), 3.78 (s, 2H), 2.43 (t, J = 6.5 Hz, 2H), 2.19 (s, 6H), 1.27 (t , J = 6.9 Hz, 3H).

Example 2 3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridyl-3 -yl)-2- fluorophenyl)acetamido) -N , Synthesis of N - dimethyl-5- (pentafluorothio)benzamide

step 1 synthetic N , N - Dimethyl-3- Nitro-5- (Pentafluorothio)benzamide

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (0.3 g, 1.02 mmol) in SOCl ₂ (10 mL), add a few drops of DMF, and then reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, and the acyl chloride was dissolved in DCM (10 mL), and the mixture was cooled to 0°C, then triethylamine (0.32 g, 3.07 mmol) was added, followed by dimethylamine (0.07 g, 1.56 mmol), the reaction was continued for half an hour at 0°C. After the reaction was complete, water was added to quench the reaction, the layers were separated, the organic phase was concentrated, and column chromatography gave 0.26 g of N , N -dimethyl-3-nitro-5-(pentafluorothio)benzamide. MS m/z (ESI): 321.5 [M+H] ⁺ .

step 2 Synthetic 3- Amino- N , N - Dimethyl-5- (Pentafluorothio)benzamide

Add N , N -dimethyl-3-nitro-5-(pentafluorothio)benzamide (0.26 g, 0.8 mmol) into methanol (10 mL), and then iron powder (0.8 g) , and then slowly added hydrochloric acid (1 mL, 12 mol/L), and the mixture was stirred and reacted at 72°C for 2 hours. After monitoring the completion of the reaction, cool, filter with suction, spin the reaction solution to dryness, and obtain 0.17 g of 3-amino- N , N -dimethyl-5-(pentafluorothio)benzamide through column chromatography. MS m/z (ESI): 291.1 [M+H] ⁺ .

step 3 Synthetic 3- (2- (4- (4- Ethoxy-6- ((4- Methoxybenzyl)oxy)pyridine-3- Base) -2- Fluorophenyl) acetamido) - N , N - Dimethyl-5- (Pentafluorothio)benzamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.2 g, 0.49 mmol) was added into pyridine (5 mL), and then added 3-amino- N , N -dimethyl-5-(pentafluorothio)benzamide (0.17 g, 0.58 mmol) and T ₃ P (0.19 g , 0.58 mmol), the mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction solution was directly spin-dried, and then column chromatography was used to obtain 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl) -2-fluorophenyl)acetamido) -N , N -dimethyl-5-(pentafluorothio)benzamide 0.22 g. MS m/z (ESI): 684.3 [M+H] ⁺ .

Step 4 Synthesis of 3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridyl-3 -yl)-2- fluorophenyl)acetamido) -N , N - Dimethyl-5- (pentafluorothio)benzamide 3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy) Pyridin-3-yl)-2-fluorophenyl)acetamido) -N , N -dimethyl-5-(pentafluorothio)benzamide (0.22 g, 0.32 mmol) was dissolved in DCM ( 6 mL), then TFA (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (10 mL*2), the organic phase was spin-dried, and column chromatography gave 3-(2-(4-(4-ethoxy -6-oxo-1,6-dihydropyridinyl-3-yl)-2-fluorophenyl)acetamido) -N , N -dimethyl-5-(pentafluorothio)benzyl Amide (Compound 2 ) 0.11 g. MS m/z (ESI): 564.5 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 11.39 (s, 1H), 10.76 (s, 1H), 8.29 (t, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.59 (dd, J = 1.9 , 1.3 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.20 (m, 2H), 5.81 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H) , 2.99 (s, 3H), 2.90 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H).

Example 3 N- (2- (diethylamino)ethyl)-3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl) Synthesis of -2- fluorophenyl)acetamido)-5-(pentafluorothio)benzamide

Step 1 synthesizes N- (2- (diethylamino)ethyl)-3 -nitro- 5-( pentafluorothio ) benzamide by converting 3-nitro-5-(pentafluorothio)benzene Formic acid (0.3 g, 1.02 mmol) was dissolved in SOCl ₂ (10 mL), and a few drops of DMF were added, followed by reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, and the acyl chloride was dissolved in DCM (10 mL), and the mixture was cooled to 0°C, then triethylamine (0.32 g, 3.07 mmol) was added, followed by N,N -diethyl Ethylenediamine (0.18 g, 1.56 mmol), continue to react at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and perform column chromatography to obtain N- (2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio) Benzamide 0.32 g. MS m/z (ESI): 392.1 [M+H] ⁺ .

step 2 Synthetic 3- Amino- N - (2- (Diethylamino) ethyl) -5-( Pentafluorothio) benzamide

Add N- (2-(diethylamino)ethyl)-3-nitro-5-(pentafluorothio)benzamide (0.32 g, 0.82 mmol) into methanol (10 mL), and then Iron powder (0.8 g) was added, and then hydrochloric acid (1 mL, 12 mol/L) was added slowly, and the mixture was stirred and reacted at 72°C for 2 hours. After monitoring the completion of the reaction, cool, filter with suction, spin the reaction solution to dryness, and obtain 3-amino- N- (2-(diethylamino)ethyl)-5-((pentafluorothio)benzyl Amide 0.25 g, MS m/z (ESI): 362.2 [M+H] ⁺ .

step 3 Synthetic N- (2- (Diethylamino)ethyl)-3- (2- (4- (4- Ethoxy-6- ((4- Methoxybenzyl)oxy)pyridine-3- Base) -2- Fluorophenyl) acetamido) -5- (Pentafluorothio)benzamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (0.25 g, 0.61 mmol) was added into pyridine (5 mL), and then added 3-amino- N- (2-(diethylamino)ethyl)-5-(pentafluorothio)benzamide (0.26 g, 0.73 mmol) and T ₃ P (0.28 g, 0.72 mmol), the mixture was reacted at room temperature for 12 hours. After the reaction is complete, the reaction solution is directly spin-dried, and then column chromatography is obtained to obtain N- (2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4 -Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide 0.19 g, MS m/z (ESI ): 755.6[M+H] ⁺ .

Step 4 Synthesis of N- (2- (diethylamino)ethyl)-3- (2- (4- (4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl) -2- fluorophenyl)acetamido)-5- ( pentafluorothio)benzamide N- (2-(diethylamino)ethyl)-3-(2-(4-( 4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzyl Amide (0.19 g, 0.25 mmol) was dissolved in DCM (5 mL), then TFA (1 mL) was added, the mixture was stirred and reacted at room temperature for 2 hours, after the reaction was complete, the reaction solution was concentrated, and then adjusted to Neutral, extracted with DCM (10 mL*2), spin-dried the organic phase, and column chromatography to obtain N- (2-(diethylamino)ethyl)-3-(2-(4-(4-ethoxy yl-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (compound 3 ) 0.081 g . MS m/z (ESI): 635.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 10.75 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H ), 7.40 – 7.32 (m, 2H), 7.28 – 7.11 (m, 2H), 5.83 (s, 1H), 4.02 (dt, J = 5.8, 2.1 Hz, 2H), 3.78 (s, 4H), 2.43 ( t, J = 6.5 Hz, 4H), 2.19(s,2H),1.17-1.35 (t, 9H).

Example 4 N- (2-( dimethylamino) ethyl)-3-(2-(4-(4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl Synthesis of )-2- fluorophenyl) acetamido) -N - methyl-5-( pentafluorothio) benzamide

step 1 Synthesis of N -(2-( Dimethylamino) Ethyl)- N - Methyl-3- Nitro-5-( Pentafluorothio) benzamide

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl ₂ (5 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete For the reaction solution, dissolve acyl chloride in DCM (5 mL), and add the mixture dropwise to triethylamine (517 mg, 5.12 mmol) and N ¹ , N ¹ , N ² -trimethylethane-1,2 - In a solution of diamine (226 mg, 2.22 mmol) in DCM (5 mL), continue to react at 0° C. for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain N- (2-(dimethylamino)ethyl) -N -methyl-3-nitro-5-( Pentafluorothio)benzamide 460 mg. MS m/z (ESI): 378 [M+H] ⁺ .

step 2 Synthetic 3- Amino- N -(2-( Dimethylamino) Ethyl)- N - Methyl-5-( Pentafluorothio) benzamide

N- (2-(dimethylamino)ethyl) -N -methyl-3-nitro-5-(pentafluorothio)benzamide (460 mg, 1.22 mmol), FeCl ₃ ( 20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (244 mg, 4.88 mmol) was slowly added to the reaction system, and the mixture was stirred and reacted at 80°C overnight. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain 3-amino- N- (2-(dimethylamino)ethyl) -N -methyl-5-(pentafluoro Thio)benzamide 400 mg. MS m/z (ESI): 348 [M+H] ⁺ .

step 3 Synthesis of N -(2-( Dimethylamino) Ethyl)-3-(2-(4-(4- Ethoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetylamino)- N - Methyl-5-( Pentafluorothio) benzamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (474 mg, 1.15 mmol) was dissolved To DMF, then add HATU (482 mg, 1.27 mmol), DMAP (14 Mg, 0.115 mmol), DIEA (446 mg, 3.46 mmol), 3-amino- N- (2-(dimethylamino ) ethyl) -N -methyl-5-(pentafluorothio)benzamide (400 mg, 1.15 mmol), and the mixture was reacted overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl)-3 -(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)- N - Methyl-5-(pentafluorothio)benzamide 380 mg. MS m/z (ESI): 741 [M+H] ⁺ .

step 4 Synthesis of N -(2-( Dimethylamino) Ethyl)-3-(2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl) Acetylamino)- N - Methyl-5-( Pentafluorothio) benzamide

N- (2-(dimethylamino)ethyl)-3-(2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido) -N -methyl-5-(pentafluorothio)benzamide (380 mg, 0.514 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl )-3-(2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido) -N -form Cyl-5-(pentafluorothio)benzamide (compound 4 ) 180 mg. MS m/z (ESI): 621 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.39 (s, 1H), 10.79 (s, 1H), 8.29 (s, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.41 – 7.32 (m, 2H), 7.29 – 7.21 (m, 2H), 5.81 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.79 (s, 2H), 3.58 (s, 1H), 3.24 (s, 1H), 2.94 (d, J = 22.5 Hz, 3H), 2.59 (s, 1H), 2.37 (s, 1H), 2.30 (s, 3H), 1.95 (s, 3H), 1.29 (t, J = 6.9 Hz, 3H).

Example 5 2-(4-(4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl)-2- fluorophenyl )-N-(3-( pentafluorothio Synthesis of )-5-( pyrrolidine-1- carbonyl) phenyl) acetamide

step 1 Synthesis (3- Nitro-5-( Pentafluorothio) Phenyl)( pyrrolidine-1- base) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in dichlorosulfone (15 mL), drop two drops of DMF into the system, heat to 80°C and reflux for 2h . After the reaction was complete, the system was spin-dried, and the acyl chloride product was dissolved with 1 mL of DCM. Pyrrolidine (243 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acyl chloride product was slowly added dropwise to the above system under ice bath, and the ice bath was removed after completion, and the reaction solution Incubate at room temperature for 30 min. Wash with water, extract with dichloromethane, combine the organic phases, dry the organic phases, spin dry, and carry out silica gel column chromatography on the crude product with EA/PE=1:3 to obtain the product (3-nitro-5-(pentafluorothio) Phenyl)(pyrrolidin-1-yl)methanone 480 mg. MS m/z (ESI): 347.3 [M+H] ⁺ .

step 2 Synthesis (3- Amino-5-( Pentafluorothio) Phenyl)( pyrrolidine-1- base) ketone

Under nitrogen protection, (3-nitro-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone (480 mg, 1.39 mmol), anhydrous ferric chloride ( 22.5 mg, 0.14 mmol), activated carbon (96 mg, 6.0 mmol), added dry ethanol (20 mL), refluxed at 80°C, then slowly added hydrazine hydrate (278 mg, 5.54 mmol) dropwise, and continued the reaction for 2 h. After monitoring the completion of the reaction, the system was filtered and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone 376 mg. MS m/z (ESI): 333.3 [M+H] ⁺ .

step 3 Synthesis of 2-(4-(4- Ethoxy-6-(((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl)- N -(3-( Pentafluorothio)-5-( pyrrolidine-1- Carbonyl) phenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (370 mg, 0.90 mmol) was dissolved In dry DMF (10 mL), add HATU (376 mg, 0.99 mmol), (3-amino-5-(pentafluorothio)phenyl)(pyrrolidin-1-yl)methanone (300 mg , 0.90 mmol), DMAP (11 mg, 0.09 mmol), and finally DIPEA (465 mg, 3.60 mmol), and stirred at room temperature for 2h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide 370 mg. MS m/z(ESI): 710.7 [M+H] ⁺ .

step 4 Synthesis of 2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl)- N -(3-( Pentafluorothio)-5-( pyrrolidine-1- Carbonyl) phenyl) Acetamide

2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2 - fluorophenyl)-N-(3-(penta Fluorothio)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide (370 mg, 0.52 mmol) was dissolved in DCM, TFA (2 ml) was added, reacted at room temperature for 30 min, TLC monitored the reaction progress , after the reaction was complete, the system was spin-dried, added water, dichloromethane extracted the combined organic phase, dried and spin-dried. The crude product was chromatographed on silica gel with EA/PE=2:1 to obtain the pure product 2-(4-(4 -Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidin-1- yl)carbonyl)phenyl)acetamide (Compound 5 ) 153.6 mg. MS m/z (ESI): 590.6 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.75 (s, 1H), 8.28 (t, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.66(s, 1H), 7.37(d, J = 8.2 Hz, 1H), 7.33(d, J = 4.3 Hz, 1H), 7.25 (d, J = 11.4 Hz, 1H), 7.22 (dd, J = 7.9, 1.7 Hz, 1H), 5.80 (s, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.78 (s, 1H), 3.46 (t, J =6.6 Hz, 2H), 3.36 (t, J = 6.3 Hz, 2H), 1.84 (dt, J = 18.4, 6.5 Hz, 3H), 1.35-1.14 (m, 4H).

Example 6 2-(4-(4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl)-2- fluorophenyl )-N-(3-( pentafluorothio Synthesis of )-5-( piperidin-1 -yl) carbonyl) phenyl) acetamide

step 1 : Synthesis (3- Nitro-5-( Pentafluorothio) Phenyl)( piperidine-1- base) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in dichlorosulfone (15 mL), then add two drops of DMF to the system, heat to 80°C, Reflux reaction 2h. After the reaction was complete, the liquid in the system was spin-dried, and the acyl chloride product was dissolved in 1 mL of DCM. Piperidine (290 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acyl chloride product was slowly added dropwise into the above system under ice bath, and the ice bath was removed after completion, and the Warm reaction for 30 min. Wash with water, extract with dichloromethane, combine the organic phases, dry, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product (3-nitro-5-(pentafluorothio)benzene yl)(piperidin-1-yl)methanone 350 mg. MS m/z (ESI): 361.3 [M+H] ⁺ .

step 2 : Synthesis (3- Amino-5-( Pentafluorothio) Phenyl)( piperidine-1- base) ketone

Add (3-nitro-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone (485 mg, 1.35 mmol), ferrous chloride (21.83 mg, 0.13 mmol), activated carbon (97 mg, 6.06 mmol), added dry ethanol (20 mL), refluxed at 80°C, then slowly added hydrazine hydrate (270.3 mg, 5.40 mmol) dropwise, and continued the reaction for 2 h. After monitoring the completion of the reaction, the system was filtered and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone 404 mg. MS m/z (ESI): 347.3 [M+H] ⁺ .

step 3 : Synthesis of 2-(4-(4- Ethoxy-6-(((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl)- N -(3-( Pentafluorothio)-5-( piperidine-1- Carbonyl) phenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.73 mmol) was dissolved In dry DMF (10 mL), add HATU (305 mg, 0.8 mmol), (3-amino-5-(pentafluorothio)phenyl)(piperidin-1-yl)methanone (241 mg , 0.73 mmol), DMAP (9 mg, 0.07 mmol), and finally DIPEA (377 mg, 2.92 mmol), and stirred at room temperature for 2h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide 340 mg. MS m/z(ESI): 724.7 [M+H] ⁺ .

step 4 : Synthesis of 2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl)- N -(3-( Pentafluorothio)-5-( piperidine-1- base) Carbonyl) phenyl) Acetamide

2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2 - fluorophenyl)-N-(3-(penta Fluorothio)-5-(piperidine-1-carbonyl)phenyl)acetamide (113 mg, 0.16 mmol) was dissolved in DCM, TFA (2 ml) was added and reacted at room temperature for 30 min. TLC monitored the reaction progress , after the reaction was complete, the system was spin-dried, added water, dichloromethane extracted the combined organic phase, dried the organic phase, and spin-dried. The crude product was chromatographed on a silica gel column with EA/PE=2:1 to obtain the pure product 2-(4 -(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(piperidine -1-yl)carbonyl)phenyl)acetamide (Compound 6 ) 53.3 mg. MS m/z (ESI): 604.6 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 11.36 (s, 1H), 10.76 (s, 1H), 8.27 (t, J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.37(d, J = 8.1 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 11.4Hz, 1H), 7.30-7.20 (m, 1H), 5.80 (s, 1H ), 4.03 (q, J = 6.9 Hz, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 3.24 (s, 2H), 1.60-1.46 (m, 4H), 1.29-1.22 (m, 6H).

Example 7 N- (3-(3-( dimethylamino) azetidine-1- carbonyl)-5-( pentafluorothio) phenyl)-2-(4-(4- ethane Synthesis of Oxy- 6- oxo-1,6- dihydropyridin-3 -yl)-2- fluorophenyl) acetamide

step 1 Synthetic (3-( Dimethylamino) Azetidine-1- Base) (3- Nitro-5-( Pentafluorothio) phenyl) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl ₂ (5 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete For the reaction solution, dissolve acyl chloride in DCM (5 mL), and add the mixture dropwise to triethylamine (517 mg, 5.12 mmol) and N , N -dimethylazetidin-3-amine (222 mg, 2.22 mmol) in DCM (5 mL), the reaction was continued at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the liquids, concentrate the organic phase, and obtain (3-(dimethylamino)azetidin-1-yl)(3-nitro-5-( Pentafluorothio)phenyl)methanone 460 mg. MS m/z (ESI): 376 [M+H] ⁺ .

step 2 Synthesis (3- Amino-5-( Pentafluorothio) Phenyl) (3-( Dimethylamino) Azetidine-1- base) ketone

(3-(Dimethylamino)azetidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (460 mg, 1.23 mmol), FeCl ₃ (20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (244 mg, 4.88 mmol) was added slowly, and the mixture was stirred and reacted overnight at 80°C. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)azetidine Alk-1-yl)methanone 330 mg. MS m/z (ESI): 346 [M+H] ⁺ .

step 3 Synthesis of N -(3-(3-( Dimethylamino) Azetidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (393 mg, 0.957 mmol) was dissolved To DMF, add HATU (400 mg, 1.05 mmol), DMAP (12 mg, 0.095 mmol), DIEA (370 mg, 2.87 mmol), (3-amino-5-(pentafluorothio)phenyl) ( 3-(Dimethylamino)azetidin-1-yl)methanone (330 mg, 0.957 mmol), and the mixture was reacted at room temperature overnight. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave N- (3-(3-(dimethylamino)azepine Cyclobutane-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine- 3-yl)-2-fluorophenyl)acetamide 300 mg. MS m/z (ESI): 739 [M+H] ⁺ .

step 4 Synthesis of N -(3-(3-( Dimethylamino) Azetidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl) Acetamide

N- (3-(3-(dimethylamino)azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy -6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (300 mg, 0.407 mmol) was dissolved in DCM (10 mL) and added TFA (2 mL), the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (3-(3-(dimethylamino )azetidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine-3 -yl)-2-fluorophenyl)acetamide (compound 7 ) 85 mg. MS m/z (ESI): 619 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.40 (s, 1H), 10.80 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.05 (t, J = 1.5 Hz, 1H) , 7.71 (t, J = 1.6 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.20 (m, 2H), 5.81 (s, 1H), 4.30 (t, J = 8.0 Hz, 1H), 4.05 (dq, J = 14.0, 7.5, 7.0 Hz, 4H), 3.85 (dd, J = 10.5, 5.1 Hz, 1H), 3.79 (s, 2H), 3.14 – 3.07 (m, 1H), 2.08 (s, 6H), 1.28 (t, J = 6.9 Hz, 3H).

Example 8 2-(4-(4- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl)-2- fluorophenyl )-N-(3-( morpholine-4 Synthesis of -carbonyl)-5-( pentafluorothio) phenyl) acetamide

step 1 Synthesis of morpholino (3- Nitro-5-( Pentafluorothio) phenyl) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in dichlorosulfone (15 mL), drop two drops of DMF into the system, heat to 80°C and reflux for 2h . After the reaction was complete, the system was spin-dried, and the acyl chloride product was dissolved in 1 mL DCM. Morpholine (298 mg, 3.41 mmol) and triethylamine (517 mg, 5.12 mmol) were dissolved in dichloromethane, and the acyl chloride product was slowly added dropwise to the above system under ice bath, and the ice bath was removed after completion, at room temperature Wait for 30 minutes. Washed with water, extracted with dichloromethane, combined organic phase, dried and spin-dried, the crude product was subjected to silica gel column chromatography with EA/PE=1:3 to obtain the product morpholino (3-nitro-5-(pentafluorothio) Phenyl)methanone 354 mg. MS m/z (ESI): 363.3 [M+H] ⁺ .

step 2 Synthesis of morpholino (3- Amino-5-( Pentafluorothio) phenyl) ketone

Add morpholino(3-amino-5-(pentafluorothio)phenyl)methanone (354 mg, 0.98 mmol), anhydrous ferric chloride (15.9 mg, 0.10 mmol) into a two-necked flask under nitrogen protection ), activated carbon (70.8 mg, 4.42 mmol), dry ethanol (20 mL), reflux at 80°C, then slowly dropwise add hydrazine hydrate (196 mg, 3.91 mmol), and continue the reaction for 2 h. After monitoring the completion of the reaction, the system was filtered and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain pure product morpholino(3-amino-5-(pentafluorothio)phenyl)methanone 307 mg. MS m/z( ESI): 349.3 [M+H] ⁺ .

step 3 Synthesis of 2-(4-(4- Ethoxy-6-(((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl)- N -(3-( Morpholine-4- Carbonyl)-5-( Pentafluorothio) phenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (362 mg, 0.88 mmol) was dissolved In dry DMF (10 mL), add HATU (368 mg, 0.97 mmol), morpholino (3-amino-5-(pentafluorothio)phenyl)methanone (307 mg, 0.88 mmol), DMAP (10.8 mg, 0.09 mmol) and finally DIPEA (455 mg, 3.52 mmol) were added and stirred at room temperature for 2h. After monitoring the completion of the reaction, the system was poured into ice water, extracted with EA, the organic phases were combined, and spin-dried. The crude product was subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridine-3 -yl)-2 - fluorophenyl)-N-(3-(morpholine-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide 600 mg. MS m/z(ESI): 726.7 [M+H] ⁺ .

step 4 Synthesis of 2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl)- N -(3-( Morpholine-4- Carbonyl)-5-( Pentafluorothio) phenyl) Acetamide

2-(4-(4-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2 - fluorophenyl)-N-(3-( Phenyl-4-carbonyl)-5-(pentafluorothio)phenyl)acetamide (600 mg, 0.83 mmol) was dissolved in DCM, TFA (2 mL) was added and reacted at room temperature for 30 min. TLC monitored the reaction progress , after the reaction was complete, the system was spin-dried, added water, dichloromethane extracted the combined organic phase, dried and spin-dried. The crude product was chromatographed on silica gel with EA/PE=2:1 to obtain the pure product 2-(4-(4 -Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2 - fluorophenyl)-N-(3-(pentafluorothio)-5-(pyrrolidin-1- yl)carbonyl)phenyl)acetamide (Compound 8 ) 225 mg. MS m/z (ESI): 606.6 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 11.37 (s, 1H), 10.77 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.37(d, J = 8.1 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.25 (d, J = 11.5 Hz, 1H), 7.20 (m, 1H), 5.80 (s, 1H), 4.03 (q, J = 6.9 Hz, 2H), 3.78 (s, 1H), 3.62-3.56 (m, 4H), 1.37-1.18 (m, 3H).

Example 9 N- (3-(3-( dimethylamino) pyrrolidine-1- carbonyl)-5-( pentafluorothio) phenyl)-2-(4-(4- ethoxy- Synthesis of 6- oxo-1,6- dihydropyridin-3 -yl)-2- fluorophenyl) acetamide

step 1 Synthetic (3-( Dimethylamino) pyrrolidine-1- Base) (3- Nitro-5-( Pentafluorothio) phenyl) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl ₂ (5 mL), add a few drops of DMF, then reflux for 2 hours, spin dry after the reaction is complete liquid. Acyl chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and N , N -dimethylpyrrolidinium butan-3-amine (253 mg, 2.22 mmol) DCM (5 mL) solution at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain ((3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorosulfur) by column chromatography Substitute) phenyl) ketone 480 mg. MS m/z (ESI): 390 [M+H] ⁺ .

step 2 Synthesis (3- Amino-5-( Pentafluorothio) Phenyl) (3-( Dimethylamino) pyrrolidine-1- base) ketone

(3-(Dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (480 mg, 1.23 mmol), FeCl ₃ (20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and hydrazine hydrate (247 mg, 4.93 mmol) was slowly added to the system, and the mixture was stirred and reacted at 80°C overnight. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain (3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidine-1 -yl) Methanone 375 mg. MS m/z (ESI): 360 [M+H] ⁺ .

step 3 Synthesis of N -(3-(3-( Dimethylamino) pyrrolidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (429 mg, 1.045 mmol) was dissolved to DMF, then added HATU (437 mg, 1.15 mmol), DMAP (13 mg, 0.104 mmol), DIEA (404 mg, 3.13 mmol), (3-amino-5-(pentafluorothio)phenyl) (3-(Dimethylamino)pyrrolidin-1-yl)methanone (375 mg, 1.045 mmol), the mixture was reacted at room temperature overnight, after the reaction was complete. Water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave N- (3-(3-(dimethylamino)pyrrolidine-1-carbonyl )-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2- Fluorophenyl) acetamide 320 mg. MS m/z (ESI): 753 [M+H] ⁺ .

step 4 Synthesis of N -(3-(3-( Dimethylamino) pyrrolidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl) Acetamide

N- (3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6- ((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (320 mg, 0.426 mmol) was dissolved in DCM (10 mL), then TFA (2 mL), the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave N- (3-(3-(dimethylamino )pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) acetamide (compound 9 ) 200 mg. MS m/z (ESI): 633 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.40 (s, 1H), 10.89 (s, 1H), 8.31 (q, J = 3.0, 1.9 Hz, 1H), 8.03 (d, J = 14.1 Hz, 1H), 7.69 (s, 1H), 7.36 (d, J = 10.5 Hz, 2H), 7.29 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.90 (dd, J = 12.6, 7.1 Hz, 1H), 3.80 (s, 2H), 3.53 (q, J = 17.8, 14.1 Hz, 4H), 2.68 (d, J = 60.3 Hz, 6H), 2.27 (s , 1H), 2.08 (s, 1H), 1.29 (t, J = 6.9 Hz, 3H).

Example 10 N- (2-( dimethylamino) ethyl)-3-(2-(2- fluoro-4-(4- isobutoxy-6- oxo-1,6 -dihydro Synthesis of pyridin -3 -yl) phenyl) acetamido)-5-( pentafluorothio) benzamide

step 1 Synthetic 2- Chloro-4- Isobutoxypyridine

Dissolve isobutanol (4.68 g, 63.29 mmol) in THF (50 mL), add NaH (60%) (3.16 g, 79.11 mmol) under ice cooling and stir for 30 minutes. 2-Chloro-4-nitropyridine (5 g, 31.65 mmol) was then added and the reaction was stirred overnight. After the reaction was complete, the reaction solution was spin-dried, extracted with ethyl acetate, dried, spin-dried, and column chromatographed to obtain 3.6 g of 2-chloro-4-isobutoxypyridine. MS m/z (ESI): 186 [M+H] ⁺ .

step 2 Synthetic 5- Bromo-2- Chloro-4- Isobutoxypyridine

Dissolve 2-chloro-4-isobutoxypyridine (3.6 g, 19.46 mmol) in concentrated sulfuric acid (20 mL), then slowly add NBS (5.2 g, 29.19 mmol) in batches to the system, and react The temperature of the solution was raised to 80° C. for 4 hours. After the reaction is complete, cool down, pour the reaction solution into ice water, extract with EA (50 mL*3), dry the organic phase and spin to dry, and obtain 5-bromo-2-chloro-4-isobutoxypyridine 1.1 by column chromatography g product. MS m/z (ESI): 264 [M+H] ⁺ .

step 3 Synthetic 5- Bromo-4- Isobutoxy-2-((4- Methoxybenzyl) oxygen) pyridine

To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (1.1 g, 4.18 mmol) in toluene (20 mL) was added (4-methoxyphenyl)methanol (693 mg , 5.02 mmol), KOH (469 mg, 8.37 mmol) and 18-crown-6 (110 mg, 0.42 mmol), the mixture was reacted at 120°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water (15 mL) was added, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave 5-bromo-4-isobutoxy -2-((4-methoxybenzyl)oxy)pyridine 950 mg. MS m/z (ESI): 366 [M+H] ⁺ .

step 4 Synthesis of 2-(2- Fluoro-4-(4- Isobutoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base) phenyl) Methyl acetate

Under nitrogen protection, 5-bromo-4-isobutoxy-2-((4-methoxybenzyl)oxy)pyridine (950 mg, 2.6 mmol), 2-(2-fluoro-4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (842 mg, 2.86 mmol), Pd(dppf)Cl ₂ (212 mg, 0.26 mmol) and cesium carbonate (1.7 g, 5.2 mmol) were added to a one-necked bottle, and then 1,4-dioxane (15 mL) and water (5 mL) were added, and the mixture was reacted at 95°C 3 hours. After the reaction was complete, it was extracted with EA (20 mL*2), the organic phase was dried, concentrated under reduced pressure and spin-dried, and column chromatography gave 2-(2-fluoro-4-(4-isobutoxy-6-((4 -Methoxybenzyl)oxy)pyridin-3-yl)phenyl)methyl acetate 980 mg. MS m/z (ESI): 454 [M+H] ⁺ .

step 5 Synthesis of 2-(2- Fluoro-4-(4- Isobutoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base) phenyl) Acetic acid

Methyl 2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetate (980 mg, 2.16 mmol) was dissolved in THF (15 mL), and then lithium hydroxide (182 mg, 4.33 mmol) aqueous solution was added to the reaction system, and the mixture was stirred and reacted at 60°C for 4 hours. After the reaction is complete, concentrate under reduced pressure to remove most of the organic phase, add dilute hydrochloric acid to adjust the pH of the system to 7, a white solid precipitates, filter with suction, wash the filter cake with water, and dry to obtain 2-(2-fluoro-4-(4- Isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid 670 mg. MS m/z (ESI): 440 [M+H] ⁺ .

step 6 Synthesis of N -(2-( Dimethylamino) Ethyl)-3-(2-(2- Fluoro-4-(4- Isobutoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base) phenyl) Acetylamino)-5 -( Pentafluorothio) benzamide

2-(2-Fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetic acid (670 mg, 1.53 mmol) Dissolved in DMF, then added HATU (638 mg, 1.68 mmol), DMAP (19 mg, 0.153 mmol), DIEA (636 mg, 4.58 mmol), 3-amino- N- (2-(dimethylamine Base) ethyl)-5-(pentafluorothio)benzamide (508 mg, 1.53 mmol), the mixture was reacted overnight at room temperature, after the reaction was complete, the reaction was quenched by adding water, and then EA (20 mL*2) extraction, the organic phase was dried, spin-dried, and column chromatography gave N- (2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy yl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide 380 mg. MS m/z (ESI): 755 [M+H] ⁺ .

step 7 Synthesis of N -(2-( Dimethylamino) Ethyl)-3-(2-(2- Fluoro-4-(4- Isobutoxy-6- Oxo-1,6- Dihydropyridine-3- base) phenyl) Acetylamino)-5-( Pentafluorothio) benzamide

N- (2-(dimethylamino)ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-((4-methoxybenzyl)oxy )pyridin-3-yl)phenyl)acetamido)-5-(pentafluorothio)benzamide (380 mg, 0.504 mmol) was dissolved in DCM (10 mL), then TFA (2 mL ), the mixture was stirred and reacted at room temperature for 2 hours. After the reaction was complete, the reaction liquid was concentrated, adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), concentrated under reduced pressure to remove the organic phase, and obtained N- (2-(dimethylamino) Ethyl)-3-(2-(2-fluoro-4-(4-isobutoxy-6-oxo-1,6-dihydropyridin-3-yl)phenyl)acetamido)- 5-(Pentafluorothio)benzamide (compound 10 ) 190 mg. MS m/z (ESI): 635 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.39 (s, 1H), 10.86 (s, 1H), 8.79 (t, J = 5.7 Hz, 1H), 8.45 (t, J = 2.0 Hz, 1H) , 8.26 (d, J = 1.6 Hz, 1H), 8.03 (t, J = 1.7 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.28 – 7.21 (m, 2H), 5.81 (s, 1H), 3.80 (s, 2H), 3.77 (d, J = 6.3 Hz, 2H), 3.40 (q, J = 6.4 Hz, 4H), 2.24 (s, 6H), 1.97 (dt, J = 13.2, 6.6 Hz, 1H ), 0.92 (d, J = 6.7 Hz, 6H).

Example 11 N- (2-( dimethylamino) ethyl)-3-(2-(4-(5- ethoxy-6- oxo-1,6- dihydropyridin-3 -yl Synthesis of )-2- fluorophenyl) acetamido)-5-( pentafluorothio )benzamide

step 1 Synthetic compound 5- Bromo-2- Chloro-3- Ethoxypyridine

5-Bromo-2-chloropyridin-3-ol (1 g, 4.83 mmol), ethyl iodide (980 mg, 6.28 mmol), potassium iodide (80 mg, 0.483 mmol) and potassium carbonate (1.33 g, 9.67 mmol) It was dissolved in DMF (20 mL), and the mixture was reacted overnight at 50°C. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was dried, spin-dried, and column chromatographed to obtain 1.1 g of 5-bromo-2-chloro-3-ethoxypyridine. MS m/z (ESI): 236 [M+H] ⁺ .

step 2 Synthetic 5- Bromo-3- Ethoxy-2-((4- Methoxybenzyl) oxygen) pyridine

5-Bromo-2-chloro-3-ethoxypyridine (1.21 g, 5.12 mmol), (4-methoxyphenyl)methanol (848 mg, 6.14 mmol), 18-crown-6 (135 mg , 0.51 mmol), potassium hydroxide (574 mg, 5.23 mmol) were dissolved in toluene (15 mL), heated to 120°C for 5 h. After the reaction is complete, add water to the system to quench, extract with EA, combine the organic phases, dry the organic phases, spin dry, and perform silica gel column chromatography on the crude product with EA/PE=1:3 to obtain the product 5-bromo-3-ethoxy - 2-((4-methoxybenzyl)oxy)pyridine 1.26 g. MS m/z (ESI): 339.2 [M+H] ⁺ .

step 3 Synthesis of 2-(4-(5- Ethoxy-6-(((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Methyl acetate

5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (1.26 g, 3.73 mmol), 2-(2-fluoro-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (1.21 g, 4.10 mmol), Pd(dppf)Cl ₂ (270 mg, 0.37 mmol), Cs ₂ CO ₃ (2.43 g, 7.45 mmol) were dissolved in a mixed solution of 1,4-dioxane/H ₂ O (40 mL, 3:1), heated to 85°C and refluxed overnight. After the reaction is complete, add water to quench, extract with EA, combine the organic phases, dry and spin dry, and carry out silica gel column chromatography on the crude product with EA/PE=1:2 to obtain the product 2-(4-(5-ethoxy-6-( Methyl ((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate 1.34 g. MS m/z (ESI): 426.5 [M+H] ⁺ .

step 4 Synthesis of 2-(4-(5- Ethoxy-6-(((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetic acid

Methyl 2-(4-(5-ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (1.34 g, 3.15 mmol), lithium hydroxide (260 mg, 6.30 mmol) were dissolved in MeOH/H ₂ O (20 mL, 3:1 ), and reacted at room temperature for 2 h. After monitoring the completion of the reaction, the system was spin-dried, washed with water, diluted Adjust the pH to weak acidity with hydrochloric acid, and extract with EA. The organic phases are combined and spin-dried. The crude product is subjected to silica gel column chromatography with EA/PE=1:1 to obtain the pure product 2-(4-(5-ethoxy-6 -(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid 1.25 g. MS m/z (ESI): 412.4 [M+H] ⁺ .

step 5 : Synthetic N -(2-( Dimethylamino) Ethyl)-3-(2-(4-(5- Ethoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetylamino)-5-( Pentafluorothio) benzamide

2-(4-(5-Ethoxy-6-(((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.73 mmol) Dissolve in dry DMF (10 mL), add HATU (305 mg, 0.8 mmol), 3-amino- N- (2-(dimethylamino)ethyl)-5-(pentafluorothio) Benzamide (243 mg, 0.73 mmol), DMAP (9.0 mg, 0.07 mmol), and finally DIPEA (377 mg, 2.92 mmol) were added and stirred at room temperature for 2 h. After monitoring the completion of the reaction, the system was poured into ice water, EA Extraction, combined organic phase, spin-drying. Thick product carries out silica gel column chromatography with DCM/MeOH=10:1, obtains pure product N- (2-(dimethylamino) ethyl)-3-(2-( 4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio ) benzamide 237 mg. MS m/z (ESI): 727.7 [M+H] ⁺ .

step 6 : Synthetic N -(2-( Dimethylamino) Ethyl)-3-(2-(4-(5- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl) Acetylamino)-5-( Pentafluorothio) benzamide

N- (2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3 -yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (191 mg, 0.26 mmol) was dissolved in DCM, TFA (2 mL) was added and reacted at room temperature 30 min. The reaction progress was monitored by TLC. After the reaction was complete, the system was spin-dried, water was added, and the combined organic phase was extracted with dichloromethane, dried and spin-dried. The crude product was subjected to silica gel column chromatography with DCM/MeOH=10:1 to obtain the pure product N- (2-(dimethylamino)ethyl)-3-(2-(4-(5-ethoxy- 6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamido)-5-(pentafluorothio)benzamide (compound 11 ) 22 mg. MS m/z (ESI): 607.6 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 10.83 (s, 1H), 8.81 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H ), 7.47 (d, J = 12.0 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 2.63 (m, 2H), 2.31 (s, 4H), 1.48-1.15 (m, 4H).

Example 12 ( S )-N-(3-(3- ( dimethylamino) pyrrolidine-1- carbonyl)-5-( pentafluorothio) phenyl)-2-(4-(4- Synthesis of Ethoxy-6- oxo-1,6- dihydropyridin-3 -yl)-2- fluorophenyl) acetamide

step 1 Synthesis of ( S )-(3-( Dimethylamino) pyrrolidine-1- Base) (3- Nitro-5-( Pentafluorothio) phenyl) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl ₂ (5 mL), add a few drops of DMF, and react under reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, the acyl chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and ( S ) -N , N -dimethylpyrrolidine In a DCM (5 mL) solution of 3-yl-3-amine (253 mg, 2.22 mmol), the reaction was continued at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain ( S )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5- (Pentafluorothio)phenyl)methanone 470 mg. MS m/z (ESI): 390 [M+H] ⁺ .

step 2 Synthesis of ( S )-(3- Amino-5-( Pentafluorothio) Phenyl) (3-( Dimethylamino) pyrrolidine-1- base) ketone

( S )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (470 mg, 1.23 mmol), FeCl ₃ (20 mg, 0.12 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and hydrazine hydrate (242 mg, 4.83 mmol) was slowly added to the system, and the mixture was stirred and reacted at 80°C overnight. After monitoring that the reaction is complete, cool, filter with suction, spin the reaction solution to dryness, and obtain ( S )-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrole Alk-1-yl)methanone 360 mg. MS m/z (ESI): 360 [M+H] ⁺ .

step 3 Synthesis ( S )- N -(3-(3-( Dimethylamino) pyrrolidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (412 mg, 1.003 mmol) was dissolved To DMF, then add HATU (419 mg, 1.103 mmol), DMAP (12 mg, 0.100 mmol), DIEA (388 mg, 3.008 mmol), ( S )-(3-Amino-5-(pentafluorosulfur Substitute) phenyl) (3-(dimethylamino) pyrrolidin-1-yl) ketone (360 mg, 1.003 mmol), the mixture was reacted overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave ( S ) -N- (3-(3-(dimethylamine Base) pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine -3-yl)-2-fluorophenyl)acetamide 310 mg. MS m/z (ESI): 753 [M+H] ⁺ .

step 4 Synthesis ( S )- N -(3-(3-( Dimethylamino) pyrrolidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6- Oxo-1, 6- Dihydropyridine-3- base)-2- Fluorophenyl) Acetamide

( S )-N-(3-(3-( dimethylamino )pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy Ethyl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (310 mg, 0.412 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin-dried, and column chromatography gave ( S ) -N- (3-(3-(di Methylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine- 3-yl)-2-fluorophenyl)acetamide (compound 12 ) 170 mg. MS m/z (ESI): 633 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.40 (s, 1H), 10.91 (s, 1H), 8.36 – 8.30 (m, 1H), 8.02 (d, J = 13.8 Hz, 1H), 7.69 ( d, J = 2.6 Hz, 1H), 7.37 (d, J = 10.5 Hz, 2H), 7.29 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.86 (d, J = 5.2 Hz, 1H), 3.81 (s, 2H), 3.56 – 3.46 (m, 4H), 2.63 (s, 3H), 2.46 (s, 3H), 2.20 (d, J = 13.1 Hz , 1H), 2.00 (s, 1H), 1.29 (t, J = 7.0 Hz, 3H).

Example 13 ( R )-N-(3-(3- ( dimethylamino) pyrrolidine-1- carbonyl)-5-( pentafluorothio) phenyl)-2-(4-(4- Synthesis of Ethoxy-6- oxo-1, 6 -dihydropyridin-3 -yl)-2- fluorophenyl) acetamide

step 1 Synthesis of ( R )-(3-( Dimethylamino) pyrrolidine-1- Base) (3- Nitro-5-( Pentafluorothio) phenyl) ketone

Dissolve 3-nitro-5-(pentafluorothio)benzoic acid (500 mg, 1.71 mmol) in SOCl ₂ (5 mL), add a few drops of DMF, and react under reflux for 2 hours. After the reaction was complete, the reaction solution was spin-dried, the acyl chloride was dissolved in DCM (5 mL), and the mixture was added dropwise to triethylamine (517 mg, 5.12 mmol) and ( R ) -N , N -dimethylpyrrolidine In a DCM (5 mL) solution of 3-yl-3-amine (253 mg, 2.22 mmol), the reaction was continued at 0°C for half an hour. After the reaction is complete, add water to quench the reaction, separate the layers, concentrate the organic phase, and obtain ( R )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5- (Pentafluorothio)phenyl)methanone 560 mg. MS m/z (ESI): 390 [M+H] ⁺ .

step 2 Synthesis of ( R )-(3- Amino-5-( Pentafluorothio) Phenyl) (3-( Dimethylamino) pyrrolidine-1- base) ketone

( R )-(3-(dimethylamino)pyrrolidin-1-yl)(3-nitro-5-(pentafluorothio)phenyl)methanone (560 mg, 1.23 mmol), FeCl3 (23 mg, 0.14 mmol), activated carbon (100 mg) were added to ethanol (10 mL), and then hydrazine hydrate (288 mg, 5.76 mmol) was added slowly, and the mixture was stirred and reacted overnight at 80°C. After the reaction was completed, the , cooled, suction filtered, the reaction solution was spin-dried, and column chromatography gave ( R )-(3-amino-5-(pentafluorothio)phenyl)(3-(dimethylamino)pyrrolidine-1- base) Methanone 420 mg. MS m/z (ESI): 360 [M+H] ⁺ .

step 3 Synthesis of ( R )- N -(3-(3-( Dimethylamino) pyrrolidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6-((4- Methoxybenzyl) oxygen) Pyridine-3- base)-2- Fluorophenyl) Acetamide

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (481 mg, 1.17 mmol) was dissolved To DMF, then add HATU (489 mg, 1.29 mmol), DMAP (14 mg, 0.117 mmol), DIEA (453 mg, 3.51 mmol), ( R )-(3-Amino-5-(pentafluorosulfur Substitute) phenyl) (3-(dimethylamino) pyrrolidin-1-yl) ketone (420 mg, 1.17 mmol), the mixture was reacted overnight at room temperature. After the reaction was complete, water was added to quench the reaction, and then extracted with EA (20 mL*2), the organic phase was dried, spin-dried, and column chromatography gave ( R )-N-(3-(3-( dimethylamine Base) pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine -3-yl)-2-fluorophenyl)acetamide 350 mg. MS m/z (ESI): 753 [M+H] ⁺ .

step 4 Synthesis of ( R )- N -(3-(3-( Dimethylamino) pyrrolidine-1- Carbonyl)-5-( Pentafluorothio) Phenyl)-2-(4-(4- Ethoxy-6- Oxo-1,6- Dihydropyridine-3- base)-2- Fluorophenyl) Acetamide

( R )-N-(3-(3-( dimethylamino )pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy Dimethyl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (350 mg, 0.465 mmol) was dissolved in DCM (10 mL), then TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, then adjusted to neutrality with aqueous sodium carbonate, extracted with DCM (20 mL*2), the organic phase was spin - dried, and column chromatography gave ( R )-N-(3-(3-(di Methylamino)pyrrolidine-1-carbonyl)-5-(pentafluorothio)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridine- 3-yl)-2-fluorophenyl)acetamide (compound 13 ) 200 mg. MS m/z (ESI): 633 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.40 (s, 1H), 10.87 (s, 1H), 8.29 (t, J = 2.1 Hz, 1H), 8.04 (d, J = 13.0 Hz, 1H) , 7.70 (s, 1H), 7.41 – 7.33 (m, 2H), 7.30 – 7.21 (m, 2H), 5.82 (s, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.95 – 3.86 (m , 1H), 3.80 (s, 2H), 3.73 – 3.47 (m, 4H), 2.75 (d, J = 50.1 Hz, 6H), 2.29 (s, 1H), 2.10 (t, J = 8.8 Hz, 1H) , 1.29 (t, J = 6.9 Hz, 3H).

Biological Activity Test Example 1 :

(a) In vitro screening test-HTRF Method for detection of compounds against RET Inhibitory activity of

式中， R0是溶媒空白組的酶標儀板平均比率 R1是測試化合物酶標儀板比率 R2是100%抑制RET酶活性的酶標儀板平均比率 通過將化合物濃度的抑制率值和對數擬合到非線性回歸(劑量反應-可變斜率)中，用GraphPad 6.0軟體計算IC₅₀ 。The method is as follows: 1. Preparation of 1x kinase buffer: mix 5x enzyme buffer with distilled water at a ratio of 1:4, and the final concentration is 5 mM magnesium chloride; 1 mM dithiothreitol. 2. Dilute the test compound (5 mM stock solution) 5-fold to 1 mM with 100% dimethylsulfoxide, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 3. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compound to a 384-well plate, with 2 replicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/v). The gradient concentrations of test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 4. Prepare 2x RET (0.1 ng/μL) in 1x Kinase Buffer. 5. Add 5 μL of 2x RET to the 384-well plate, centrifuge at 1000 g for 30 s, and incubate at room temperature for 10 min. 6. Prepare 2x tyrosine kinase-biotin-labeled substrate (2 μM) and adenosine triphosphate (20 μM) mixture in 1x kinase buffer. 7. Add 5 μL of tyrosine kinase-biotin-labeled substrate and adenosine triphosphate mixture to start the reaction. Centrifuge at 1000 g for 30 s, seal the plate, and incubate at room temperature for 30 min. 8. Prepare 2x Sa-XL 665 (Note: a reagent) (125 μM) and tyrosine kinase-antibody-cryptate mixture with homogeneous time-resolved fluorescence detection buffer. 9. Add 10 μL of Sa-XL 665 and tyrosine kinase-antibody-cryptate mixture to each well, centrifuge at 1000 g for 30 s, and incubate at room temperature for 1 h. 10. Read the plate with Envision 2104 microplate reader at 615 nm and 665 nm, and calculate the ratio (665/615 nm). 11. The inhibition rate is calculated as follows:

In the formula, R0 is the average ratio of the microplate instrument plate of the solvent blank group, R1 is the average ratio of the microplate instrument plate of the test compound, and R2 is the average ratio of the microplate instrument plate of 100% inhibition of RET enzyme activity. Integrated into nonlinear regression (dose response - variable slope), _IC50 was calculated using GraphPad 6.0 software.

(b ) in vitro screening test - HTRF method Test compounds inhibit VEGFR2 activity test

式中， R0是溶媒空白組的酶標儀板平均比率 R1是測試化合物酶標儀板比率 R2是100%抑制RET酶活性的酶標儀板平均比率 通過將化合物濃度的抑制率值和對數擬合到非線性回歸(劑量反應-可變斜率)中，用GraphPad 6.0計算IC₅₀ 。Experimental steps: 1. 1x kinase buffer preparation: 5x enzyme buffer and distilled water were mixed at a ratio of 1:4, and the final concentration was 5 mM magnesium chloride; 1 mM dithiothreitol; 1 mM manganese chloride. 2. Dilute the test compound (5 mM stock solution) 5-fold to 1 mM with 100% dimethylsulfoxide, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 3. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compound to a 384-well cell culture plate (Corning, 3570), with 2 duplicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/ v). The gradient concentrations of test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 4. Prepare 2x VEGFR2 (0.02 ng/μL) in 1x Kinase Buffer. 5. Add 5 μL of 2x VEGFR2 to the 384-well plate, centrifuge at 1000 g for 30 s, and incubate at room temperature for 10 min. 6. Prepare 2x tyrosine kinase-biotin-labeled substrate (2 μM) and ATP (8 μM) mixture with 1x kinase buffer. 7. Add 5 μL of tyrosine kinase-biotin-labeled substrate and adenosine triphosphate mixture to start the reaction. Centrifuge at 1000 g for 30 s, seal the plate, and incubate at room temperature for 40 min. 8. Prepare 2x Sa-XL 665 (125 μM) and tyrosine kinase-antibody-cryptate mixture in homogeneous time-resolved fluorescence detection buffer. 9. Add 10 μL Sa-XL 665 and tyrosine kinase-antibody-cryptate mixture to each well, centrifuge at 1000 g for 30 s, and incubate at room temperature for 1 h. 10. Read the plate with Envision 2104 microplate reader at 615 nm and 665 nm, and calculate the ratio (665/615nm). 11. The inhibition rate is calculated as follows:

In the formula, R0 is the average ratio of the microplate instrument plate of the solvent blank group, R1 is the average ratio of the microplate instrument plate of the test compound, and R2 is the average ratio of the microplate instrument plate of 100% inhibition of RET enzyme activity. Fitting into nonlinear regression (dose response - variable slope), _IC50 was calculated using GraphPad 6.0.

(c ) In vitro screening experiment-CellTiter-Glo Luminescence Detection of Compounds Inhibiting Ba/F3-KIF5B-RET Cell Viability Test

Experimental steps: 1. Using the Neon® transfection system method, the mammalian cell expression vector containing human KIF5B-RET cDNA was introduced into Ba/F3 cells, and the surviving clones were selected by puromycin for cell growth inhibition function experiments and The cell lines with stable and high expression of RET were verified by western blotting. 2. Cells were cultured in RPMI 1640 culture medium, 10% fetal bovine serum, 1% penicillin-streptomycin, 2 μg/mL puromycin, and cultured in a 37°C, 5% carbon dioxide cell incubator. 3. Dilute the test compound (5 mM stock solution) 2.5-fold to 2 mM with 100% dimethylsulfoxide, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 4. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compound to a 384-well cell culture plate (Corning, 3570), with 2 duplicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/ v). The gradient concentrations of test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 5. Add 40 μL of 800 Ba/F3-KIF5B-RET cell suspension to each well and incubate in a 5% carbon dioxide incubator for 72 h. 6. Add 20 μL of Cell Titer-Glo reagent per well to the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature for 30 minutes, and read the fluorescence signal value with an Envision 2104 microplate reader. 7. The data were fitted by XLfit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)) to calculate the IC ₅₀ value.

(d ) In vitro screening experiment-CellTiter-Glo Luminescent detection of compounds that inhibit TT (Human Medullary Thyroid Cancer Cell) Cell Viability

Experimental steps: 1. Cells were cultured in a 384-well cell culture plate (Corning, 3570) in a medium containing F12K medium, 20% fetal bovine serum, and 1% penicillin-streptomycin at 37°C and 5% CO ₂ Incubate overnight in the cell culture incubator. 2. Dilute the test compound (5 mM stock solution) 2.5 times to 2 mM with 100% DMSO, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 3. Use Echo 550 to add 0.2 μL of serially diluted compounds to 384-well cells, with 2 replicate wells for each concentration, and the final concentration of DMSO is 0.5% (v/v). The gradient concentrations of test compounds were 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM. Cultured in a 5% carbon dioxide incubator for 72 h. 4. Add 30 μL Cell Titer-Glo Reagent to each well of the cell culture plate, shake and mix for 2 minutes to lyse the cells, then incubate at room temperature in the dark for 30 minutes, and use Envision 2104 to read the luminescence signal value. 5. The data were fitted by XLfit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)) to calculate the IC ₅₀ value.

The test results are shown in Table 1 [Table 1] compound RET kinase activity (nM) Ba/F3-KIF5B-RET cell activity (nM) TT cell activity (nM) VEGFR2 kinase activity (nM) BOS 589 0.23 556.3 25.04 92.97 Compound 1 0.26 89.28 2.45 14.65 Compound 2 2.12 660.9 - - Compound 3 0.67 592.8 - - Compound 4 0.935 - - - Compound 5 2.729 - - - Compound 6 6.355 - - - Compound 7 1.295 - - - Compound 8 2.193 - - - Compound 9 1.563 - - - Compound 10 0.467 - - - Compound 11 0.529 - - - Compound 12 1.575 - - - Compound 13 1.269 - - - '-' means not provided.

(e) In vitro screening test-HTRF Method to detect compounds against TRK Inhibitory activity of

式中， R0是溶媒空白組的酶標儀板平均比率 R1是測試化合物酶標儀板比率 R2是100%抑制RET酶活性的酶標儀板平均比率 通過將化合物濃度的抑制率值和對數擬合到非線性回歸(劑量反應-可變斜率)中，用GraphPad 6.0軟體計算IC₅₀ 。 數據由XLfit 5.0按4參數公式：Y=Bottom+(Top-Bottom)/(1+10^((LogIC₅₀ -X)*HillSlope))擬合計算IC₅₀ 值.The method is as follows: 1. Preparation of 1x kinase buffer: mix 5x enzyme buffer with distilled water at a ratio of 1:4, and the final concentration is 5 mM magnesium chloride; 1 mM dithiothreitol. 2. Dilute the test compound (5 mM stock solution) 5-fold to 1 mM with 100% dimethylsulfoxide, and dilute 10 concentrations at 1:3 in a 384-well dilution plate. 3. Use the Echo 550 pipetting system to add 0.2 μL of the serially diluted compound to a 384-well plate, with 2 replicate wells for each concentration, and the final concentration of dimethylsulfoxide is 0.5% (v/v). The gradient concentrations of test compounds were 5000, 1666.7, 555.5, 185.18, 61.72, 20.57, 6.858, 2.286, 0.764, 0.254 nM. 4. Prepare 2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C in 1x Kinase Buffer. 5. Add 5 μL of 2x TRK A/TRK B/TRK C/TRK A G595R/TRK A G667C to a 384-well plate, centrifuge at 1000 g for 30 s, and incubate at room temperature for 10 min. 6. Prepare 2x threonine protein phosphatase-biotin-labeled substrate and adenosine triphosphate mixture with 1x kinase buffer. 7. Add 5 μL of tyrosine kinase-biotin-labeled substrate and adenosine triphosphate mixture to start the reaction. Centrifuge at 1000 g for 30 s, seal the plate, and incubate at room temperature for 40 min. 8. Prepare 4x Sa-XL 665 (Note: a reagent) and tyrosine kinase-antibody-cryptate mixture with homogeneous time-resolved fluorescence detection buffer. 9. Add 5 μL Sa-XL 665 and 5 μL threonine protein phosphatase-antibody-cryptate mixture to each well, centrifuge at 1000 g for 30 s, and incubate at room temperature for 1 h. 10. Read the plate with Envision 2104 microplate reader at 615 nm and 665 nm, and calculate the ratio (665/615 nm). 11. The inhibition rate is calculated as follows:

In the formula, R0 is the average ratio of the microplate instrument plate of the solvent blank group, R1 is the average ratio of the microplate instrument plate of the test compound, and R2 is the average ratio of the microplate instrument plate of 100% inhibition of RET enzyme activity. Integrated into nonlinear regression (dose response - variable slope), _IC50 was calculated using GraphPad 6.0 software. The data were fitted by XLfit 5.0 according to the 4-parameter formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)) to calculate the IC ₅₀ value.

The test results are shown in Table 2: [Table 2] compound TRK A (nM) TRK B (nM) TRK C (nM) TRK A G595R (nM) TRK A G667C (nM) LOXO-195 0.31 0.39 1.61 0.77 14.28 BOS 589 10.73 9.99 16.47 51.31 0.42 GSK-3179106 620.0 61.53 78.50 2099 0.686 Compound 1 1.37 0.77 2.10 2.79 0.26 Compound 2 - - - - - Compound 3 - - - - - Compound 4 24.38 15.40 12.96 111.3 0.926 Compound 5 167.2 57.26 66.50 874.5 1.073 Compound 6 332.6 180.9 181.8 >2000 2.623 Compound 7 20.14 9.476 6.282 84.58 0.979 Compound 8 152.9 57.08 64.63 991.1 1.155 Compound 9 28.18 17.66 13.80 122.0 0.654 Compound 10 1.375 0.761 0.452 2.511 0.466 Compound 11 1.761 0.858 0.637 5.765 0.538 Compound 12 24.23 18.19 10.23 109.4 1.839 Compound 13 26.88 5.854 8.018 83.20 1.104 '-' means not provided.

It can be seen from the above data that the compounds listed in the present invention have good inhibitory activity on Trk A, Trk B, Trk C, and some mutants thereof.

(f ) In vivo efficacy evaluation- Compounds in Telemetry for Irritable Bowel Syndrome (IBS) effect in the model

Experimental animals: normal SD rats, 280-350 g;

Tested compounds: Compound 1 (10 mg/kg), BOS-589 (10 mg/kg);

Experimental steps: 1. Animals were anesthetized with 50 mg/kg pentobarbital sodium, and DSI telemetry implants were embedded in the external oblique muscle to record EMG signals; 2. Define the day of administration as the first day of the experiment (D1), D1-D3, intragastric administration twice a day; D3.5, rectal dilation test after administration in the morning and acetic acid stimulation in the rectum for 1 hour, and the balloon pressure setting When the temperature is 60 mmHg, the EMG signal is recorded and the detection lasts for 10 minutes.

Data analysis: The original data were collected by the DSI system Ponemah software, and analyzed by NeuroScore software and Spike2. For calculating the recorded EMG signal, each pressure value is counted for 10 minutes. The experimental data is represented by the mean value (Mean), and the t-test is used for statistical analysis. P < 0.05 indicates statistical significance, p < 0.01 indicates significant difference, and p < 0.001 indicates extremely significant difference.

Experimental results: group Burst number (0 mm Hg) Burst number (60 mm Hg) negative control group 33 60 BOS-589 (10 mg/kg) 19 (p<0.05) 41 (p<0.05) Compound 1 (10 mg/kg) 12 (p<0.01) 32 (p<0.01)

The results of this experiment showed that the EMG signal burst number of the external oblique muscle in the compound 1 (10 mg/kg) group was significantly reduced in the rectal dilation test after administration. It shows that compound 1 has a certain curative effect on the acetic acid-induced visceral sensitivity model in rats, and the therapeutic effect of compound 1 at the same dose is more significant than that of BOS-589.

。The structure of BOS 589 is as follows:

.

。The structure of LOXO-195 is as follows:

.

。The structure of GSK-3179106 is as follows:

.

In summary, the compounds of the present invention have good RET kinase inhibitory activity and TRK kinase inhibitory activity; the inventors also unexpectedly found that BOS 589 and GSK-3179106 also have certain TRK kinase inhibitory activity through research.

Compared with compound BOS 589, the Ba/F3-KIF5B-RET cell activity of the compound of the present invention increases 6 times, and the TT cell activity improves 12 times; TRK A G595R/TRK A G667C) has stronger inhibitory activity; the therapeutic effect of the compound of the present invention in the IBS model (acetic acid-induced intestinal hypersensitivity model) is significantly better than the same dose of BOS-589 (experimental results of some compounds not shown). The inventor speculates that the possible reason for the unexpected technical effect of the compound claimed in the present invention is that the sulfur pentafluoride functional group in the compound makes it have unique physical and chemical properties and three-dimensional space structure, which can better combine RET/TRK The corresponding pocket of the protein makes the compound of the present invention have better RET/TRK kinase inhibitory activity.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended patent scope of the present application.

Claims (18)

A compound of formula I or a pharmaceutically acceptable salt, hydrate or isotopic compound thereof;

In the formula, each R ₁ is independently H, halogen or selected from substituted or unsubstituted hydroxyl, amino, C1-C6 alkyl,

, C3-C6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl,

,

; R', R "are independently selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl , wherein, the substitution refers to being substituted by one or more groups selected from the following groups: halogen, hydroxyl, C1-C6 alkyl; or when two R ₁ are connected to two adjacent atoms on the ring, It can be fused to form a substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered heterocyclyl, C6 _- C10 aryl, 5-10 membered heteroaryl; each R is independently H, halogen, cyano group, nitro group or selected from substituted or unsubstituted hydroxyl group, amino group,

,

,

, C1-C6 alkyl, C3-C6 cycloalkyl; or when two R ₂ are connected to two adjacent atoms on the ring, it can be fused to form a substituted or unsubstituted C4-C8 cycloalkenyl, 4 -8-membered heterocyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group; each R _b is independently halogen, cyano, nitro or selected from substituted or unsubstituted amino,

,

,

, C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl,

,

, wherein, the substitution refers to being substituted by one or more R _a : each R _a is independently selected from halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy Base, halogenated C1-C6 alkoxy,

; R ₆ , R ₇ and R' ₇ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 Member cycloheteroalkyl; R ₅ is -H, cyano, halogen, nitro or selected from substituted or unsubstituted aldehydes,

,

, amino, hydroxyl, C1-C6 alkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C2-C6 alkenyl, C2- C6 alkynyl, -(L ₁ ) _p -OH, -(L ₁ ) _p -(C1-C6 alkoxy),

Or when R _b and R ₅ are located at two adjacent C atoms, the C atoms connected to them are fused to form substituted or unsubstituted C4-C8 cycloalkenyl, 4-8 membered cycloheteroyl, C6-C10 aryl, 5-10 membered heteroaryl; R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C1-C6 Alkoxy, C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl, the substitution means being replaced by one or more groups selected from the following group Group substitution: halogen, hydroxyl, C1-C6 alkyl, N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen, C1-C6 alkyl; or R ₁₀ and R' ₁₀ forms a substituted or unsubstituted 3-8 membered heterocyclic group together with its connected N atom; or R' ₁₁ and R" ₁₁ form a substituted or unsubstituted 3-8 membered heterocyclic group with its connected N atom ; R ₉ and R' ₉ are each independently H, cyano or selected from substituted or unsubstituted aldehydes, C1-C6 alkyl,

, hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from C1-C6 alkane group, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl; or R ₉ and R' ₉ together form a substituted or unsubstituted The 3-8 membered heterocyclic group; the substitution refers to being substituted by one or more R; each R is independently selected from halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 Alkoxy _; each L and L are independently selected from _:

, CO, SO ₂ ; wherein, R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino; r is 1, 2 or 3; m and p are each independently is 1, 2, 3, 4, 5 or 6; n is 0, 1 or 2; n' is 0, 1, 2 or 3; n" is 0, 1, 2 or 3. The compound of formula I or its pharmaceutically acceptable salt, hydrate or isotopic compound as described in Claim 1, is characterized in that it has the structure shown in formula I':

In the formula, R is selected from H, halogen, hydroxyl, amino, _C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 ring Alkyl, halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, (C1-C6 alkyl) NH-, (C1-C6 alkyl) (C1- C6 alkyl) N- _; each R2 is independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, Halogenated C3-C6 cycloalkyl; R ₃ and R ₄ are each independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkane Base, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl,

,

, wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from the group consisting of cyano, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,

, the C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl; R ₆ , R ₇ and R' ₇ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 membered cyclohetero Alkyl _; R is selected from: hydrogen, cyano, aldehyde,

, amino, hydroxyl, halogen, C1-C6 alkyl, 3-8 membered heteroalkyl, halogenated C1-C6 alkyl, C1-C6 alkylene-OH, -(L ₁ ) _p -(C1-C6 Alkoxy), C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,

,

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, 3-6 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; or R ₁₀ and R' ₁₀ together form a substituted or unsubstituted 3-8 Member heterocyclic group, wherein, the substitution refers to being substituted by one or more groups selected from the following group: halogen, cyano, -CHO, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy group, N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen or C1-C6 alkyl; R ₉ and R' ₉ are each independently selected from cyano, aldehyde base, C1-C6 alkyl,

, hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, 5-10 heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl; or R ₉ and R' ₉ together form a substituted or unsubstituted 3-8 membered heterocycle group, wherein the substitution refers to being substituted by one or more groups selected from the following group: halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; L ₁ and _L2 are each independently

, wherein, said R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino; n is 0, 1 or 2; m and p are each independently 1, 2, 3, 4, 5 or 6. The compound as claimed in item 2 or its pharmaceutically acceptable salt, hydrate or isotope compound, is characterized in that R is selected from: _C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3- C6 cycloalkoxy, halogenated C3 _- C6 cycloalkoxy; R is selected from cyano, aldehyde,

, C1-C6 alkyl, halogenated C1-C6 alkyl, 3-8 membered heteroalkyl, -C1-C6 alkylene-OH, C2-C6 alkenyl, C2-C6 alkynyl, -(L ₁ ) _p -(C1-C6alkoxy),

,

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C3-C6 cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl; or R ₁₀ and R' ₁₀ together form a substituted or unsubstituted 3-8 membered N atom Heterocyclic group, wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy , N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, halogen, C1-C6 alkyl; R ₉ and R' ₉ are each independently selected from cyano, aldehyde , C1-C6 alkyl,

, hydroxyl, 3-8 membered heteroalkyl, 3-8 membered heterocyclic group, 5-10 heteroaryl, wherein, R ₁₂ and R' ₁₂ are each independently selected from: C1-C6 alkyl, halogenated C1- C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl; or R ₉ and R' ₉ together form a substituted or unsubstituted 3-8 membered hetero Cyclic group, wherein the substitution refers to being substituted by one or more groups selected from the following group: halogen, cyano, aldehyde, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy; L ₁ and L ₂ are each independently

, wherein, said R _f and R _g are each independently selected from H, C1-C6 alkyl, halogen, cyano, hydroxyl, amino; m and p are each independently 1, 2, 3, 4, 5 or ₆ ; each R2 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogenated C1 _- C6 alkyl; _R3 and R4 are each independently selected from H, halogen, hydroxyl, amino, Cyano, C1-C6 alkyl, halogenated C1-C6 alkyl. The formula I compound or its pharmaceutically acceptable salt, hydrate, isotope compound as described in claim item 1, it is characterized in that, each R ₁ is independently

; R' are each independently selected from unsubstituted C1-C6 alkyl; each R ₂ is independently halogen; each R _b is independently halogen, cyano, nitro or selected from substituted or unsubstituted amino,

,

,

, C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered cycloheteroalkyl, C6-C10 aryl, 5-10 membered heteroaryl,

,

, wherein, the substitution refers to being substituted by one or more R _a : each R _a is independently selected from halogen, cyano, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy Base, halogenated C1-C6 alkoxy,

; R ₆ , R ₇ and R' ₇ are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, 3-8 Member cycloheteroalkyl; R ₅ is a cyano group or is selected from an unsubstituted aldehyde group,

, C2-C6 alkenyl, C2-C6 alkynyl, -(L ₁ ) _p -OH, -(L ₁ ) _p -(C1-C6 alkoxy),

R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently H or selected from substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member Cycloheteroalkyl, the substitution refers to being substituted by one or more groups selected from the following group: N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H, C1 -C6 alkyl; or R ₁₀ and R' ₁₀ together form a substituted or unsubstituted 3-8 membered heterocyclic group with its connected N atom; or R' ₁₁ and R" ₁₁ form a substituted or unsubstituted N atom with its connected Substituted 3-8 membered heterocyclic group; R ₉ and R' ₉ are each independently H or selected from C1-C6 alkyl; or R ₉ and R' ₉ together form an unsubstituted 3-8 member heterocyclyl _; each L and L are independently selected from _:

; wherein, R _f and R _g are each independently selected from H, C1-C6 alkyl; r is 1; m and p are each independently 1, 2, or 3; n is 1; n' is 1; n" is 0. The formula I compound or its pharmaceutically acceptable salt, hydrate, isotope compound as described in claim item 2, is characterized in that, R ₁ is selected from C1-C6 alkoxy; Each R ₂ is independently selected from halogen; R ₃ and R ₄ are each independently selected from H; R ₅ is selected from: cyano, aldehyde,

, C2-C6 alkenyl, C2-C6 alkynyl,

,

,

,

; R ₈ , R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered cycloheteroalkyl; Or R ₁₀ and R' ₁₀ form a substituted or unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: N( R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are each independently selected from H or C1-C6 alkyl; R ₉ and R' ₉ are each independently selected from C1-C6 alkyl; or R ₉ and R' ₉ forms an unsubstituted 3-8 membered heterocyclic group together with the N atom it is connected to; L ₁ and L ₂ are each independently

, wherein, said R _f and R _g are each independently selected from H, C1-C6 alkyl; n is 1; m and p are each independently 1, 2, or 3. The formula I compound or its pharmaceutically acceptable salt, hydrate, isotope compound as described in claim item 2, is characterized in that, R ₁ is selected from C1-C6 alkoxy; Each R ₂ is independently selected from halogen; R ₃ and R are each independently selected from H _; R _is selected from:

,

; R ₁₀ , R' ₁₀ , R ₁₁ , R' ₁₁ and R" ₁₁ are each independently selected from H, C1-C6 alkyl; or R ₁₀ and R' ₁₀ together form a substituted or unsubstituted 3-8 membered heterocyclic group, wherein, the substitution refers to being substituted by one or more groups selected from the following group: N(R' ₁₃ )(R" ₁₃ ); R' ₁₃ and R" ₁₃ are independently Be selected from C1-C6 alkyl; L ₂ are each independently

, wherein, the R _f and R _g are each independently selected from H; n is 1; m is 1, 2, or 3 each independently. The compound or its pharmaceutically acceptable salt, hydrate or isotope compound as described in Claim 1 or 2, is characterized in that, the compound is selected from

The compound as claimed in item 1 or 2 or its pharmaceutically acceptable salt, hydrate or isotope compound, is characterized in that, the compound is

A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, hydrate or isotopic compound thereof; and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to claim 9, further comprising one or more therapeutic agents selected from the group consisting of aminosalicylic acid preparations, glucocorticoids, PD-1 inhibitors, and PD-L1 inhibitors , CD20 antibody, CD47 antibody, ALK inhibitor, PI3K inhibitor, BTK inhibitor, EGFR inhibitor, VEGFR inhibitor, HDAC inhibitor, CDK inhibitor, MEK Inhibitors, Akt inhibitors, mTOR inhibitors, SHP2 inhibitors, IGF-1R inhibitors. The pharmaceutical composition as claimed in item 10, wherein the aminosalicylic acid preparation is sulfasalazine; the glucocorticoid is selected from the group consisting of hydrocortisone and dexamethasone; The PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs; the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB- A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs; the CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ofatum monoclonal antibody, tositumomab, imolimomab; the CD47 antibody is selected from the group consisting of: Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX- 148, NI-1701, SHR-1603, IBI188, IMM01; the ALK inhibitor is selected from the group consisting of ceritinib, alectinib, brigatinib, lorlatinib, ocatinib; The PI3K inhibitor is selected from the following group: Idelaris, Dactolisib, Taselisib, Buparlisib; the BTK inhibitor is selected from the following group: Ibrutinib, Tirabrutinib, Acalabrutinib; The EGFR inhibitor is selected from the group consisting of Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib; the VEGFR inhibitor Selected from the following group: Sorafenib, Pazopanib, Rivatinib, Cabozantinib, Sunitinib, Donafenib; the HDAC inhibitor is selected from the following group: Givinostat, Droxinostat, Enzyme Tenote, dalcylast, tekedinaline; the CDK inhibitor is selected from the group consisting of palbociclib, ribociclib, Abemaciclib, Lerociclib; the MEK inhibitor is selected from the group consisting of Sime Tini (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040); the Akt inhibitor is selected from the group consisting of: MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib The mTOR inhibitor is Vistusertib; the SHP2 inhibitor is selected from the group: RMC-4630, JAB-3068, TNO155; and the IGF-1R inhibitor is selected from the group: Ceritinib, Ocatinib, linsitinib , BMS-754807, GSK1838705A. A compound as described in any one of claim items 1 to 8 or a pharmaceutically acceptable salt, hydrate, isotopic compound thereof or a pharmaceutical composition as described in claim item 9 in the preparation of treating irritable bowel syndrome, other Use in medicine for bowel-related diseases and/or cancer. The use according to claim 12, wherein the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome, constipation-dominant irritable bowel syndrome syndrome, mixed irritable bowel syndrome, unspecified irritable bowel syndrome; the other intestinal related diseases are functional flatulence, functional constipation, non-specific functional bowel disorder, functional abdominal pain syndrome, Chronic idiopathic constipation, functional gastroduodenal disease. Use according to claim 12, characterized in that the cancer is bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , familial adenomatous polypoid carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, Renal parenchymal cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia , hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, or multiple myeloma. Use according to claim 12, characterized in that the cancer is non-small cell lung cancer, glioma, multiple myeloma, hepatobiliary liver cancer, medullary thyroid cancer, thyroid papillary tumor, neuroblastoma, colon Carcinoma, squamous cell carcinoma of the head and neck, pancreatic cancer, sarcoma, melanoma, fibrosarcoma, pancreatic tumor, soft tissue sarcoma, high-solid tumor, breast tumor, or cholangiocarcinoma. A compound as described in any one of claim items 1 to 8 or a pharmaceutically acceptable salt, hydrate or isotopic compound thereof is used in the preparation of treatment of neurodegenerative diseases, chronic pain, acute pain, inflammatory diseases, inflammatory bowel disease sick, Use in medicine for Trypanosoma cruzi infection or diseases associated with imbalances in the regulation of bone remodeling. A compound as described in any one of claim items 1 to 8 or a pharmaceutically acceptable salt, hydrate, isotopic compound or a pharmaceutical composition as described in any one of claim items 9 to 11 is used in the preparation of Use in a medicament for inhibiting RET kinase and/or TRK kinase activity in a cell or a subject. A method for preparing the compound as described in claim 1 or a pharmaceutically acceptable salt, hydrate or isotopic compound thereof, comprising the steps of:

1) reacting the compound of formula M with the compound of formula N to obtain the compound of formula A;

2) reacting the compound of formula A with an acid to obtain the compound of formula I; wherein, Y is selected from OH and halogen; other groups are as defined in Claim 1.