Polycyclic compound containing fused spirocyclic structure, and pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a polycyclic compound containing a fused spirocyclic structure, and a pharmaceutical composition thereof and the use thereof. Specifically, provided in the present invention are a compound having a skeleton structure as represented by formula (I), a pharmaceutically acceptable salt, isotopic derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule or metabolite thereof, and a pharmaceutical composition thereof and the use thereof. The compound of the present invention can efficiently inhibit the activity of DDR1, DDR2, and other kinases, achieves a strong signal inhibitory effect on a downstream pathway thereof, and can be used for preparing anti-tumor drugs and drugs for preventing and treating inflammatory diseases.

Description

A class of polycyclic compounds containing fused spirocyclic structures, their pharmaceutical compositions and applications Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically relating to a class of polycyclic compounds containing fused spirocyclic structures, their pharmaceutical compositions, and applications. Background Technology

[0002] Discoidin domain receptors (DDRs) are members of the transmembrane receptor tyrosine kinase (RTK) superfamily, discovered in the early 1990s. They include two proteins, DDR1 and DDR2. Unlike other receptor tyrosine kinases, DDRs contain a discoid domain and a discoid-like domain in their extracellular region. DDRs are activated by the abundant triple-helical collagen in the extracellular matrix (ECM), which is also the most abundant component of the extracellular matrix. DDR1 is widely expressed in epithelial cells of organs such as the lung, kidney, colon, and brain, and can bind to many reported types of collagen. DDR2 is mainly expressed in mesenchymal cells of the kidney, skin, lung, heart, bone, and connective tissues, including fibroblasts and myofibroblasts. Many studies have shown that DDR1 and DDR2 play important roles in fundamental cellular processes such as proliferation, survival, differentiation, adhesion, and matrix remodeling.

[0003] Dysregulation of matrix metalloproteinases (DDRs) is closely related to numerous human diseases, including fibrosis, atherosclerosis, and cancer. In human smooth muscle cells, activation of DDR1 and DDR2 enhances the activity of matrix metalloproteinases, leading to further extracellular matrix remodeling in pulmonary and vascular obstructive diseases. Related reports have confirmed the crucial role of collagen-DDR1 interaction in severe renal fibrosis and Alport syndrome. Further scientific research has demonstrated that knocking out DDR1 to block the activation of the p38 MAPK pathway can alleviate bleomycin-induced pulmonary fibrosis. Furthermore, in various kidney disease models, gene-level knockout and inhibition of DDR1 expression can alleviate renal fibrosis inflammation, reduce renal proteinuria symptoms, and slow down structural kidney disease.

[0004] Besides its crucial role in inflammatory diseases, DDR1 is also closely associated with various types of tumors. High expression of DDR1 or DDR1 mutations are frequently found in multiple cancer cell lines and primary tumors of the lung, breast, brain, ovary, head and neck, liver, pancreas, and prostate. Studies have demonstrated that interfering with DDR1 expression using short interfering RNA fragments can inhibit tumorigenesis and formation, reduce bone metastasis in lung cancer cells, and enhance the chemosensitivity of cancer cells. In conclusion, DDR1 is an important molecular target for the treatment of inflammatory diseases and cancer.

[0005] However, existing DDR1 / 2 inhibitors cannot meet the broad clinical needs. Therefore, there is an urgent need in the field to develop a DDR1 / 2 inhibitor that is highly selective, potent, and safe. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a class of polycyclic compounds containing a fused spirocyclic structure, pharmaceutical compositions thereof, and their use as DDR1 / 2 inhibitors. The compounds and / or pharmaceutical compositions of this invention can efficiently and selectively inhibit DDR1 / 2 tyrosine protein kinases and can be used to prepare preparations for the prevention and / or treatment of various diseases mediated by DDR1 / 2 tyrosine protein kinases, such as inflammatory diseases, cardiovascular diseases, fibrotic diseases, and cancer.

[0007] In a first aspect, the present invention provides a compound having the structure shown in formula (I), a pharmaceutically acceptable salt thereof, an isotopic derivative thereof, a solvate thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a prodrug molecule thereof, or a metabolite thereof:

[0008] in,

[0009] U, V, W, E, X, Y, and Z are each independently N or CR3;

[0010] B is selected from the following group:

[0011] C and D are each independently selected from the following groups:

[0012] Each R3 is independently selected from the following groups:

[0013] 1) Substituted or unsubstituted groups selected from the following group: C3-C 12 Saturated or unsaturated carbon rings, 3-12 membered saturated or unsaturated heterocycles, 7-12 membered fused heterocycles, 7-12 membered spirocyclic heterocycles, 7-12 membered bridged heterocycles, C6-C 10 Aromatic rings, 5-12 quinary aromatic rings;

[0014] 2) Hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 heteroalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, -(CH2) m R4、-NH(CH2) m R4, -NR5(CH2) m R4、-O(CH2) m R4;

[0015] Where m is 0, 1, 2 or 3;

[0016] R4 and R5 are each independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C. 12 Saturated or unsaturated carbocyclic rings, substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-12-membered heteroaromatic rings, C1-C8 alkyl groups, C1-C8 alkoxy groups, C3-C8 cycloalkyl groups, C1-C8 azaalkyl groups, C1-C8 haloalkyl groups, C1-C8 haloalkoxy groups, C3-C8 halocycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C2-C8 ester groups, C1-C8 amide groups, -S(O)C1-C8 alkyl groups, -S(O)2C1-C8 alkyl groups, or R4, R5 and the atoms they are attached to form substituted or unsubstituted groups selected from the group consisting of: 4-12-membered monoheterocycles, 7-12-membered fused heterocycles, 7-12-membered spiroheterocycles or 7-12-membered bridged heterocycles;

[0017] L is selected from the following group: chemical bond, C1-C4 straight-chain alkylene, C1-C3 alkylene-C(O)O-C1-C3 alkylene.

[0018] Ring A is selected from the following group: C 6-10 Aromatic rings, 5-12 membered heterocyclic rings, 3-8 membered heterocyclic rings;

[0019] R1 and R2 are each independently selected from the following groups:

[0020] 1) by 1, 2, 3 or 4 R a Replaced or not replaced Where L2 is C 0-4 Alkylene, cyclic B is selected from the following group: C3-C 12 Saturated or unsaturated carbon rings, 3-12 membered saturated or unsaturated heterocycles, 7-12 membered fused heterocycles, 7-12 membered spirocyclic heterocycles, 7-12 membered bridged heterocycles, C6-C 10Aromatic rings, 5-12 heterocyclic aromatic rings;

[0021] 2) Hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, -SF5, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, -(CH2) m R6、-NH(CH2) m R6, -NR7(CH2) m R6, -O(CH2) m R6;

[0022] R6 and R7 are selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C. 12 Saturated or unsaturated carbocyclic rings, substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-12 membered heteroaromatic rings, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, -CR 6a R 6b R 6c -OR8, -NR 7a R 7b ;

[0023] Among them, R 6a R 6b R 6c R8, R 7a and R 7b Each is independently selected from the group consisting of: hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, or R 6a R 6b R 6c Together with the carbon atom to which it is attached, they form substituted or unsubstituted groups selected from the group consisting of: 4-12 membered monoheterocycles, 7-12 membered fused heterocycles, 7-12 membered spiroheterocycles, and 7-12 membered bridged heterocycles; or R 7a R 7bTogether with the carbon atom to which it is attached, it forms a substituted or unsubstituted group selected from the group consisting of: 5-12-membered heteroaromatic rings, 4-12-membered monoheterocyclic rings, 7-12-membered fused heterocyclic rings, 7-12-membered spiroheterocyclic rings, and 7-12-membered bridged heterocyclic rings.

[0024] R a Selected from the following groups: hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -OS(O)2-halogen, -S(O)2C1-C8 alkyl, -CONR 12 R 13 -C 0-4 alkylene-4-10-membered heterocyclic group, -C 0-4 Alkylene-C 6-10 Aromatic ring, -C 0-4 alkylene-5-9 membered heteroaryl rings, or two Rs on adjacent atoms a Together with the atoms they are attached to, they form 5-9 membered heteroaromatic rings or 4-8 membered heterocycles;

[0025] R 12 and R 13 Each is independently selected from the following group: hydrogen, deuterium, C1-C8 alkyl, -C 0-4 alkylene-C1-C8 alkylamino;

[0026] Unless otherwise specified, "substitution" as used above refers to the replacement of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, oxo, unsubstituted or halogenated C1-C6 sulfone, unsubstituted or halogenated C1-C6 sulfoxide, unsubstituted or halogenated C1-C6 sulfinyl, unsubstituted or halogenated C1-C6 sulfonylimide, unsubstituted or halogenated C1-C6 alkyl, Unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C1-C6 acyl, unsubstituted or halogenated C1-C6 amide, unsubstituted or halogenated C1-C6 alkylamine, unsubstituted or halogenated C1-C6 alkyl-hydroxy, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic groups;

[0027] The heterocycle refers to a cyclic group containing one, two, or three heteroatoms selected from N, O, or S, which is saturated or partially unsaturated and non-aromatic. It can be a monocyclic, fused, bridged, or spirocyclic ring.

[0028] In a preferred embodiment, ring A is selected from the group consisting of: phenyl, naphthyl, 5-7 membered heteroaromatic rings, benzo[a] 5-7 membered heteroaromatic rings, 5-7 membered heteroaromatic rings, and 3-8 membered heterocycles;

[0029] Ring A is selected from the following group: pyrazole, imidazole, pyrrole, triazole, phenyl, pyridine, diazine, triazine, thiophene, thiazole, isothiazine, furan, oxazole, isoxazole, indole, isoindole, benzopyrazole, benzimidazole, benzothiophene, benzofuran, quinoline, isoquinoline, benzodiazine, benzotriazine, 3-8 membered heterocycles;

[0030] Preferably, ring A is selected from the group consisting of: pyrazole, imidazole, pyrrole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1,3,4-triazine, indole, isoindole, benzopyrazole, benzimidazole, quinoline, isoquinoline, benzodiazine, and benzotriazine.

[0031] In a preferred embodiment, L is selected from the group consisting of:

[0032] In a preferred embodiment, R1 is selected from the group consisting of:

[0033] 1) by 1, 2 or 3 R 1a Substituted or unsubstituted groups selected from the group consisting of: C3-C 10 Cycloalkyl, 4-10 membered saturated or unsaturated heterocycles, C6-C 10 Aromatic rings, 5-9 quintile aromatic rings;

[0034] 2) Hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, cyano, amino, -SF5, C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -NHR6, -NR7R6;

[0035] R6 and R7 are each independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, or R6 and R7 together with the atoms they are attached to form substituted or unsubstituted groups selected from the following group: 4-7 membered monoheterocycles, 7-12 membered fused heterocycles, 7-12 membered spiroheterocycles, 7-12 membered bridged heterocycles;

[0036] R 1aSelected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, 4-7 membered heterocyclic group, C 6-10 Aromatic rings, 5-7 quintile aromatic rings;

[0037] Preferably, R1 is selected from the group consisting of:

[0038] 1) by 1, 2 or 3 R 1a Substituted or unsubstituted groups selected from the group consisting of: C3-C8 cycloalkyl, 4-7 membered saturated or unsaturated heterocycles, C6-C 10 Aromatic rings, 5-7 quintile aromatic rings;

[0039] 2) Hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, halogen, hydroxyl, cyano, amino, -SF5, C2-C4 ester, C1-C4 amide, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, -NHR6, -NR7R6;

[0040] R6 and R7 are each independently selected from the following group: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, or R6 and R7 together with the atoms they are attached to form substituted or unsubstituted groups selected from the following group: 4-7 membered monoheterocycles, 7-10 membered fused heterocycles, 7-10 membered spiroheterocycles, 7-10 membered bridged heterocycles;

[0041] R 1a Selected from the following groups: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C 2-4 Ester group, C1-C4 amide group, -S(O)C1-C4 alkyl group, -S(O)2C1-C4 alkyl group, 4-7 membered heterocyclic group, phenyl, naphthyl, 5-7 membered heteroaromatic ring.

[0042] In a preferred embodiment, R2 is selected from the group consisting of:

[0043] 1) by 1, 2, 3 or 4 R 2a Replaced or not replaced Where L2 is C 0-4Alkylene, cyclic B is selected from the following group: C3-C 10 Cycloalkyl, 4-10 fused or unsaturated heterocycles, 7-10 fused heterocycles, 7-10 spirocyclic heterocycles, 7-10 bridged heterocycles, C6-C 10 Aromatic rings, 5-12 heterocyclic aromatic rings;

[0044] 2) Hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, cyano, amino, C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -(CH2) m R 10 -NH(CH2) m R 10 -NR 11 (CH2) m R 10 -O(CH2) m R 10 ;

[0045] Where m is 0, 1, 2 or 3;

[0046] R 10 and R 11 Each is independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C. 10 Saturated or unsaturated carbocyclic rings, substituted or unsubstituted 4-10 member saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-9 membered heteroaromatic rings, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, or R 10 R 11 It forms, together with the atoms it is attached to, a substituent or unsubstituent group selected from the following group: 5-9 membered heteroaromatic rings, 4-7 membered monoheterocyclic rings, 7-10 membered fused heterocyclic rings, 7-10 membered spiroheterocyclic rings, and 7-10 membered bridged heterocyclic rings;

[0047] R 2a Selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C6 ester, C1-C6 amide, -OS(O)2-halogen, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -CONR 12 R 13 -C 0-4 alkylene-4-7-membered heterocyclic group, -C0-4 Alkylene-C 6-10 Aromatic ring, -C 0-4 alkylene-5-7-membered heteroaryl ring, or two R atoms on adjacent atoms 2a Together with the atoms they are attached to, they form 5-7 membered heteroaromatic rings or 4-8 membered heterocycles;

[0048] R 12 and R 13 Each is independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, -C 0-4 alkylene-C1-C6 alkylamino;

[0049] Preferably, R2 is selected from the group consisting of:

[0050] 1) by 1, 2 or 3 R 2a Replaced or not replaced Where L2 is C 0-4 Alkylene, ring B is selected from the following group: C3-C8 cycloalkyl, 4-7 saturated or unsaturated heterocycles, 7-10 fused heterocycles, 7-10 spiroheterocycles, 7-10 bridged heterocycles, benzene rings, naphthalene rings, 5-7 heteroaromatic rings, benzo5-7 heteroaromatic rings;

[0051] 2) Hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halogen, hydroxyl, cyano, amino, C2-C4 ester, C1-C4 amide, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, -(CH2) m R 10 -NH(CH2) m R 10 -NR 11 (CH2) m R 10 -O(CH2) m R 10 ;

[0052] Where m is 0, 1, 2 or 3;

[0053] R 10 and R 11 Each is independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C8 saturated or unsaturated carbon rings, substituted or unsubstituted 4-7 membered saturated or unsaturated heterocycles, substituted or unsubstituted benzene rings, substituted or unsubstituted 5-9 membered heteroaromatic rings, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, or R 10 R 11It forms, together with the atoms it is attached to, a substituent or unsubstituent group selected from the following groups: 5-7 membered heteroaromatic rings, 4-7 membered monoheterocyclic rings, 7-10 membered fused heterocyclic rings, 7-10 membered spiroheterocyclic rings, and 7-10 membered bridged heterocyclic rings;

[0054] R 2a Selected from the following groups: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C4 ester, C1-C4 amide, -OS(O)2-F, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, -CONR 12 R 13 -C 0-4 alkylene-4-7-membered heterocyclic group, -C 0-4 alkylene-benzene ring, -C 0-4 alkylene-5-7-membered heteroaryl ring, or two R atoms on adjacent atoms 2a Together with the atoms they are attached to, they form 5-7 membered heteroaromatic rings or 4-8 membered heterocycles;

[0055] R 12 and R 13 Each is independently selected from the following group: hydrogen, deuterium, C1-C4 alkyl, -C 0-4 Alkylene-C1-C4 alkylamino.

[0056] In another preferred embodiment, ring B is selected from the group consisting of: pyrazole, imidazole, pyrrole, triazole, phenyl, pyridine, diazine, triazine, thiophene, thiazole, isothiazine, furan, oxazole, isoxazole, indole, isoindole, benzopyrazole, benzimidazole, benzothiophene, benzofuran, quinoline, isoquinoline, benzodiazine, benzotriazine, and 4-7 member nitrogen-containing heterocycles.

[0057] In another preferred embodiment, B is selected from the group consisting of:

[0058] In another preferred embodiment, both C and D are

[0059] In another preferred embodiment, E is CH or N.

[0060] In another preferred embodiment, U, V, W, E, X, Y and Z are each independently N or CR3;

[0061] Each R3 is independently selected from the group consisting of: hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 aziralkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, substituted or unsubstituted C3-C 12 Cycloalkyl, substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-12 membered heterocyclic aromatic rings.

[0062] In another preferred embodiment, U, V, W, E, X, Y and Z are each independently N or CR3;

[0063] Each R3 is independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 azaalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, cyano, amino, C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered saturated or unsaturated heterocycles, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-9 membered heteroaromatic rings.

[0064] In another preferred embodiment, U, V, W, E, X, Y and Z are each independently N or CR3;

[0065] Each R3 is independently selected from the following group: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aziralkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, halogen, hydroxyl, cyano, amino, C 2-4 Ester group, C1-C4 amide group, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-7 membered saturated or unsaturated heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-7 membered heteroaromatic ring.

[0066] In a preferred embodiment, the Selected from the following group: Preferably, the Selected from the following group:

[0067] Among them, R 3a R 3u and R 3wThe definitions are the same as for R3; the definitions of B and D are as described above.

[0068] More preferably, the Selected from the following group:

[0069] In a preferred embodiment, the compound has the structure shown in formula (II):

[0070] The definitions of U, V, W, E, X, Y, Z, B, R3, L, ring A, R1, and R2 are as described above.

[0071] In another preferred embodiment, the compound has the structure shown in formula (III):

[0072] Where n is 0, 1, 2 or 3;

[0073] U, V, W, E, Y, B, R3, ring A, R1, L2, ring B and R 2a The definition is as described above.

[0074] In another preferred embodiment, the compound has the structure shown in formula (IV) or formula (V):

[0075] Among them, U, V, W, E, Y, R3, R1, L2, ring B, n and R 2a The definition is as described above. In another preferred embodiment, the compound has the structure shown in formula (VI) or formula (VII):

[0076] Among them, U, V, W, E, Y, R3, R1, L2, n and R 2a The definition is as described above.

[0077] In a preferred embodiment, the compound is selected from the group consisting of:

[0078] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0079] (i) the compounds, pharmaceutically acceptable salts, isotopic derivatives, solvates, stereoisomers, geometric isomers, tautomers, prodrug molecules, or metabolites described in the first aspect of the invention, and

[0080] (ii) Pharmaceutically acceptable carriers, excipients or excipients.

[0081] A third aspect of the invention provides the use of the compounds described in the first aspect of the invention, pharmaceutically acceptable salts thereof, isotope derivatives, solvates, stereoisomers, geometric isomers, tautomers, prodrug molecules or metabolites, or pharmaceutical compositions as described in the second aspect of the invention, for the preparation of medicaments for the prevention and / or treatment of DDR1 / 2-mediated diseases.

[0082] Preferably, the diseases mediated by DDR1 / 2 are selected from the group consisting of: inflammatory diseases, cardiovascular diseases, fibrotic diseases, and cancer;

[0083] More preferably, the diseases mediated by DDR1 / 2 are selected from the group consisting of: pulmonary fibrosis, renal fibrosis, acute lung injury, lung cancer, breast cancer, and pancreatic cancer.

[0084] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0085] In some embodiments, the use of a novel class of DDR1 / 2 inhibitors containing a spirocyclic structure or pharmaceutical compositions thereof in the preparation of DDR1 / 2 inhibitors is provided.

[0086] Another object of the present invention is to provide the use of the above-mentioned DDR1 / 2 inhibitor or its pharmaceutically acceptable salt, isotope derivative, solvate, or stereoisomer, geometric isomer, tautomer containing absolute configuration, or its prodrug molecule and metabolite in the preparation of a drug for the prevention and / or treatment of inflammatory diseases, cardiovascular diseases, fibrotic diseases and cancer mediated by DDR1 / 2 tyrosine protein kinase.

[0087] Another object of the present invention is to provide a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases, cardiovascular diseases, fibrotic diseases and cancer mediated by DDR1 / 2 tyrosine protein kinase, comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the above-described DDR1 / 2 inhibitor or a pharmaceutical composition thereof, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof containing absolute configuration, or a prodrug molecule and metabolite thereof.

[0088] the term

[0089] Unless otherwise specified, the experimental methods described in the following embodiments of the present invention are generally performed under conventional conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the embodiments are commercially available products.

[0090] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0091] The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0092] The terms “containing” or “including” as used herein can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0093] In this invention, "multiple" refers to two or more, such as 2, 3, 4, 5, or 6. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0094] In the compounds of this invention, when any variable (e.g., R1, R2, etc.) appears more than once in any component, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. A line drawn from a substituent into the ring system indicates that the bond referred to can be attached to any substituted ring atom. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of a neighboring ring. It will be understood that those skilled in the art can select the substituents and substitution forms of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these groups can be on the same carbon atom or different carbon atoms, as long as structural stability is achieved.

[0095] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbons having a specific number of carbon atoms. For example, the definition of "C1-C8 alkyl" includes saturated aliphatic hydrocarbon groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched manner.

[0096] As used in this article, the term "alkylene" refers to the group obtained by removing a hydrogen atom from an alkyl group as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0097] As used herein, the term "haloalkyl" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group as described above with the same or different halogens. "C1-C6 haloalkyl" is preferably a C1-C4 haloalkyl, and examples of haloalkyl include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3-, -CF2CF3), etc.

[0098] As used in this article, the term "heteroalkyl" refers to a group in which a non-terminal carbon atom of an alkyl group is replaced by one or more heteroatoms such as O, S, or NH. For example, "C1-C8 heteroalkyl" refers to a heteroalkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms and 1, 2, or 3 heteroatoms such as O, S, or NH. For example, "azaalkyl" refers to a group in which a non-terminal carbon atom of an alkyl group is replaced by one or more NH atoms. Examples of “C1-C8 heteroalkyl” include, but are not limited to: -CH2-O-CH2CH3, -CH2-O-(CH2)2CH3, -CH2CH2-O-CH2CH3, -CH2-O-CH2CH2CH3, -CH2-S-CH2CH3, -CH2-S-(CH2)2CH3, -CH2CH2-S-CH2CH3, -CH2-S-CH2CH2CH3, -CH2-NH-CH2CH3, -CH2-NH-(CH2)2CH3, -CH2CH2-NH-CH2CH3, -CH2-NH-CH2CH2CH3, etc.

[0099] As used herein, the term "alkoxy" refers to an alkyl-oxy group, i.e., -O-alkyl, where alkyl is defined as described above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0100] As used herein, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group as described above with the same or different halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0101] As used herein, the term "hydroxyalkyl" refers to an alkyl group containing one or more hydroxyl groups, and the definition of an alkyl group is as described above. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, etc.

[0102] The term "amide group" as used in this article refers to -CONR x R x', where R x and R x' It can be independently selected from the following group: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic. For example, "C1-C8 amide group" refers to -CONR x R x' , where R x and R x' Independently hydrogen or C1-C8 alkyl, and R x and R x The total number of carbon atoms in ' is 0, 1, 2, 3, 4, 5, 6, 7, or 8. R x and R x' They can be the same or different. Examples of amide groups include, but are not limited to: -CONH2, -CONHCH3, -CON(CH3)2, etc.

[0103] As used herein, the term "ester group" refers to -COOR y , where R y It can be independently selected from the following group: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic. For example, "C1-C8 ester group" refers to -COOR. y , where R y It is a C1-C8 alkyl group. Examples of C1-C8 ester groups include, but are not limited to: -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2, etc.

[0104] As used herein, the term "cycloalkyl" refers to a cyclic aliphatic alkane having a specific number of carbon atoms, and whose ring skeleton consists entirely of carbon atoms. In some preferred embodiments, the carbon ring may be saturated or partially unsaturated, but it does not possess aromaticity. For example, C3-C8 cycloalkyl refers to a cyclic alkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms as its ring skeleton, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, or similar structures.

[0105] As used herein, the term "aryl" or "aromatic ring" refers to an aromatic cyclic group having a specific number of carbon atoms, such as an aryl group having 6, 7, 8, 9, 10, 11, or 12 carbon atoms, including monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, or similar groups.

[0106] The term "heterocycle" refers to a saturated or unsaturated cyclic substituent (including monocyclic or polycyclic cyclic groups) having a specific number of ring atoms, but without aromaticity. For example, a 3-12 membered heterocycle refers to a saturated or unsaturated cyclic substituent having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 members, wherein the ring skeleton includes at least one (e.g., 2, 3, 4, or 5) heteroatoms selected from O, S, or N, such as monocyclic heterocycles: piperidinyl, morpholinyl, dihydropiperidinyl, thiomorpholinyl, piperidinyl, piperazine, tetrahydropyranyl, dihydropyranyl, pyrrololinyl, tetrahydrothiophene, tetrahydrofuranyl, oxobutane, thiobutane, azabutane, or similar groups, preferably 4-12 membered heterocyclic groups; polycyclic heterocyclic groups include, but are not limited to, spiroheterocycles, fused heterocycles, and bridged heterocycles.

[0107] As used herein, the term "heteroaryl" or "heteroary ring" refers to an aromatic cyclic group having a specific number of heteroatoms, wherein at least one (e.g., 2, 3, or 4) heteroatoms is selected from O, S, or N, for example, a heteroaryl having 5, 6, 7, 8, 9, or 10 heteroatoms, including monocyclic or bicyclic heteroaryls, such as pyridine, pyrimidine, pyridazine, tetrazine, and triazine (including 1,2,3-triazine, 1,3,5-triazine, 1,3,4-triazine). Azides, diazons (including pyridazine, pyrimidine, pyrazine), pyrrole, thiophene, furan, tetrazolium, triazole (including 1,2,3-triazole and 1,2,4-triazole), imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, oxadiazole, thiadiazole, naphthalene, indole, indazole, quinoline, isoquinoline, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzoisothiazole, benzoisoxazole, benzotriazole, or similar groups.

[0108] As will be understood by those skilled in the art, the term “halogen” as used herein refers to chlorine, fluorine, bromine, and iodine.

[0109] This invention includes the free form of compounds of formula (I), including pharmaceutically acceptable salts, isotopic derivatives, solvates thereof, or stereoisomers, geometric isomers, tautomers containing absolute configurations, or prodrug molecules and metabolites thereof. The term "free form" refers to a compound in a non-salt form. Pharmaceutically acceptable salts included hereinclude not only exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formula (I). The free form of a specific salt of the compound can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous solution of a base, such as a dilute aqueous solution of NaOH, potassium carbonate, dilute ammonia, or sodium bicarbonate. The free form may differ somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0110] Active ingredients

[0111] This document discloses compounds of formula (I), including compounds of formulas (II) to (VII) (the structures of which are disclosed herein) and their pharmaceutically acceptable salts, isotopic derivatives, solvates, or stereoisomers, geometric isomers, tautomers containing absolute configurations, or their prodrug molecules and metabolites.

[0112] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing either a basic or acidic moiety using conventional chemical methods. Typically, salts of basic compounds are prepared by ion-exchange chromatography or by reacting a free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0113] Therefore, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting the compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, etc.

[0114] If the compounds of this invention are acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary, and tertiary amines, wherein substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

[0115] The compounds disclosed in this invention comprise at least one asymmetric or chiral center and can therefore exist in stereoisomer form. Each chiral center is “R” or “S”, depending on the configuration of the substituents surrounding the chiral carbon atom. Various stereoisomers and mixtures thereof are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. A single stereoisomer of a compound can be prepared by synthesis from commercially available starting materials containing an asymmetric or chiral center, or by preparing a racemic mixture and then resolving it according to methods well known to those skilled in the art. Examples of such resolving methods are as follows: (1) linking an enantiomer mixture to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and optionally releasing the optically pure product from the auxiliary agent; (2) directly separating the optically enantiomer mixture on a chiral chromatographic column; (3) fractional recrystallization.

[0116] The compounds disclosed in this invention may exist in different geometric isomers and tautomers, and all such forms are included within the scope of this disclosure.

[0117] The compounds disclosed in this invention may also be in prodrug form. As used herein, the term "prodrug" refers to a compound that produces an active compound upon metabolism (e.g., in vivo or in vitro). In some embodiments, a prodrug may be inactive or have lower activity than the free drug, but may provide advantageous treatment, administration, or metabolic properties. Exemplary prodrug portions of this invention may be linked to the free drug via a hydroxyl, amino, phosphate, or thiophosphate backbone of a nucleotide, and may comprise esters, carbamates, carbonyl groups, thioesters, amides, isocyanates, ureas, thioureas, or other physiologically acceptable metabolically unstable moieties. In some embodiments, the prodrug is activated by enzymatic hydrolysis.

[0118] The compounds disclosed in this invention can exert their pharmacological effects in the form of their metabolites in vivo (including in animals and humans), and all such metabolites are included within the scope of this disclosure.

[0119] This disclosure also includes isotopically labeled compounds, identical to those listed in formulas (I) and (II), which also contain one or more atoms replaced by atoms having atomic mass numbers different from those commonly found in nature. Examples of isotopes suitable for inclusion in compounds of this disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, but not limited to... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 34 S, 18F and 37 Cl. Using heavier isotopes (e.g., deuterium, i.e.) 2 Substitution with H) can provide certain therapeutic advantages stemming from increased metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. This compound can be combined with positron emission isotopes for medical imaging and positron emission tomography (PET) studies for determining receptor distribution. Suitable positron emission isotopes that can be incorporated into compounds of formulas (I) and (II) are... 11 C 13 N、 15 O and 18 F. Isotopically labeled compounds of formula (I) and (II) can generally be replaced by a suitable isotopically labeled reagent instead of a non-isotopically labeled reagent using conventional techniques known to those skilled in the art or by methods similar to those described herein.

[0120] The compounds disclosed herein can exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and this disclosure is intended to cover both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In yet another embodiment, the compound is in crystalline form.

[0121] Pharmaceutical Compositions and Administration

[0122] Since the compounds disclosed herein are DDR1 / 2 inhibitors, the following description relates to the activity of DDR1 / 2.

[0123] Because the compounds of the present invention can inhibit DDR1 / 2 and are used to treat diseases such as inflammatory diseases, cardiovascular diseases, fibrotic diseases, and cancer, the compounds of the present invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotopic derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) diseases mediated by DDR1 / 2 (inflammatory diseases, cardiovascular diseases, fibrotic diseases, and cancer, etc.).

[0124] The pharmaceutical compositions of the present invention comprise an effective amount, such as a safe and effective amount, of the compound of the present invention or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof containing absolute configuration, or a prodrug molecule and metabolite thereof. "Effective amount" means an amount sufficient to elicit a desired biological response (e.g., treatment of a condition). "Safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition comprises 1 to 3000 mg of the compound of the present invention per dose, more preferably 10 to 2000 mg of the compound of the present invention per dose. Preferably, "one dose" is a capsule or tablet.

[0125] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels suitable for human use, which must have sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be mixed and blended with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier portions include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, and cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid and magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, and olive oil), polyols (e.g., propylene glycol, glycerin, mannitol, and sorbitol), emulsifiers (e.g., ... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, and pyrogen-free raw water.

[0126] There are no particular limitations on the administration routes of the compounds or pharmaceutical compositions of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), or local administration.

[0127] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or fillers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, some complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) absorption enhancers, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the formulation may also include a buffer.

[0128] Solid dosage forms, such as tablets, sugar-coated pills, capsules, pellets, and granules, can be prepared from coating and shell materials, such as enteric coatings and other materials well known in the art. They may contain light-blocking agents, and the active compound, or compounds in such compositions, may be released in a delayed manner into a portion of the digestive tract. Examples of usable embedded ingredients are polymers and waxes. If necessary, the active compound may also form microcapsules with one or more of the excipients described above.

[0129] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.

[0130] In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0131] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0132] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0133] Dosage forms for topical application of the compounds disclosed herein include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under aseptic conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants (if desired).

[0134] The compounds disclosed herein may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0135] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for use in mammals (such as humans) requiring treatment. The dosage is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dosage is typically 1-2000 mg, preferably 6-600 mg. Of course, the specific dosage should also be determined by taking into account factors such as the route of administration and the patient's health condition, which are all within the skill range of a skilled physician.

[0136] Therapeutic uses and methods

[0137] As described above, the compounds disclosed in this invention are DDR1 / 2 inhibitors, and therefore, the compounds or compositions comprising the compounds can be used to treat, prevent, and alleviate diseases associated with or abnormally expressed DDR1 / 2 activity. In some embodiments, the compounds disclosed herein are used for the prevention and / or treatment of diseases mediated by DDR1 / 2 tyrosine protein kinase. In some embodiments, a method of treating diseases mediated by DDR1 / 2 tyrosine protein kinase in a subject of need is disclosed herein, comprising administering an effective amount of the compounds disclosed herein to the subject. In some embodiments, diseases mediated by DDR1 / 2 tyrosine protein kinase include: inflammatory diseases, cardiovascular diseases, fibrotic diseases, and cancer.

[0138] When used in the purposes and methods disclosed herein, the disclosed compounds and compositions may be used in combination with other known therapies. As used herein, “combined” administration means administering two (or more) different treatments to a subject during the course of a disease, for example, after the subject has been diagnosed and before the disease is cured, eliminated, or discontinued for other reasons. In some embodiments, one treatment is still in progress when the second treatment begins, thus there is overlap in the administration of treatment. This is referred to herein as “simultaneous” or “concurrent” in some cases. In other embodiments, one treatment ends before the other treatment begins. In some embodiments of either case, combined treatment is more effective.

[0139] For example, the second treatment may show a better effect, such as achieving the same effect with less second treatment compared to when it was administered without the second treatment, or the second treatment may alleviate symptoms to a greater extent, or a similar situation may have been observed with the first treatment. In some embodiments, such combined treatment results in a greater improvement in symptoms or other parameters related to the condition than would have been observed with the first treatment in the absence of the second. The effects of the two treatments may be partially cumulative, fully cumulative, or greater than cumulative. The treatment may be such that the effect of the first treatment remains detectable when the second treatment is administered.

[0140] The compounds or compositions disclosed herein and at least one additional therapeutic agent may be administered simultaneously, in the same or different compositions, or sequentially. For sequential administration, the compound described herein may be administered first, followed by the other agent, or the order of administration may be reversed.

[0141] In some embodiments, the compounds described herein are administered in combination with other therapeutic modalities, including surgery, radiation, transplantation (e.g., stem cell transplantation, bone marrow transplantation), chemotherapy, immunotherapy, cryotherapy, and / or thermotherapy. Such combination therapies may allow for lower doses of the administered agents and / or other agents, thereby avoiding potential toxicities or complications associated with various therapies.

[0142] In some embodiments, the compounds described herein are administered in combination with at least one other therapeutic agent, such as a chemotherapeutic agent. In some embodiments, the compounds described herein are administered in combination with one or more other chemotherapeutic agents. The chemotherapeutic agent may be one identified in the Cancer Drugs A-Z List published by the National Cancer Institute.

[0143] Compared with the prior art, the present invention has the following beneficial effects:

[0144] 1. The compounds or pharmaceutical compositions thereof of the present invention can effectively inhibit DDR1 / 2 protein kinases and can be used to prepare drugs for the prevention or treatment of diseases mediated by DDR1 / 2 protein kinases, such as inflammatory diseases, cardiovascular diseases, fibrotic diseases and cancer.

[0145] 2. The compounds of the present invention have strong inhibitory activity against DDR1 / 2 protein kinase, kinase selectivity, and good pharmacokinetic properties.

[0146] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0147] Experiment 1. Synthesis of Compound 36

[0148] Compounds 35 (4.0 g, 15.1 mmol, 1.0 eq), 33 (5.1 g, 16.6 mmol, 1.1 eq), and cesium carbonate (16.3 g, 50 mmol, 3.3 eq) were mixed in a 200 mL reaction flask at room temperature. 60 mL of N,N-dimethylformamide solvent was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 100 mL of water was added to quench the mixture. The mixture was extracted twice with 150 mL of ethyl acetate. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE:EA = 4:1) to give 3.5 g of an orange-yellow foamy solid, with a yield of 56%. The product is a known compound.

[0149] Experiment 2. Synthesis of Compound 37

[0150] Compound 36 (3.5 g, 8.5 mmol, 1.0 eq) was mixed with PdC (302 mg, 2.8 mmol, 0.33 eq) in a 100 mL reaction flask at room temperature. 60 mL of ethanol was added, and the mixture was stirred for 12 hours in the presence of a hydrogen balloon. After the reaction was complete, the PdC was filtered off, and the residue was washed twice with 10 mL of ethanol. The filtrate was evaporated to dryness to give 3.1 g of a brownish-gray solid, with a yield of 96%. The product is a known compound.

[0151] Experiment 3. Synthesis of aminopyrazole compound 40

[0152] At room temperature, hydrazine hydrochlorides with different substitutions (1.0 g, 1.0 eq) were mixed with neopentanoyl acetonitrile (1.15 eq) in a 100 mL reaction flask. 40 mL of ethanol solvent and 1 mL of concentrated hydrochloric acid were added. The mixture was refluxed at 100 °C for 12 hours. After the reaction was complete, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was quenched with 50 mL of water. The mixture was extracted three times with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography. (All compounds are known; unknown compounds are listed separately.)

[0153] Experiment 4. Synthesis of DDR1 Inhibitor

[0154] Step 1: Place triphosgene (62 mg, 0.21 mmol, 1.0 eq) in a 100 mL Schlenk flask. Under Ar atmosphere protection, add 5 mL of THF solvent and place the system in an ice bath at 0 °C. Dissolve different substituted aminopyrazole compounds 40 (0.21 mmol, 1.0 eq) in 5 mL of THF. While stirring continuously, slowly add the mixture dropwise to the system. Add triethylamine (45 mg, 0.44 mmol, 2.1 eq) dropwise to the system. A large amount of precipitate forms in the reaction solution. Allow the system to return to room temperature naturally and stir for 1 hour. Then, remove the volatile liquid from the system and redissolve it in 5 mL of THF. Dissolve compound 37 (80 mg, 0.21 mmol, 1.0 eq) in 5 mL of THF. While stirring continuously, slowly add the mixture dropwise to the system. Heat the system at 50 °C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the reaction. The system was extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by a preparative plate.

[0155] Step 2: Place the compound obtained in Step 1 into a 100 mL reaction flask, add 10 mL of dichloromethane to dissolve it, and slowly add 0.5 mL of trifluoroacetic acid dropwise to the solution. Stir the mixture overnight at room temperature. After the reaction is complete, adjust the pH of the system to neutral with saturated sodium bicarbonate solution, extract three times with 20 mL of dichloromethane, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate it, and separate the crude product using a preparative plate.

[0156] Example 1:

[0157] The synthesis method was the same as in Experiment 4, yielding 82 mg of yellow solid, with a total yield of 75%. 1 H NMR (600MHz, DMSO-d6) δ11.06(s,1H),9.08(s,1H),8.06(dd,J=5.3,1.6Hz,1H),7.48–7.39(m,3H),7.21–7.14(m,3H),7.08(d,J= 8.9Hz,2H),6.87(dd,J=7.3,5.2Hz,1H),6.33(s,1H),3.82(s,3H),3.37–3.24(m,2H),3.05(dd,J=22.4,15.9Hz,2H),1.27(s,9H). 13C NMR (151MHz, DMSO-d6) δ180.58,160.25,158.46,156.16,151.63,146.58,141.61,138.53,137.41,134.25,131.49,129. 84,129.21,126.28,124.45,117.83,117.02,114.39,114.32,94.39,55.48,53.77,43.01,42.37,31.98,30.25.HRMS(ESI m / z):[M+Na] + Calculated for C 30 H 30 N6O3Na,545.2272; found,545.2276.HPLC purity:97.57%.Melting point:>180℃.IR(neat,cm -1 )2961,1712,1548,1513,1431,1254,1212,1099,1021,798,779.

[0158] Example 2:

[0159] The synthesis method was the same as in Experiment 4, yielding 54 mg of yellow solid, with a total yield of 47%. 1 H NMR(600MHz,DMSO-d6)δ11.07(s,1H),9.06(s,1H),8.29(s,1H),8.06(dd,J =5.3,1.6Hz,1H),7.44(s,1H),7.20–7.15(m,3H),7.11–7.06(m,2H),7.01(d d,J=8.5,2.4Hz,1H),6.87(dd,J=7.3,5.3Hz,1H),6.36(s,1H),3.82(s,3H), 3.80(s,3H),3.36–3.25(m,2H),3.05(dd,J=22.3,15.9Hz,2H),1.27(s,9H). 13C NMR(151MHz,DMSO-d6)δ180.55,160.21,156.11,151.46,148.83,148.23,146.60,141.66,138.47,137.44,134.33,131.35,129.82, 129.25,124.49,117.87,117.29,117.01,114.32,111.83,109.24,93.97,55.80,55.67,53.77,43.01,42.37,32.00,30.27.HRMS (ESI m / z):[M+Na] + Calculated for C 31 H 32 N6O4Na,575.2377; found,575.2379.HPLC purity:97.85%.Melting point:>180℃.IR(neat,cm -1 )3367,2964,1711,1562,1547,1512,1433,1214,643,604.

[0160] Example 3:

[0161] The synthesis method was the same as in Experiment 4, yielding 47 mg of yellow solid, with a total yield of 46%. 1 H NMR (600MHz, CDCl3) δ9.84 (s, 1H), 8.08 (dd, J = 5.3, 1.6Hz, 1H), 7.75 (s, 1H), 7.41–7.3 7(m,2H),7.37–7.30(m,3H),7.23(td,J=7.2,1.4Hz,1H),7.20(d,J=1.9Hz,1H),7.08(d d,J=7.3,1.6Hz,1H),7.04(d,J=8.2Hz,1H),6.99–6.94(m,1H),6.81(dd,J=7.3,5.3Hz ,1H),6.40(s,1H),3.40(d,J=15.9Hz,2H),2.96(dd,J=20.3,15.9Hz,2H),1.31(s,9H). 13C NMR (151MHz, CDCl3) δ181.50,162.85,155.21,152.21,146.63,141.52,138.32,137.55,136.69,135.65,130.41,13 0.05,129.55,127.89,125.04,124.86,119.39,118.74,116.59,95.75,54.75,43.51,42.97,32.58,30.45.HRMS(ESI m / z):[M+Na] + Calculated for C 29 H 28 N6O2Na,515.2166; found,515.2161.HPLC purity:95.72%.Melting point:>180℃.IR(neat,cm -1 )2961,1714,1547,1431,1259,1092,1014,795,687.

[0162] Example 4:

[0163] The synthesis method was the same as in Experiment 4, yielding 14 mg of yellow solid, with a total yield of 13%. 1 H NMR (600MHz, Methanol-d4) δ8.05(d,J=5.4Hz,1H),7.87(d,J=8.3Hz,2H),7.79(d,J=8.4Hz,2H),7.37(s,1H),7.24–7.17(m,2H),7 .14(d,J=7.3Hz,1H),6.88(dd,J=7.3,5.3Hz,1H),6.42(s,1H),3.50(t,J=14.8Hz,2H),3.05(dd,J=15.7,7.7Hz,2H),1.35(s,9H). 13 C NMR(151MHz,Methanol-d4)δ183.02,164.69,156.95,154.80,147.53,143.85,142.95,139.35,138.82,136.89,134.51,132 .26,130.83,125.80,125.69,120.00,119.55,119.27,117.12,111.75,99.94,56.14,44.43,43.92,33.48,30.58.HRMS(ESI m / z):[M+Na] + Calculated for C30 H 27 N7O2Na,540.2118; found,540.2108.HPLC purity:95.15%.Melting point:>180℃.IR(neat,cm -1 )3350,2961,1604,1547,1259,1095,1013,794.

[0164] Example 5:

[0165] The synthesis method was the same as in Experiment 4, yielding 68 mg of yellow solid, with a total yield of 64%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),8.99(s,1H),8.32(s,1H),8.06(dd,J=5.3,1.6Hz,1H),7.44(s,1H),7.39(d,J=8.3Hz,2H),7.34(d,J=8.1H z,2H),7.21–7.15(m,3H),6.87(dd,J=7.2,5.4Hz,1H),6.35(s,1H),3.3 5–3.26(m,2H),3.05(dd,J=22.2,15.9Hz,2H),2.38(s,3H),1.27(s,9H). 13 C NMR (151MHz, DMSO-d6) δ180.55,160.53,156.11,151.55,146.60,141.64,138.46,137.26,136.81,136.07,134.34,129. 82,129.72,129.25,124.92,124.42,117.86,117.05,114.36,94.81,53.77,43.01,42.37,32.01,30.23,25.13.HRMS(ESI m / z):[M+Na] + Calculated for C 30 H 30 N6O2Na,529.2322; found,529.2319.HPLC purity:95.88%.Melting point:>180℃.IR(neat,cm -1 )3339,2960,1714,1604,1546,1431,1210,1099,1014,799,779,645,501.

[0166] Example 6:

[0167] The synthesis method was the same as in Experiment 4, yielding 87 mg of a yellow solid with a total yield of 82%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),9.00(s,1H),8.36(s,1H),8.06(dd,J=5.2, 1.6Hz,1H),7.44(s,1H),7.42(t,J=7.7Hz,1H),7.34(s,1H),7.31(d,J=9.0Hz,1H ),7.24(d,J=7.5Hz,1H),7.20–7.15(m,3H),6.87(dd,J=7.3,5.3Hz,1H),6.37(s, 1H),3.35–3.26(m,2H),3.05(dd,J=22.6,15.9Hz,2H),2.39(s,3H),1.27(s,9H). 13 C NMR (151MHz, DMSO-d6) δ180.55,160.66,156.11,151.55,146.60,141.65,138.91,138.45,138.43,137.31,134.37,129.82,129. 25,129.11,127.99,125.05,124.48,121.49,117.86,117.10,114.41,94.87,53.78,43.01,42.37,32.02,30.22,20.97.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 31 N6O2,507.2503; found,507.2506.HPLC purity:99.13%.Melting point:>180℃.IR(neat,cm -1 )3312,2961,1714,1605,1546,1492,1431,1260,1210,1097,1014,796,780.

[0168] Example 7:

[0169] The synthesis method was the same as in Experiment 4, yielding 103 mg of yellow solid, with a total yield of 93%. 1H NMR (600MHz, DMSO-d6) δ11.07(s,1H),8.96(s,1H),8.42(s,1H),8.06(dd,J=5.2,1.6Hz,1H),7.61–7.54(m,4H),7.44(s,1H) ,7.21–7.14(m,3H),6.87(dd,J=7.3,5.3Hz,1H),6.37(s,1H),3.35–3.26(m,2H),3.05(dd,J=22.1,15.9Hz,2H),1.28(s,9H). 13 C NMR(151MHz,DMSO-d6)δ180.56,161.17,156.11,151.72,146.60,141.64,138.39,137.49,137.47,134.44,131.5 0,129.80,129.24,125.80,124.48,117.86,117.17,114.46,96.09,53.76,43.01,42.37,32.07,30.14.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O2Cl,527.1957; found,527.1963.HPLC purity:97.00%.Melting point:>180℃.IR(neat,cm -1 )3290,2960,1713,1604,1547,1494,1431,1210,1092,1011,798,779.

[0170] Example 8:

[0171] The synthesis method was the same as in Experiment 4, yielding 74 mg of white solid with a total yield of 62%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),8.98(s,1H),8.45(s,1H),8.06(dd,J=5.2,1.6Hz,1H),7.72(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H) ,7.44(s,1H),7.21–7.14(m,3H),6.87(dd,J=7.3,5.3Hz,1H),6.37(s,1H),3.36–3.26(m,2H),3.05(dd,J=21.9,15.9Hz,2H),1.27(s,9H). 13C NMR(151MHz,DMSO-d6)δ180.55,161.21,156.11,151.73,146.60,141.64,138.40,137.91,137.48,134.41,132.16,1 29.81,129.25,126.05,124.47,119.83,117.86,117.16,114.46,96.13,53.76,43.01,42.37,32.07,30.13.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O2Br,571.1452; found,571.1448.HPLC purity:95.39%.Melting point:>180℃.IR(neat,cm -1 )2960,1709,1662,1603,1542,1492,1430,1204,1098,1009,796,778.

[0172] Example 9:

[0173] The synthesis method was the same as in Experiment 4, yielding 73 mg of yellow solid with a total yield of 66%. 1 H NMR (600MHz, CDCl3) δ10.29(s,1H),8.05(s,1H),7.79(s,1H),7.58(s,1H),7.44 (s,1H),7.32(d,J=8.2Hz,1H),7.21(t,J=8.0Hz,1H),7.17–7.10(m,2H),7.06(d ,J=7.1Hz,1H),7.02(d,J=8.2Hz,1H),6.99–6.92(m,1H),6.79(t,J=6.3Hz,1H), 6.36(s,1H),3.37(t,J=11.8Hz,2H),2.95(dd,J=33.6,15.1Hz,2H),1.28(s,9H). 13C NMR (151MHz, CDCl3) δ181.85,163.17,155.36,152.62,146.41,141.48,139.56,137.40,136.59,135.75,134.86,130.49,13 0.35,130.10,127.50,124.87,124.65,122.45,119.50,118.76,116.67,96.92,54.72,43.46,42.91,32.57,30.35.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O2Cl,527.19568; found,527.19584.HPLC purity:95.04%.Melting point:>180℃.IR(neat,cm -1 )3322,2959,1714,1596,1546,1490,1431,1211,1098,777,644.

[0174] Example 10:

[0175] The synthesis method was the same as in Experiment 4, yielding 85 mg of yellow solid with a total yield of 78%. 1 H NMR (600MHz, CDCl3) δ10.39(d,J=119.0Hz,1H),8.11–8.06(m,1H),7.78(d,J=95.7Hz,1H),7.35–7.15(m,4H),7.08–7.01(m,2H),7.00–6.86( m,3H),6.82–6.76(m,1H),6.33(s,1H),3.62(d,J=17.4Hz,3H),3.52–3.40(m,2H),2.96(td,J=19.3,17.9,8.3Hz,2H),1.30(d,J=9.4Hz,9H). 13C NMR (126MHz, CDCl3) δ181.34,162.96,155.47,153.64,152.33,146.39,141.53,138.24,137.64,135.55,130.66,130.17,129.9 0,129.27,127.12,124.78,121.57,119.25,118.51,116.52,112.63,94.81,56.24,54.69,43.52,42.95,32.54,30.44.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 31 N6O3,523.2452; found,523.2455.HPLC purity:97.07%.Melting point:>180℃.IR(neat,cm -1 )3323,2958,1713,1603,1551,1493,1432,1211,1018,755,644.

[0176] Example 11:

[0177] The synthesis method was the same as in Experiment 4, yielding 56 mg of yellow solid, with a total yield of 52%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),9.00(s,1H),8.52(s,1H),8.06(dd,J=5.3 ,1.6Hz,1H),8.03(t,J=1.9Hz,1H),7.92(d,J=8.3Hz,1H),7.86(d,J=7.8Hz,1H) ,7.73(t,J=7.9Hz,1H),7.42(s,1H),7.21–7.14(m,3H),6.87(dd,J=7.3,5.3Hz, 1H), 6.41 (s, 1H), 3.37–3.27 (m, 2H), 3.05 (dd, J = 21.0, 15.9Hz, 2H), 1.29 (s, 9H). 13C NMR(151MHz,DMSO-d6)δ180.55,161.71,156.11,151.85,146.60,141.64,139.38,138.33,137.73,134.52,130.74,130.65,129.8 0,129.26,128.61,126.82,124.48,118.21,117.86,117.30,114.59,112.17,97.04,53.76,43.00,42.37,32.13,30.06.HRMS(ESI m / z):[M+Na] + Calculated for C 30 H 27 N7O2Na,540.2118; found,540.2113.HPLC purity:95.18%.Melting point:>180℃.IR(neat,cm -1 )2961,2231,1714,1604,1546,1491,1431,1260,1211,1096,1016,797,683.

[0178] Example 12:

[0179] The synthesis method was the same as in Experiment 4, yielding 54 mg of yellow solid, with a total yield of 46%. 1 H NMR(500MHz, CDCl3)δ9.99(s,1H),8.23(s,1H),8.12(s,1H),7.66(s,1H),7.50(d,J=19.8Hz,4H),7.09(s,1H),7.04(d,J=7.4Hz,1H), 6.95(s,2H),6.78(s,1H),6.50(s,1H),3.35(dd,J=30.3,15.9Hz,2H),3.16(s,3H),3.01(s,3H),2.90(t,J=14.7Hz,2H),1.30(s,9H). 13C NMR (151MHz, CDCl3) δ181.82,171.66,163.40,155.23,151.73,147.19,141.10,139.33,137.85,137.26,135.47,135.29,130.7 6,129.61,128.22,125.92,124.72,119.68,118.69,117.31,93.67,54.75,43.69,43.10,39.71,35.73,32.57,30.42.HRMS (ESI m / z):[M+Na] + Calculated for C 32 H 33 N7O3Na,586.2537; found,586.2540.HPLC purity:99.51%.Melting point:>180℃.IR(neat,cm -1 )2958,1715,1604,1546,1492,1432,1210,1087,779,644.

[0180] Example 13:

[0181] The synthesis method was the same as in Experiment 4, yielding 41 mg of yellow solid, with a total yield of 35%. 1 H NMR (600MHz, CDCl3) δ10.41(d,J=34.5Hz,1H),8.34(d,J=13.6Hz,1H),8.11(d,J=5.4Hz,1H),7.84(d,J= 12.5Hz,1H),7.63(d,J=9.4Hz,1H),7.48(s,1H),7.41(t,J=7.9Hz,1H),7.30(d,J=6.9Hz,1H),7.23(d,J= 8.1Hz,1H),7.12(d,J=5.7Hz,1H),7.06(d,J=12.3Hz,1H),6.98(d,J=8.2Hz,1H),6.85–6.79(m,1H),6.60 (d,J=5.2Hz,1H),3.35(d,J=16.0Hz,1H),3.22(d,J=15.7Hz,1H),3.13(s,3H),2.97(m,5H),1.33(s,9H). 13C NMR (126MHz, CDCl3) δ182.29,171.62,163.41,155.45,151.31,146.90,140.85,138.86,138.20,137.99,136.21,134.52,130.14,130.0 9,129.88,127.42,125.67,124.62,122.34,118.53,118.37,115.69,93.52,54.66,43.44,42.74,39.67,35.67,32.56,30.41.HRMS (ESI m / z):[M+Na] + Calculated for C 32 H 33 N7O3Na,586.2537; found,586.2543.HPLC purity:99.71%.Melting point:>180℃.IR(neat,cm -1 )2959,1713,1604,1548,1491,1432,1330,1199,1097,803,778,681,641.

[0182] Example 14:

[0183] The synthesis method was the same as in Experiment 4, yielding 56 mg of yellow solid, with a total yield of 50%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),9.05(s,1H),8.66(s,1H),8.37(d,J=9.1Hz,2H),8.06(dd,J=5.2,1.6Hz,1H),7.89(d,J=9.1Hz,2H) ,7.43(s,1H),7.22–7.14(m,3H),6.87(dd,J=7.2,5.3Hz,1H),6.44(s,1H),3.35–3.26(m,2H),3.05(dd,J=19.8,15.9Hz,2H),1.30(s,9H). 13C NMR (151MHz, DMSO-d6) δ180.55,162.46,156.11,152.04,146.60,144.98,144.11,141.62,138.35,138.16,134.53,129. 79,129.24,124.87,124.46,123.22,117.85,117.32,114.61,98.60,53.76,43.00,42.36,32.20,30.42,29.95.HRMS (ESI m / z):[M+H] + Calculated for C 29 H 28 N7O4,538.2197; found,538.2204.HPLC purity:95.38%.Melting point:>180℃.IR(neat,cm -1 )3336,2961,1714,1599,1548,1519,1495,1334,1260,1095,1014,796.

[0184] Example 15:

[0185] The synthesis method was the same as in Experiment 4, yielding 39 mg of white solid, with a total yield of 38%. 1 H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.98(s,1H),8.79(d,J=1.8Hz,1H),8.60(dd ,J=4.8,1.5Hz,1H),8.50(s,1H),8.06(dd,J=5.3,1.6Hz,1H),7.98(ddd,J=8.2,2.5 ,1.5Hz,1H),7.58(dd,J=8.5,4.5Hz,1H),7.43(s,1H),7.21–7.13(m,3H),6.87(dd ,J=7.3,5.3Hz,1H),6.41(s,1H),3.29(m,2H),3.05(t,J=16.8Hz,2H),1.29(s,9H). 13C NMR(151MHz,DMSO-d6)δ180.51,161.75,156.09,151.82,147.97,146.57,144.71,141.61,138.34,137.79,135.40,134.4 4,131.50,129.79,129.23,124.44,124.14,117.83,117.20,114.49,96.65,53.74,42.99,42.35,32.10,30.08.HRMS(ESI m / z):[M+H] + Calculated for C 28 H 28 N7O2,494.22990; found,494.22973.HPLC purity:99.51%.Melting point:>180℃.IR(neat,cm -1 )2962,2922,1709,1608,1547,1492,1433,1198,782,652.

[0186] Example 16:

[0187] The synthesis method was the same as in Experiment 4, yielding 30 mg of a pale yellow solid with a total yield of 29%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),9.44(s,1H),9.08(s,1H),8.64(d,J=6.4Hz,2H),8.06(dd,J=5.3,1.6Hz,1H),7.67(d,J=6.4Hz,2H) ,7.45(s,1H),7.28–7.09(m,3H),6.87(dd,J=7.2,5.4Hz,1H),6.40(s,1H),3.33–3.30(m,2H),3.05(dd,J=19.7,15.9Hz,2H),1.29(s,9H). 13 C NMR (151MHz, CDCl3) δ181.50,164.49,155.46,152.52,150.49,146.63,146.15,141.82,137.58,137.19,135.93 ,130.56,129.92,125.05,119.06,118.64,117.45,116.30,98.26,54.85,43.52,43.01,32.71,30.15.HRMS(ESI m / z):[M+H] +Calculated for C 28 H 28 N7O2,494.2299; found,494.2303.HPLC purity:96.92%.Melting point:>180℃.IR(neat,cm -1 )2961,2920,1715,1595,1544,1431,1260,1211,1094,1015,796,688.

[0188] Example 17:

[0189] The synthesis method was the same as in Experiment 4, yielding 78 mg of white solid, with an overall yield of 71%. 1 H NMR(600MHz, CDCl3)δ10.58(s,1H),8.08(s,1H),7.95(s,1H),7.40–7.27(m,3H),7.22–7.14(m,2H),7.13–7.04(m,2H),7.02–6.9 5(m,1H),6.88(d,J=8.0Hz,1H),6.80(t,J=6.4Hz,1H),6.34(s,1H),3.36(d,J=13.5Hz,2H),2.93(t,J=16.5Hz,2H),1.27(s,9H). 13 C NMR (126MHz, CDCl3) δ181.85,163.39,155.39,151.97,146.40,141.25,138.33,137.56,135.50,135.27,132.74,130.51,13 0.51,130.42,130.42,127.95,125.61,124.72,118.80,118.80,116.18,94.31,54.64,43.51,42.85,32.57,30.41.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O2Cl,527.1957; found,527.1962.HPLC purity:95.37%.Melting point:>180℃.IR(neat,cm -1 )3306,2959,1715,1604,1548,1492,1431,1209,765,644.

[0190] Example 18:

[0191] The synthesis method was the same as in Experiment 4, yielding 64 mg of yellow solid, with a total yield of 60%. 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),8.95(s,1H),8.36(s,1H),8.06(dd,J=5.3,1.6Hz,1H),7.59–7.54(m,2H),7.44(s,1H),7.40–7. 35(m,2H),7.20–7.15(m,3H),6.87(dd,J=7.3,5.3Hz,1H),6.36(s,1H),3.32–3.26(m,2H),3.05(dd,J=22.3,15.9Hz,2H),1.27(s,9H). 13 C NMR(151MHz,DMSO-d6)δ180.55,160.81,156.11,151.68,146.60,141.64,138.40,137.46,135.00,134.40,129.80,1 29.25,126.68,126.63,124.47,117.86,117.12,116.14,115.99,114.42,95.41,53.76,43.01,42.36,32.03,30.18. 19 F NMR(376MHz,DMSO-d6)δ-114.78.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O2F,511.2252; found,511.2258.HPLC purity:97.95%.Melting point:>180℃.IR(neat,cm -1 )2961,1715,1605,1547,1511,1431,1260,1216,1094,1013,798,780.

[0192] The S-isomer 4-20-1 and the R-isomer 4-20-2 are shown below:

[0193] Example 19:

[0194] The synthesis method was the same as in Experiment 4, yielding 73 mg of yellow solid with a total yield of 67%. 1H NMR(600MHz,DMSO-d6)δ11.07(s,1H),9.05(s,1H),8.40(s,1H),8.06(dd,J =5.3,1.6Hz,1H),7.46–7.41(m,2H),7.21–7.14(m,3H),7.13–7.07(m,2H),6 .99(ddd,J=8.3,2.5,0.9Hz,1H),6.87(dd,J=7.3,5.3Hz,1H),6.38(s,1H), 3.81(s,3H),3.32–3.27(m,2H),3.05(dd,J=22.2,15.9Hz,2H),1.28(s,9H). 13 C NMR (151MHz, DMSO-d6) δ180.55,160.74,159.71,156.11,151.64,146.60,141.65,139.60,138.45,137.33,134.37,130.13,129. 82,129.25,124.48,117.86,117.11,116.51,114.41,113.08,109.77,95.37,55.36,53.78,43.01,42.37,32.03,30.19.HRMS (ESI m / z):[M+H] + Calculated for C 30 H 30 N6O3,523.2452; found,523.2458.HPLC purity:98.16%.Melting point:>180℃.IR(neat,cm -1 )2960,1713,1604,1548,1492,1431,1216,1098,1024,797,778.

[0195] Example 20:

[0196] The synthesis method was the same as in Experiment 4, yielding 52 mg of yellow solid, with a total yield of 45%. 1H NMR (600MHz, DMSO-d6) δ11.07(s,1H),9.02(s,1H),8.60(s,1H),8.11–8.04(m,3H),7.75(d,J=8.7Hz,2H),7.43(s,1H),7.21–7. 14(m,3H),6.87(dd,J=7.3,5.2Hz,1H),6.41(s,1H),3.88(s,3H),3.33–3.27(m,2H),3.05(dd,J=20.1,15.9Hz,2H),1.29(s,9H). 13 C NMR(151MHz,DMSO-d6)δ180.55,165.68,161.75,156.12,151.96,146.59,142.63,141.61,138.46,134.38,130.33,129.83, 129.24,127.39,124.45,123.17,117.86,117.22,114.51,97.22,79.18,53.77,52.28,43.00,42.37,32.13,30.07.HRMS(ESI m / z):[M+H] + Calculated for C 31 H 31 N6O4,551.2401; found,551.2407.HPLC purity:90.11%.Melting point:>180℃.IR(neat,cm -1 )2961,1717,1605,1541,1431,1260,1096,1014,797.

[0197] Example 21:

[0198] The synthesis method was the same as in Experiment 4, yielding 23 mg of yellow solid, with a total yield of 20%. 1 H NMR (600MHz, CDCl3) δ10.12(s,1H),8.04(d,J=5.2Hz,1H),7.67(s,1H),7.64–7.54(m,5H),7.15(s,1H),7.09–6.94( m,3H),6.79(t,J=6.4Hz,1H),6.35(s,1H),3.38(d,J=15.9Hz,76H),2.94(dd,J=32.9,15.9Hz,68H),1.30(s,314H). 13C NMR (126MHz, CDCl3) δ181.72,163.54,155.22,152.72,146.56,141.60,141.52,137.29,136.39,135.93,135.88,130.29,130.07,129.36,12 9.11,128.84,128.58,126.51,126.48,125.66,124.95,124.04,122.7 9,119.47,118.77,116.65,98.20,54.75,43.38,42.85,32.64,30.29. 19 F NMR(376MHz, CDCl3)δ-57.92.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 28 N6O2F3,561.2220; found,561.2228.HPLC purity:95.72%.Melting point:>180℃.IR(neat,cm -1 )2959,1603,1542,1323,1260,1099,1066,1012,796.

[0199] Example 22:

[0200] The synthesis method was the same as in Experiment 4, yielding 22 mg of yellow solid, with a total yield of 18%. 1 H NMR (600MHz, CDCl3) δ9.95 (s, 1H), 8.06 (d, J = 3.8Hz, 1H), 7.57–7.47 (m, 3H ),7.35(s,1H),7.21(d,J=8.4Hz,2H),7.17(s,1H),7.08(d,J=7.3Hz,1H),7 .05(d,J=8.2Hz,1H),7.02–6.96(m,1H),6.81(dd,J=7.4,5.3Hz,1H),6.35( s,1H),3.42(d,J=15.0Hz,2H),2.97(dd,J=25.1,15.9Hz,2H),1.31(s,9H). 13C NMR (126MHz, CDCl3) δ181.58,163.20,155.21,152.57,148.12,146.61,141.62,137.25,137.01,136.36,136.00,130.30,130.0 6,125.99,124.92,123.51,121.96,121.46,119.57,119.41,118.75,117.36,116.77,97.42,54.77,43.43,42.89,32.61,30.35. 19 F NMR(376MHz, CDCl3)δ-62.26.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 28 N6O3F3,577.21695; found,577.21708.HPLC purity:98.28%.Melting point:>180℃.IR(neat,cm -1 )2961,1716,1604,1547,1259,1206,1088,1013,796.

[0201] Example 23:

[0202] The synthesis method was the same as in Experiment 4, yielding 42 mg of yellow solid, with a total yield of 37%. 1 H NMR (600MHz, CDCl3) δ10.29 (s, 1H), 8.73 (d, J = 2.7Hz, 1H), 8.63 (s, 1H), 8.10 ( s,1H),8.05(d,J=3.8Hz,1H),7.89(d,J=8.3Hz,1H),7.80(d,J=8.8Hz,1H),7.7 4–7.65(m,2H),7.31–7.24(m,2H),7.04–6.95(m,3H),6.75(t,J=6.5Hz,1H),6 .52(s,1H),3.40(dd,J=15.9,8.3Hz,2H),2.90(t,J=18.1Hz,1H),1.32(s,9H). 13C NMR (126MHz, CDCl3) δ181.28,163.61,155.34,152.04,150.42,146.48,146.03,141.67,137.81,137.63,137.04,136.62,135.42,130.58 ,129.83,129.73,128.09,127.73,125.64,124.90,123.09,121.99,118.52,115.81,94.82,54.79,43.47,42.93,32.63,30.42.HRMS(ESI m / z):[M+H] + Calculated for C 32 H 30 N7O2,544.24555; found,544.24538.HPLC purity:96.97%.Melting point:>180℃.IR(neat,cm -1 )2962,1711,1604,1544,1492,1431,1260,1199,1098,1015,798,781.

[0203] Example 24:

[0204] The synthesis method was the same as in Experiment 4, yielding 76 mg of yellow solid, with a total yield of 70%. 1 H NMR (600MHz, CDCl3) δ9.98 (s, 1H), 8.07 (dd, J = 5.3, 1.6Hz, 1H), 7.80 (s, 1H), 7.32 (s, 1H), 7.2 8–7.24(m,2H),7.18(s,1H),7.15(d,J=8.1Hz,2H),7.09(dd,J=7.4,1.6Hz,1H),7.02(d,J=8. 0Hz,1H),6.95(d,J=7.8Hz,1H),6.81(dd,J=7.4,5.3Hz,1H),6.38(s,1H),3.39(t,J=15.0Hz, 2H), 2.96 (dd, J=15.9, 10.7Hz, 2H), 2.53 (q, J=7.7Hz, 2H), 1.29 (s, 9H), 1.12 (t, J=7.6Hz, 3H). 13C NMR (126MHz, CDCl3) δ181.64,162.60,155.25,152.04,146.55,144.36,141.40,137.68,136.84,135.80,135.37,130.41,1 30.08,128.91,125.17,124.77,119.15,118.72,116.35,94.98,54.73,43.48,42.90,32.53,30.46,28.44,15.52.HRMS(ESI m / z):[M+H] + Calculated for C 31 H 33 N6O2,521.26595; found,521.26622.HPLC purity:96.30%.Melting point:>180℃.IR(neat,cm -1 )2960,1717,1604,1546,1431,1261,1205,1099,1013,797,779.

[0205] Example 25:

[0206] The synthesis method was the same as in Experiment 4, yielding 71 mg of yellow solid with a total yield of 63%. 1 H NMR (600MHz, CDCl3) δ9.29 (s, 1H), 8.08 (dd, J = 5.3, 1.5Hz, 1H), 7.39 (s, 1H), 7.34 ( d,J=8.3Hz,2H),7.25(d,J=8.9Hz,2H),7.22(s,1H),7.11–7.02(m,3H),6.98(d,J= 7.4Hz,1H),6.82(dd,J=7.3,5.3Hz,1H),6.39(s,1H),3.45(t,J=14.3Hz,2H),2.99 (dd,J=16.0,4.9Hz,2H),2.87(p,J=6.8Hz,1H),1.33(s,9H),1.18(d,J=6.8Hz,6H). 13C NMR (126MHz, CDCl3) δ181.24,162.63,155.07,152.10,149.03,146.76,141.55,137.41,136.40,135.98,135.80,130.30,130. 02,127.62,125.05,124.86,119.55,118.75,116.76,95.64,54.78,43.52,42.98,33.87,32.59,30.48,24.01,23.99.HRMS(ESI m / z):[M+H] + Calculated for C 32 H 35 N6O2,535.28160; found,535.28175.HPLC purity:98.20%.Melting point:>180℃.IR(neat,cm -1 )2960,1717,1604,1545,1431,1261,1209,1097,1013,798,779.

[0207] Example 26:

[0208] The synthesis method was the same as in Experiment 4, yielding 57 mg of yellow solid, with a total yield of 50%. 1 H NMR (600MHz, CDCl3) δ10.15 (s, 1H), 8.06 (d, J = 3.8Hz, 1H), 7.74 (s, 1H), 7.36 (d, J=8.5Hz,3H),7.29(d,J=8.4Hz,2H),7.18(s,1H),7.07(d,J=5.7Hz,1H),7.02(d ,J=8.2Hz,1H),6.94(d,J=9.0Hz,1H),6.79(dd,J=7.3,5.3Hz,1H),6.38(s,1H), 3.40(t,J=14.5Hz,2H),2.95(dd,J=15.9,11.3Hz,2H),1.30(s,9H),1.21(s,9H). 13C NMR (126MHz, CDCl3) δ181.55,162.58,155.32,152.11,151.17,146.47,141.45,137.61,136.65,135.64,135.44,130.45,1 30.06,126.43,124.77,124.64,119.17,118.66,116.39,95.26,54.72,43.44,42.89,34.70,32.39,31.28,30.45.HRMS(ESI m / z):[M+H] + Calculated for C 33 H 37 N6O2,549.29725; found,549.29688.HPLC purity:98.65%.Melting point:>180oC.IR(neat,cm -1 )2961,1719,1605,1546,1431,1261,1210,1099,1012,797,780.

[0209] Example 27:

[0210] The synthesis method was the same as in Experiment 4, yielding 60 mg of yellow solid with a total yield of 56%. 1 H NMR (600MHz, CDCl3) δ10.30 (s, 1H), 8.08 (dd, J = 5.3, 1.6Hz, 1H), 7.34 (s, 1H) ,7.25(s,1H),7.17(t,J=7.3Hz,2H),7.12(t,J=7.3Hz,1H),7.08(s,1H),7.0 6–6.97(m,4H),6.90(d,J=7.5Hz,1H),6.79(dd,J=7.4,5.3Hz,1H),6.19(s,1 H), 5.16 (s, 2H), 3.43 (d, J = 15.8Hz, 2H), 2.93 (t, J = 14.6Hz, 2H), 1.28 (s, 9H). 13C NMR (126MHz, CDCl3) δ181.58,161.76,155.38,152.99,146.50,141.44,137.29,136.96,136.21,135.70,130.64,129.9 7,128.84,127.69,126.55,124.80,119.33,118.63,116.57,96.85,54.77,51.57,43.49,42.93,32.46,30.53.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 31 N6O2,507.25030; found,507.25044.HPLC purity:99.40%.Melting point:>180℃.IR(neat,cm -1 )2961,1714,1604,1552,1431,1260,1213,1097,1015,797,780.

[0211] Example 28:

[0212] The synthesis method was the same as in Experiment 4, yielding 39 mg of white solid, with a total yield of 37%. 1 H NMR(600MHz, CDCl3)δ9.64(s,1H),8.12(dd,J=5.4,1.6Hz,1H),7.38(s,1H),7.19–7.10(m,2H),7.07(dd,J=7.3,1.6Hz,1H),6.92–6.77(m,3 H),6.05(s,1H),4.10(tt,J=11.5,3.8Hz,1H),3.60(dd,J=15.7,9.7Hz,2H),3.03(dd,J=15.8,9.9Hz,2H),2.01–1.63(m,10H),1.29(s,9H). 13 C NMR (126MHz, CDCl3) δ180.63,160.78,155.32,154.08,146.67,141.86,137.16,136.20,133.30,130.73,129.81, 124.98,119.39,118.50,116.70,98.17,56.89,55.03,43.62,43.10,32.80,32.58,30.59,25.74,25.22.HRMS(ESI m / z):[M+H] +Calculated for C 29 H 35 N6O2,499.28160; found,499.28200.HPLC purity:98.98%.Melting point:>180℃.IR(neat,cm -1 )2958,2930,2856,1715,1658,1604,1552,1432,1213,1097,1012,799,778,644.

[0213] Example 29:

[0214] The synthesis method was the same as in Experiment 4, yielding 21 mg of white solid, with an overall yield of 18%. 1 H NMR (500MHz, CDCl3) δ10.14(s,1H),8.09–8.01(m,2H),7.85(d,J=8.8Hz,3H),7.72(d,J=8.4Hz,2H),7.25(s,1H) ,7.10–7.03(m,3H),6.79(t,J=6.5Hz,1H),6.40(s,1H),3.40(t,J=14.9Hz,2H),3.04–2.86(m,5H),1.27(s,9H). 13 C NMR (126MHz, CDCl3) δ181.45,164.02,155.28,152.46,146.57,143.36,141.72,137.71,137.44,136.88,135.87,130.4 8,130.03,128.74,125.01,124.22,119.11,118.69,116.35,97.84,54.77,44.66,43.47,42.95,32.65,30.23.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 31 N6O4S,571.21220; found,571.21269.HPLC purity:97.65%.Melting point:>180℃.IR(neat,cm -1 )2961,2923,1715,1546,1260,1090,1014,796,778.

[0215] Example 30:

[0216] The synthesis method was the same as in Experiment 4, yielding 31 mg of white solid, with a total yield of 27%. 1 H NMR(600MHz,DMSO-d6)δ11.06(s,1H),9.38(s,1H),8.99(s,1H),8.62(s,1H) ,8.56(d,J=5.7Hz,1H),8.28(d,J=8.8Hz,1H),8.14(s,1H),8.06(dd,J=5.3,1 .6Hz,1H),7.95–7.89(m,2H),7.42(s,1H),7.20–7.12(m,3H),6.89–6.84(m,1 H), 6.46 (s, 1H), 3.30 (t, J = 15.4Hz, 2H), 3.04 (t, J = 16.6Hz, 2H), 1.32 (s, 9H). 13 C NMR (126MHz, DMSO-d6) δ180.57,161.81,156.13,152.13,151.68,146.62,143.69,141.67,139.74,138.36,137.99,135.63,134.48,129.8 0,129.28,129.16,126.61,124.50,124.20,120.67,119.65,117.88,117.19,114.49,96.22,53.77,43.00,42.37,32.19,30.14.HRMS(ESI m / z):[M+H] + Calculated for C 32 H 30 N7O2,544.24555; found,544.24566.HPLC purity:95.09%.Melting point:>180℃.IR(neat,cm -1 )2961,1712,1555,1494,1260,1205,1099,1017,799,776.

[0217] Example 31:

[0218] The synthesis method was the same as in Experiment 4, yielding 41 mg of white solid, with an overall yield of 39%. 1H NMR(600MHz, CDCl3)δ9.94(s,1H),8.12(dd,J=5.3,1.6Hz,1H),7.74(s,1H),7.21–7.15(m,3H),7.15–7.05(m,4H),6.99(d,J=8.2Hz,1H),6.9 0(d,J=8.1Hz,1H),6.85(dd,J=7.3,5.3Hz,1H),6.39(s,1H),3.34(dd,J=21.5,16.0Hz,2H),2.97(t,J=14.6Hz,2H),2.01(s,3H),1.30(s,9H). 13 C NMR (126MHz, CDCl3) δ181.93,162.69,155.21,151.62,146.61,141.16,137.96,137.61,137.38,136.63,135.27,131.46,130.3 3,130.20,129.57,128.27,126.92,124.72,119.20,118.85,116.39,92.72,54.62,43.52,42.84,32.53,30.52,17.50.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 31 N6O2,507.25030; found,507.24980.HPLC purity:99.44%.Melting point:>180℃.IR(neat,cm -1 )2961,1712,1604,1547,1492,1432,1261,1210,1097,1017,799,779.

[0219] Example 32:

[0220] Experiment 5. Synthesis of compound 3-93

[0221] At room temperature, compound 3-88 (21 mg, 0.04 mmol, 1.0 eq) and PdC (10 mg, 0.13 mmol, 3.3 eq) were mixed in a 50 mL reaction flask, and 10 mL of ethanol was added. The mixture was stirred for 6 hours in the presence of a hydrogen balloon. After the reaction was complete, the PdC was filtered off, and the residue was washed twice with 10 mL of ethanol. The filtrate was evaporated to dryness, and the crude product was purified by preparative agar (DCM:MeOH = 30:1) to give 11 mg of a white foamy solid, with a yield of 55%. 1H NMR (600MHz, Methanol-d4) δ8.04(dd,J=5.3,1.6Hz,1H),7.36(s,1H),7.20–7.17(m,2H),7.17–7.12(m,3H),6.88(dd,J= 7.4, 5.3Hz, 1H), 6.81 (d, J = 8.7Hz, 2H), 6.38 (s, 1H), 3.49 (t, J = 15.9Hz, 2H), 3.05 (dd, J = 15.7, 10.4Hz, 2H), 1.32 (s, 9H). 13 C NMR(151MHz,Methanol-d4)δ183.03,162.83,156.93,153.93,150.43,147.50,142.94,139.48,139.28,136.62,132.29 ,130.84,128.78,126.13,125.81,119.69,119.55,116.80,116.14,94.56,56.13,44.43,43.91,33.24,30.83.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 30 N7O2,508.24555; found,508.24549.HPLC purity:97.94%.Melting point:>180℃.IR(neat,cm -1 )2961,2923,1712,1606,1549,1432,1259,1092,1014,795.

[0222] Example 33:

[0223] Experiment 6. Synthesis of Compound 4-87

[0224] At room temperature, compound 4-35 (81 mg, 0.15 mmol, 1.0 eq) was placed in a 50 mL reaction flask and dissolved in 10 mL of methanol. Then, 5 mL of 2 M NaOH aqueous solution was added with constant stirring, and the mixture was stirred for 1 hour. After the reaction was complete, the pH was adjusted to 5 with 2 M HCl solution. The mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative agar (DCM:MeOH = 20:1) to give 64 mg of a yellow solid, with a yield of 81%. 1H NMR (600MHz, DMSO-d6) δ11.07(s,1H),10.80(s,1H),8.05(dt,J=5.3,1.3Hz,1H),7.67(s,1H),7.59(d,J=7.9Hz,2H),7.47(d,J=8.2Hz,1H),7.28 (d,J=8.0Hz,2H),7.20–7.13(m,2H),6.89–6.83(m,2H),6.44(s,1H),3.4 1–3.27(m,2H),3.03(dd,J=28.7,15.7Hz,2H),2.18(s,1H),1.29(s,9H). 13 C NMR(151MHz,DMSO-d6)δ180.52,170.46,160.52,156.04,152.54,146.51,141.14,140.21,139.37,138.82,132.98,130.1 3,129.62,129.16,124.91,124.19,122.61,117.89,117.10,114.25,93.85,53.98,43.10,42.47,32.00,30.30.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 29 N6O4,537.22448; found,537.22401.HPLC purity:97.29%.Melting point:>180oC.IR(neat,cm -1 )3335,2959,1675,1602,1543,1385,1203,1137,1100,793,779.

[0225] Example 34:

[0226] Experiment 7. Synthesis of compounds 5-8

[0227] Step 1: Compound 4-105 (38 mg, 0.16 mmol, 1.0 eq) and HATU (72 mg, 0.19 mmol, 1.2 eq) were mixed in a 50 mL reaction flask. 5 mL of DMF and DIPEA (61 mg, 0.47 mmol, 3.0 eq) were added. Compound 37 (60 mg, 0.16 mmol, 1.0 eq) was dissolved in 5 mL of DMF, and the mixture was added dropwise to the reaction system. After the reaction was complete, the system was quenched with 10 mL of water, extracted twice with 20 mL of ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative chromatography (DCM:MeOH = 100:1) to obtain 90 mg of a white solid.

[0228] Step 2: The product from Step 1 (90 mg, 0.15 mmol, 1.0 eq) was placed in a 100 mL reaction flask, dissolved in 10 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was slowly added dropwise. The reaction was stirred overnight at room temperature. After the reaction was complete, the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative agar (DCM:MeOH = 30:1) to obtain 58 mg of a pale yellow solid. The overall yield of the two steps was 55%. 1 H NMR(500MHz, CDCl3)δ9.16(s,1H),8.71(s,1H),8.15–8.10(m,1H),7.74(s,1H),7.57–7.48(m,3H),7.46–7.37(m,3H),7.20(d ,J=8.1Hz,1H),7.08(ddd,J=7.4,3.0,1.6Hz,1H),6.87–6.78(m,2H),3.64(t,J=16.5Hz,2H),3.11–2.98(m,2H),1.22(s,9H). 13 C NMR (151MHz, CDCl3) δ180.25,160.22,155.96,155.10,146.77,145.81,141.78,141.73,137.51,136.14,130.82,129 .97,129.80,129.09,128.66,124.94,119.03,118.56,116.37,105.10,55.10,43.77,43.30,32.38,30.76.HRMS(ESI m / z):[M+Na] + Calculated for C 29 H 27N5O2Na,500.20570; found,500.20593.HPLC purity:99.64%.Melting point:>180℃.IR(neat,cm -1 )2963,1718,1674,1598,1538,1494,1430,1226,1099,1011,799,774,696.

[0229] Example 35:

[0230] Experiment 8. Synthesis of Compounds 4-96

[0231] At room temperature, compound 4-93 (976 mg, 2.3 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 10 mL of methanol. Then, 10 mL of 1 M NaOH aqueous solution was added with constant stirring, and the mixture was stirred for 1 hour. After the reaction was complete, the pH was adjusted to 5 with 1 M HCl solution. The mixture was extracted three times with 40 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE:EA = 1:1) to give 873 mg of a white solid, with a yield of 81%. 1 H NMR(500MHz, CDCl3)δ8.23(dd,J=5.3,1.6Hz,1H),8.08–8.00(m,2H),7.39(d,J=7.9Hz,1H),7.06(dd,J=7.3,1.6Hz,1H), 6.86(dd,J=7.3,5.2Hz,1H),5.32(s,2H),3.77–3.66(m,4H),3.14(d,J=14.2Hz,1H),1.00(t,J=8.4Hz,2H),-0.01(s,9H). 13 C NMR (126MHz, CDCl3) δ179.44,155.16,147.63,147.28,141.40,129.94,129.40,129.23,12 8.93,126.48,124.81,119.07,68.28,67.18,54.17,43.95,43.56,18.03,-1.29.HRMS(ESI m / z):[M+H] + Calculated for C 22 H 27 N2O4Si,411.17346; found,411.17353.IR(neat,cm -1)2951,1722,1696,1675,1598,1441,1304,1243,1092,1077,935,859,831,779,760.

[0232] Experiment 9. Synthesis of Compound 5-31

[0233] Step 1: Under Ar protection, compound 40-3-34 (61 mg, 0.28 mmol, 2.0 eq) was placed in a 100 mL reaction flask and dissolved in 5 mL of THF. NaHMDS (2 M, 0.16 mL, 0.31 mmol, 2.2 eq) was slowly added dropwise to the system with constant stirring. The reaction was allowed to proceed for 10 minutes, then the flask was placed in a refrigerator for later use. Compound 4-96 (60 mg, 0.14 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 5 mL of THF under Ar protection. 0.3 mL of thionyl chloride was slowly added dropwise to the system, causing the color to deepen. Then, 0.5 mL of DMF was added dropwise to the system, and the mixture was heated and stirred at 50 °C for 1 hour. The volatile components in the system were drained using an oil pump, and the mixture was redissolved in 10 mL of THF. The 40-3-34 mixture was then slowly transferred to this system, and the mixture was heated and stirred at 50 °C for 2 hours. After the reaction was complete, 10 mL of water was added to quench the system, and the mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by a preparative plate (PE:EA = 2:1) to obtain 21 mg of yellow solid.

[0234] Step 2: The product from Step 1 (21 mg, 0.035 mmol, 1.0 eq) was placed in a 100 mL reaction flask, dissolved in 10 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was slowly added dropwise. The reaction was stirred overnight at room temperature. After the reaction was complete, the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative agar (DCM:MeOH = 30:1) to obtain 12 mg of white solid. The overall yield of the two steps was 55%. 1H NMR (500MHz, CDCl3) δ9.57(s,1H),8.16(dd,J=5.3,1.6Hz,1H),8.01(s,1H),7.67(s,1H),7.61–7.49(m,5H),7.45–7.37(m,1H),7.34(d,J=7. 9Hz,1H),7.06(dd,J=7.4,1.6Hz,1H),6.84(dd,J=7.4,5.3Hz,1H),6.77(s,1H),3.67(d,J=17.2Hz,2H),3.14(d,J=16.2Hz,2H),1.38(s,9H). 13 C NMR (126MHz, CDCl3) δ180.09,162.92,155.28,146.98,145.79,142.03,138.31,135.63,133.04,130.11,130.00 ,129.85,128.35,126.28,125.11,124.90,123.74,118.59,95.53,54.67,43.55,43.40,32.66,30.49.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N5O2,478.22375; found,478.22409.HPLC purity:99.38%.Melting point:>180℃.IR(neat,cm -1 )2962,1720,1658,1603,1545,1502,1432,1259,1091,1015,795.

[0235] Example 36:

[0236] Experiment 10. Synthesis of Compound 5-5

[0237] Compound 4-101 (150 mg, 0.62 mmol, 1.0 eq) and HATU (281 mg, 0.74 mmol, 1.2 eq) were mixed in a 100 mL reaction flask. 20 mL of DMF and DIPEA (239 mg, 1.85 mmol, 3.0 eq) were added. While stirring continuously, 3 mL of a 1 M THF solution of dimethylamine was added dropwise to the reaction system, and the mixture was stirred overnight. After the reaction was complete, the system was quenched with 10 mL of water, extracted twice with 50 mL of ethyl acetate, and the organic phase was washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM:MeOH = 100:1) to give 114 mg of a yellow solid, with a yield of 81%. 1 H NMR (500MHz, CDCl3) δ7.58(d,J=8.4Hz,2H),7.46(d,J=8.6Hz,2H),5.25(s,1H),3.86(s,2H), 3.08(s,3H),2.96(s,3H),1.85(tt,J=8.5,5.0Hz,1H),0.91–0.84(m,2H),0.72–0.66(m,2H). 13 C NMR (126MHz, CDCl3) δ170.93,156.48,145.66,139.79,134.49,128.41,123.24,87.58,39.66,35.50,9.54,7.86.HRMS(ESI m / z):[M+H] + Calculated for C 15 H 19 N4O,271.15534; found,271.15600.IR(neat,cm -1 )3318,3216,2924,1604,1558,1450,1409,1392,1262,1085,838,763,555.

[0238] Experiment 11. Synthesis of Compounds 5-14

[0239] Following step 1 of Experiment 4, 58 mg of yellow solid was obtained.

[0240] Following step 2 of Experiment 4, 25 mg of yellow solid was obtained, with a total yield of 22%. 1H NMR(500MHz, CDCl3)δ9.68(s,1H),8.16–8.11(m,2H),7.65(s,1H),7.53–7.45 (m,4H),7.07–7.02(m,2H),6.96(s,2H),6.79(dd,J=7.4,5.3Hz,1H),6.28(s,1 H),3.34(dd,J=20.4,15.9Hz,2H),3.18(s,3H),3.02(s,3H),2.92(dd,J=16.0, 4.9Hz,2H),1.94(tt,J=8.4,5.0Hz,1H),0.96–0.89(m,2H),0.80–0.74(m,2H). 13 C NMR (151MHz, CDCl3) δ181.82,171.59,157.05,155.14,151.53,147.37,141.03,139.02,138.40,137.18,135.55,135.51,130.64 ,129.61,128.24,125.90,124.74,119.76,118.75,117.37,92.94,54.73,43.75,43.11,39.71,35.73,9.73,8.11,8.08.HRMS(ESI m / z):[M+H] + Calculated for C 31 H 30 N7O3,548.24046; found,548.24036.HPLC purity:98.38%.Melting point:>180℃.IR(neat,cm -1 )2962,1711,1605,1545,1491,1432,1260,1086,1013,797.

[0241] Example 37:

[0242] Experiment 12. Synthesis of Compound 4-100

[0243] At room temperature, p-phenylhydrazine hydrochloride (500 mg, 2.7 mmol, 1.0 eq) and acylacetonitrile (461 mg, 3.0 mmol, 1.15 eq) were mixed in a 100 mL reaction flask, 40 mL of ethanol and 1 mL of concentrated hydrochloric acid were added, and the mixture was refluxed at 100 °C for 12 hours. After the reaction was complete, the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution, and the system was quenched with 50 mL of water. The system was extracted three times with 100 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE:EA = 5:1) to obtain 345 mg of a yellow oily liquid. 138 mg of the starting material p-phenylhydrazine hydrochloride was recovered, with a yield of 57%. 1 H NMR (500MHz, CDCl3) δ7.98(dt,J=9.8,4.8Hz,2H),7.58(dt,J=8.3,3.7Hz,2H),5.35(q,J=4.2,3.3Hz,1H),4.27(td,J=7.3,3.7Hz,2H),4.00(s, 2H),2.49(ddt,J=11.7,8.0,3.8Hz,1H),1.88(d,J=8.4Hz,2H),1.77–1. 68(m,2H),1.64(d,J=12.7Hz,1H),1.37–1.24(m,7H),1.22–1.13(m,1H). 13 C NMR (126MHz, CDCl3) δ165.84,159.67,145.54,142.71,130.59,127.63,122.02,89.03,60.95,37.84,32.90,26.22,25.98,14.15.HRMS (ESI m / z):[M+H] + Calculated for C 18 H 24 N3O2,314.18630; found,314.18565.IR(neat,cm -1 )3326,2924,2850,1704,1606,1560,1517,1389,1270,1100,1015,858,769,701.

[0244] Experiment 13. Synthesis of Compound 4-102

[0245] At room temperature, compound 4-100 (345 mg, 1.1 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 20 mL of methanol. Then, 10 mL of 2 M NaOH aqueous solution was added with constant stirring, and the mixture was stirred for 1 hour. After the reaction was complete, the pH was adjusted to 5 with 2 M HCl solution, and the mixture was directly dried using an oil pump. The crude product was separated by column chromatography (DCM:MeOH = 30:1) to give 255 mg of an orange-yellow solid, with a yield of 81%. 1 H NMR(500MHz,Methanol-d4)δ8.13(d,J=8.1Hz,1H),7.64(d,J=8.1Hz,1H),5.32(s,3H),2.60–2.47(m,1H),1 .93(d,J=11.6Hz,2H),1.80(d,J=11.4Hz,2H),1.71(d,J=12.7Hz,1H),1.50–1.31(m,4H),1.31–1.21(m,1H). 13 C NMR(126MHz,Methanol-d4)δ169.72,160.82,149.47,142.52,132.00,131.10,124.27,89.43,38.69,33.89,27.28,27.00.HRMS(ESI m / z):[M+H] + Calculated for C 16 H 20 N3O2,286.15500; found,286.15486.IR(neat,cm -1 )3318,2923,2851,1694,1604,1556,1517,1414,1388,1260,773.

[0246] Experiment 14. Synthesis of compounds 5-6

[0247] Compound 4-102 (150 mg, 0.53 mmol, 1.0 eq) and HATU (240 mg, 0.63 mmol, 1.2 eq) were mixed in a 100 mL reaction flask. 20 mL of DMF and DIPEA (204 mg, 1.58 mmol, 3.0 eq) were added. While stirring continuously, 3 mL of a 1 M THF solution of dimethylamine was added dropwise to the reaction system, and the mixture was stirred overnight. After the reaction was complete, the system was quenched with 10 mL of water, extracted twice with 50 mL of ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM:MeOH = 100:1) to give 112 mg of a yellow solid, with a yield of 68%. 1 H NMR (500MHz, CDCl3) δ7.59(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),5.43(s,1H),3.84(s,2H),3.08(s,3H),2.96(s,3H ),2.59–2.50(m,1H),1.94(d,J=10.9Hz,2H),1.77(dd,J=9.4,3.3Hz,2H),1.68(d,J=13.6Hz,1H),1.45–1.17(m,5H). 13 C NMR (126MHz, CDCl3) δ170.95,159.53,145.26,139.96,134.40,128.36,123.25,88.69,39.64,38.06,35.48,33.15,26.44,26.19.HRMS(ESI m / z):[M+H] + Calculated for C 18 H 25 N4O,313.20229; found,313.20255.IR(neat,cm -1 )3346,2917,2846,1621,1605,1555,1489,1389,1264,1082,1010,859,741,479.

[0248] Experiment 15. Synthesis of compounds 5-15

[0249] Following step 1 of Experiment 4, 79 mg of a yellow solid was obtained.

[0250] Following step 2 of Experiment 4, 36 mg of yellow solid was obtained, with a total yield of 29%. 1H NMR (500MHz, CDCl3) δ10.01(s,1H),8.32(s,1H),8.11(dd,J=5.3,1.6Hz,1H),7.82(s,1H),7.48(d,J=8. 5Hz,2H),7.41(d,J=8.5Hz,2H),7.17(s,1H),7.04(dd,J=7.3,1.6Hz,1H),6.99(s,2H),6.79(dd,J=7.3,5 .3Hz,1H),6.42(s,1H),3.39(dd,J=21.0,15.8Hz,2H),3.12(s,3H),3.00–2.85(m,5H),2.60(td,J=11.5 ,5.8Hz,1H),1.95(d,J=10.5Hz,2H),1.77(dt,J=12.5,3.1Hz,2H),1.73–1.64(m,1H),1.47–1.16(m,5H). 13 C NMR (151MHz, CDCl3) δ181.52,171.48,159.94,155.31,151.87,146.98,141.31,139.35,137.75,137.53,135.41,135.03,130.73,129. 68,128.16,125.27,124.77,119.24,118.62,116.71,94.80,54.78,43.65,43.09,39.71,38.18,35.70,33.12,26.47,26.22.HRMS(ESI m / z):[M+H] + Calculated for C 34 H 36 N7O3,590.28741; found,590.28776.HPLC purity:96.12%.Melting point:>180℃.IR(neat,cm -1 )2961,2923,2849,1717,1604,1544,1492,1432,1260,1210,1086,1013,797.

[0251] Example 38:

[0252] Experiment 16. Synthesis of Compounds 5-20

[0253] Compound 5-16 (200 mg, 0.92 mmol, 1.0 eq) and HATU (420 mg, 1.1 mmol, 1.2 eq) were mixed in a 100 mL reaction flask. 20 mL of DMF and DIPEA (357 mg, 2.8 mmol, 3.0 eq) were added. While stirring continuously, 5 mL of a 1 M THF solution of dimethylamine was added dropwise to the reaction system, and the mixture was stirred overnight. After the reaction was complete, the system was quenched with 10 mL of water, extracted twice with 60 mL of ethyl acetate, and the organic phase was washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM:MeOH = 100:1) to give 190 mg of a yellow solid, with a yield of 84%. 1 H NMR (500MHz, CDCl3) δ7.59(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),5.43(s,1H),3.85(s,2H),3.09(s,3H),2.97(s,3H),2.20(s,3H). 13 C NMR(126MHz, CDCl3)δ170.92,150.02,145.66,139.84,134.60,128.43,123.25,91.35,39.65,35.51,13.99.HRMS(ESI m / z):[M+H] + Calculated for C 13 H 17 N4O,245.13969; found,245.13972.IR(neat,cm -1 )3315,3213,2923,1620,1604,1556,1493,1391,1085,837,556.

[0254] Experiment 17. Synthesis of Compounds 5-29

[0255] Following step 1 of Experiment 4, 13 mg of a yellow solid was obtained.

[0256] Following step 2 of Experiment 4, 4 mg of yellow solid was obtained, with a total yield of 29%. 1H NMR(500MHz, CDCl3)δ9.54(s,1H),8.13(dd,J=5.3,1.6Hz,1H),8.10(d,J=2.7Hz,1H),7.64(s,1H),7.53–7.45(m,4H),7.11–7.04(m,2H),6.99 (s,2H),6.80(dd,J=7.3,5.3Hz,1H),6.43(s,1H),3.37(t,J=15.9Hz,2H),3.17(s,3H),3.01(s,3H),2.93(dd,J=15.9,3.8Hz,2H),2.29(s,3H). 13 C NMR (151MHz, CDCl3) δ181.63,171.53,155.11,151.61,150.47,147.32,141.13,139.09,138.30,137.29,135.54,130.61,12 9.90,129.64,128.23,125.71,124.78,119.65,118.74,117.16,97.23,54.78,43.75,43.11,39.71,35.71,14.14.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N7O3,522.22481; found,522.22468.HPLC purity:95.15%.Melting point:>180℃.IR(neat,cm -1 )2962,2923,1712,1606,1546,1492,1432,1259,1086,1013,794.

[0257] Example 39:

[0258] Experiment 18. Synthesis of Compound 5-33

[0259] Following step 1 of Experiment 4, 30 mg of a yellow solid was obtained.

[0260] Following step 2 of Experiment 4, 16 mg of white solid was obtained, with a total yield of 13%. 1H NMR(500MHz, CDCl3)δ8.14(s,1H),8.11(dd,J=5.3,1.6Hz,1H),7.69(s,1H),7.49–7.45(m,1H),7 .42(s,1H),7.40–7.34(m,2H),7.20(d,J=7.6Hz,1H),7.11(dd,J=7.3,1.6Hz,1H),7.09–7.01(m,2 H),6.82(dd,J=7.3,5.3Hz,1H),6.49(s,1H),3.58(d,J=4.0Hz,2H),3.47(dd,J=15.8,11.5Hz,2H ), 3.01(dd,J=15.9,5.3Hz,2H),2.64(s,2H),2.49(s,2H),2.28(s,3H),2.23(s,4H),1.34(s,9H). 13 C NMR (126MHz, CDCl3) δ181.30,162.91,155.16,151.78,146.97,141.45,138.71,138.07,137.56,137.19,135.06,130.51,129.81,129.60, 129.45,125.75,125.06,124.77,118.67,118.60,115.95,94.82,62.77,54.83,54.68,52.78,45.94,43.72,43.05,32.59,30.48.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N7O3,605.33470; found,605.33413.HPLC purity:95.74%.Melting point:>180℃.IR(neat,cm -1 )2962,1717,1605,1547,1492,1431,1259,1088,1011,793,684.

[0261] Example 40:

[0262] Experiment 19. Synthesis of Compound 6-84

[0263] Step 1: Compound 6-81 (73 mg, 0.28 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 5 mL of THF under Ar protection. 0.1 mL of thionyl chloride was slowly added dropwise, followed by 0.1 mL of DMF. The mixture was heated and stirred at 50 °C for 1 hour. Volatile substances in the mixture were removed by pumping dry and redissolved in 10 mL of THF. 3 mL of a THF solution containing 37 (160 mg, 0.42 mmol, 1.5 eq) was slowly transferred to this mixture, and 0.2 mL of triethylamine was added. A large amount of solid was produced. The mixture was heated and stirred at 50 °C for 1 hour. After the reaction was complete, 10 mL of water was added to quench the reaction. The mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative chromatography (PE:EA = 1:1) to obtain 39 mg of a yellow solid.

[0264] Step 2: The product from Step 1 (39 mg, 0.06 mmol, 1.0 eq) was placed in a 100 mL reaction flask, dissolved in 10 mL of dichloromethane, and 2.0 mL of trifluoroacetic acid was slowly added dropwise. The reaction was stirred overnight at room temperature. After the reaction was complete, the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative agar (DCM:MeOH = 30:1) to obtain 23 mg of white solid. The overall yield of the two steps was 17%. 1 H NMR (600MHz, CDCl3) δ10.00(s,1H),8.13(d,J=5.4Hz,1H),7.61(s,1H),7.49–7.41(m,5H),7.36(dq,J=6.1,3.4Hz,1H),7.15(q,J=10.1,9.6Hz,2H ),7.06(d,J=7.3Hz,1H),6.80(t,J=6.7Hz,1H),6.36(s,1H),3.76(s,2H) ,3.59(dd,J=15.2,6.4Hz,2H),3.02(dd,J=15.8,5.9Hz,2H),1.37(s,9H). 13C NMR (151MHz, CDCl3) δ180.49,166.73,163.12,155.42,146.65,141.87,139.48,137.07,136.85,136.21,130.68,129.77 ,129.52,128.20,125.44,124.95,119.22,118.43,116.64,104.82,54.95,43.62,43.17,35.61,32.38,30.65.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 30 N5O2,492.23940; found,492.23975.HPLC purity:98.35%.Melting point:>180℃.IR(neat,cm -1 )3068,2960,1717,1662,1601,1545,1501,1431,1260,1211,1097,1015,798,778,765.

[0265] Example 41:

[0266] Experiment 20. Synthesis of compounds 6-79

[0267] Pretreated Zn powder (393 mg, 6.0 mmol, 3.0 eq) and methyl bromoacetate (459 mg, 3.0 mmol, 1.5 eq) were placed in a 100 mL reaction flask. Under Ar protection, 10 mL of THF was added, and the system was heated to 50 °C. 38 μL of TMSCl was added to the system with constant stirring, and the reaction was carried out at this temperature for 3 hours. The reaction solution turned green and was stored in a refrigerator for later use. Compound 41 (891 mg, 2.0 mmol, 1.0 eq), Pd2dba3 (92 mg, 0.1 mmol, 0.05 eq), and Xphos (96 mg, 0.2 mmol, 0.1 eq) were placed in a 100 mL reaction flask. Under Ar protection, 20 mL of THF was added to dissolve the mixture. The zinc bromide ethyl acetate reaction solution was transferred to the system, and the system was heated and stirred at 80 °C for 10 hours. After the reaction was complete, 20 mL of water was added to quench the system, and the mixture was extracted three times with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE:EA = 2:1) to obtain 902 mg of orange-yellow solid, with a yield >98%. 1H NMR(500MHz, CDCl3)δ8.15(ddd,J=4.8,3.0,1.6Hz,1H),7.20–7.10(m,3H),7.04(dt,J=7.4,2.0Hz,1H),6.79(ddd ,J=7.7,5.0,2.5Hz,1H),5.26(s,2H),3.70–3.55(m,9H),3.01(d,J=15.9Hz,2H),0.98–0.92(m,2H),-0.05(s,9H). 13 C NMR (126MHz, CDCl3) δ179.60,172.04,155.02,147.20,141.04,139.43,133.08,129.54,129.17,128. 31,125.45,124.59,118.77,67.98,66.84,53.95,52.03,43.61,43.43,40.86,17.80,-1.44.HRMS(ESI m / z):[M+H] + Calculated for C 24 H 31 N2O4Si,439.20476; found,439.20493.IR(neat,cm -1 )3017,2950,1730,1595,1450,1339,1244,1077,857,834,780.

[0268] Experiment 21. Synthesis of Compounds 6-82

[0269] At room temperature, compound 6-79 (730 mg, 1.7 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 20 mL of methanol. Then, 10 mL of 2 M NaOH aqueous solution was added with constant stirring, and the mixture was stirred for 1 hour. After the reaction was complete, the pH was adjusted to 5 with 2 M HCl solution. The mixture was extracted three times with 40 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM:MeOH = 100:1) to give 554 mg of a yellow solid, with a yield of 78%. 1H NMR(500MHz, CDCl3)δ8.20(s,1H),7.23–7.13(m,3H),7.11–7.05(m,1H),7.86–6.79(m,1H),5 .29(s,2H),3.73–3.56(m,6H),3.02(dd,J=15.8,2.8Hz,2H),1.01–0.91(m,2H),-0.04(s,9H). 13 C NMR (126MHz, CDCl3) δ179.70,176.27,154.83,146.92,140.98,139.45,132.93,129.73,129.51,1 28.49,125.61,124.63,118.92,68.05,66.86,53.98,43.60,43.44,40.88,17.79,-1.45.HRMS(ESI m / z):[M+H] + Calculated for C 23 H 29 N2O4Si,425.18911; found,425.18882.IR(neat,cm -1 )2949,2897,1728,1597,1451,1340,1244,1077,857,833,779.

[0270] Experiment 22. Synthesis of Compounds 6-87

[0271] Step 1: Compound 6-82 (200 mg, 0.47 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 5 mL THF under Ar protection. 0.2 mL of thionyl chloride was slowly added dropwise, followed by 0.2 mL of DMF. The mixture was heated and stirred at 50 °C for 1 hour. Volatile substances in the mixture were removed by pumping dry and redissolved in 15 mL of THF. 10 mL of a THF solution of 40-3-34 (203 mg, 0.94 mmol, 2.0 eq) was slowly added dropwise to the mixture. 0.3 mL of triethylamine was added, resulting in the formation of a large amount of solid. The mixture was heated and stirred at 50 °C for 1 hour. After the reaction was complete, 10 mL of water was added to quench the reaction. The mixture was extracted three times with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE:EA = 3:1) to obtain 174 mg of a yellow solid.

[0272] Step 2: The product from Step 1 (174 mg, 0.28 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 15 mL of dichloromethane. 4.0 mL of trifluoroacetic acid was slowly added dropwise to the solution, and the reaction was stirred overnight at room temperature. After the reaction was complete, the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted three times with 40 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM:MeOH = 30:1) to obtain 132 mg of a white solid. The overall yield of the two steps was 57%. 1 H NMR(500MHz, CDCl3)δ8.14(d,J=5.3Hz,1H),7.89(d,J=4.6Hz,1H),7.66–7.60(m,2H),7.38–7.32(m,3H),7.23–7.17(m,3H),7.07(d,J=6.1Hz,2H), 6.94(d,J=7.4Hz,1H),6.78(t,J=6.1Hz,1H),6.60(s,1H),3.67(s,2H),3 .57(dd,J=42.4,15.9Hz,2H),3.01(dd,J=36.6,16.0Hz,2H),1.31(s,9H). 13 C NMR (126MHz, CDCl3) δ180.65,167.56,162.61,155.70,146.45,142.04,140.43,137.84,135.43,133.00,130.70,12 9.65,128.61,127.97,125.69,125.38,124.52,118.29,94.72,54.57,43.82,43.40,43.29,32.47,30.35.HRMS(ESI m / z):[M+H] + Calculated for C 30 H 30 N5O2,492.23940; found,492.23959.HPLC purity:95.52%.Melting point:>180℃.IR(neat,cm -1 )2960,1723,1666,1601,1546,1500,1432,1261,1212,1098,1016,798,778,763,692.

[0273] Example 42:

[0274] Experiment 23. Synthesis of compounds 6-23

[0275] Step 1: Place triphosgene (124 mg, 0.42 mmol, 1.0 eq) in a 100 mL Schlenk flask. Under Ar atmosphere protection, add 5 mL of THF solvent and place the system in an ice bath at 0 °C. Dissolve compound 40-3-31 (103 mg, 0.42 mmol, 1.0 eq) in 5 mL of THF. While stirring continuously, slowly add the mixture dropwise to the system. Add triethylamine (89 mg, 0.88 mmol, 2.1 eq) dropwise to the system. A large amount of precipitate forms in the reaction solution. Allow the system to return to room temperature naturally and stir for 1 hour. Then, remove the volatile liquid from the system and redissolve it in 15 mL of THF. Dissolve compound 37 (160 mg, 0.42 mmol, 1.0 eq) in 5 mL of THF. While stirring continuously, slowly add the mixture dropwise to the system. Heat the system at 50 °C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the reaction. The system was extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by a preparative plate (PE:EA = 1:1) to obtain 273 mg of yellow solid.

[0276] Step 2: The product from Step 1 (273 mg, 0.42 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 15 mL of dichloromethane. The system was placed in a cold trap at -70 °C. Under constant stirring, 3.0 mL of BBr3 was slowly added dropwise to the system, and the reaction solution became turbid. The system was allowed to return to room temperature naturally and stirred for 10 hours. After the reaction was complete, the pH of the system was adjusted to neutral with NaOH solution, and the mixture was extracted three times with a mixed solvent of 50 mL dichloromethane and 5 mL methanol. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM:MeOH = 30:1) to obtain 121 mg of a yellow solid.

[0277] Step 3: The product from Step 2 (121 mg, 0.24 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 3 mL of DMF. The system was protected with a sulfonyl fluoride balloon. Triethylamine (72 mg, 0.71 mmol, 3.0 eq) was slowly added dropwise to the system under constant stirring for 12 hours. After the reaction was complete, the system was quenched with a small amount of saturated brine, extracted twice with 50 mL of dichloromethane, and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative agar (DCM:MeOH = 30:1) to obtain 62 mg of a yellow solid. The overall yield of the three steps was 25%. 1H NMR (600MHz, CDCl3) δ10.62 (s, 1H), 8.05 (d, J = 4.4Hz, 1H), 7.87 (s, 1H), 7. 75(s,1H),7.57(d,J=8.8Hz,2H),7.27(d,J=9.7Hz,2H),7.14(s,1H),7.08( d,J=6.7Hz,1H),7.01(d,J=8.3Hz,1H),6.97(d,J=10.5Hz,1H),6.80(t,J=6 .2Hz,1H),6.32(s,1H),3.41–3.31(m,2H),3.02–2.86(m,2H),1.27(s,9H). 13 C NMR (151MHz, CDCl3) δ181.90,163.44,155.36,152.76,148.24,146.43,141.58,138.80,137.37,136.54,135.8 3,130.38,130.14,125.90,124.90,121.90,119.31,118.76,116.49,97.85,54.72,43.37,42.83,32.59,30.27. 19 F NMR(376MHz, CDCl3)δ37.79.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O5FS,591.18204; found,591.18147.HPLC purity:97.06%.Melting point:>180℃.IR(neat,cm -1 )2961,1715,1664,1604,1550,1503,1433,1232,1098,1014,911,800,777,582.

[0278] Example 43:

[0279] Experiment 24. Synthesis of Compounds 6-33

[0280] Step 1: Place triphosgene (117 mg, 0.39 mmol, 1.0 eq) in a 100 mL Schlenk flask. Under Ar atmosphere protection, add 5 mL of THF solvent and place the system in an ice bath at 0 °C. Dissolve compound 40-4-21 (96 mg, 0.39 mmol, 1.0 eq) in 5 mL of THF. While stirring continuously, slowly add the mixture dropwise to the system. Add triethylamine (84 mg, 0.83 mmol, 2.1 eq) dropwise to the system. A large amount of precipitate forms in the reaction solution. Allow the system to return to room temperature naturally and stir for 1 hour. Then, remove the volatile liquid from the system and redissolve it in 15 mL of THF. Dissolve compound 37 (150 mg, 0.39 mmol, 1.0 eq) in 5 mL of THF. While stirring continuously, slowly add the mixture dropwise to the system. Heat the system at 50 °C for 2 hours. After the reaction was complete, 20 mL of water was added to quench the reaction. The system was extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE:EA = 3:1) to obtain 228 mg of yellow solid.

[0281] Step 2: The product from Step 1 (228 mg, 0.35 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 20 mL of dichloromethane. The system was placed in a cold trap at -70 °C. Under constant stirring, 2.0 mL of BBr3 was slowly added dropwise to the system, and the reaction solution became turbid. The system was allowed to return to room temperature naturally and stirred for 10 hours. After the reaction was complete, the pH of the system was adjusted to neutral with NaOH solution, and the mixture was extracted three times with a mixed solvent of 50 mL dichloromethane and 5 mL methanol. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative chromatography (DCM:MeOH = 30:1) to obtain 154 mg of a yellow solid.

[0282] Step 3: The product from Step 2 (154 mg, 0.29 mmol, 1.0 eq) was placed in a 100 mL reaction flask and dissolved in 5 mL of DMF. The system was protected with a sulfonyl fluoride balloon. Triethylamine (87 mg, 0.86 mmol, 3.0 eq) was slowly added dropwise to the system under constant stirring for 12 hours. After the reaction was complete, the system was quenched with a small amount of saturated brine, extracted twice with 50 mL of dichloromethane, and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative agar (DCM:MeOH = 30:1) to obtain 136 mg of a yellow solid. The overall yield of the three steps was 59%. 1H NMR(600MHz, CDCl3)δ10.78(s,1H),8.07–7.78(m,3H),7.59–7.48(m,2H),7.35(s,1H),7.12(s,2H), 7.06–6.89(m,3H),6.76(s,1H),6.30(s,1H),3.34(t,J=15.1Hz,2H),3.01–2.77(m,2H),1.26(s,9H). 13 C NMR (151MHz, CDCl3) δ181.84,163.44,155.37,153.08,149.93,146.33,141.51,140.46,137.37,136.43,135.75,130.9 4,130.52,130.05,124.85,123.59,119.35,118.92,118.69,116.38,116.38,98.77,54.74,43.33,42.82,32.58,30.21. 19 F NMR(565MHz,CDCl3)δ38.54.HRMS(ESI m / z):[M+H] + Calculated for C 29 H 28 N6O5FS,591.18204; found,591.18111.HPLC purity:95.47%.Melting point:>180℃.IR(neat,cm -1 )2961,1715,1660,1607,1547,1493,1433,1229,929,795,779,566.

[0283] Example 44:

[0284] Compound 8-34

[0285] LRMS(ESI m / z):[M+H] + found,525.4.HPLC purity:98.21%.

[0286] Example 45:

[0287] Compounds 9-12

[0288] LRMS(ESI m / z):[M+H] + Found, 512.5. HPLC purity: 97.12%. Example 46:

[0289] Compound 9-22

[0290] LRMS(ESI m / z):[M+H] + found,605.5.HPLC purity:95.66%.

[0291] Example 47:

[0292] Compound 9-26

[0293] LRMS(ESI m / z):[M+H] + found,510.4.HPLC purity:95.82%.

[0294] Example 48:

[0295] Compound 9-31

[0296] LRMS(ESI m / z):[M+H] + Found, 621.6. HPLC purity: 99.33%. Example 49:

[0297] Compound 9-32

[0298] LRMS(ESI m / z):[M+H] + found,619.6.HPLC purity:97.00%.

[0299] Example 50:

[0300] Compounds 9-61

[0301] LRMS(ESI m / z):[M+H] + found,543.5.HPLC purity:98.01%.

[0302] Example 51:

[0303] Compounds 9-62

[0304] LRMS(ESI m / z):[M+H] + Found, 543.5. HPLC purity: 99.17%. Example 52:

[0305] Compounds 9-65

[0306] LRMS(ESI m / z):[M+H] + found,431.6.HPLC purity:95.56%.

[0307] Example 53:

[0308] Compounds 9-66

[0309] LRMS(ESI m / z):[M+H] + found,445.5.HPLC purity:95.05%.

[0310] Example 54:

[0311] Compounds 9-71

[0312] LRMS(ESI m / z):[M+H] + found,551.7.HPLC purity:100.00%.

[0313] Example 55:

[0314] Compounds 9-72

[0315] LRMS(ESI m / z):[M+H] + found,557.4.HPLC purity:99.49%.

[0316] Example 56:

[0317] Compounds 9-81

[0318] LRMS(ESI m / z):[M+H] + found,673.7.HPLC purity:95.44%.

[0319] Example 57:

[0320] Compounds 9-82

[0321] LRMS(ESI m / z):[M+H] + found,541.5.HPLC purity:99.17%.

[0322] Example 58:

[0323] Compounds 9-84

[0324] LRMS(ESI m / z):[M+H] + Found, 623.8. HPLC purity: 95.04%. Example 59: Inhibition test of the compound on DDR1 and DDR2 kinase activity.

[0325] Table 1. Results of tests on the inhibitory activity of the compounds against kinases.

[0326] IC 50 :<20nM=*; 20-50nM=**; 50-500nM=***; >500nM=****.

[0327] Experimental results show that the compounds of this invention have excellent inhibitory activity against DDR1 / 2 protein kinase.

[0328] Example 60: Pharmacokinetic Test

[0329] Blood samples were collected from SD rats at appropriate time points after single oral (po. 10 mg / kg) and intravenous (iv. 2 mg / kg) administration. Samples were anticoagulated with EDTA-K2, centrifuged at 6800g for 6 minutes at 2-8℃; the supernatant was collected and stored at -80℃ for analysis. Proteins in plasma samples were precipitated with methanol, vortexed for 1 minute, followed by centrifugation at 14000 rpm for 7 minutes; the supernatant was used for HPCL-MS analysis. Data were fitted using DAS2.0 to obtain parameters for both compartmentalized and non-compartmental models. The oral bioavailability F of the compound was calculated based on the area under the plasma concentration-time curve (AUC). Results are shown in Table 2.

[0330] Table 2. Pharmacokinetic results of compound 4-20-2

[0331] Experimental results show that compound 4-20-2 (the enantiomer of compound 4-20 with better activity) of the present invention has excellent oral pharmacokinetic properties.

[0332] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

A compound having the structure shown in formula (I), its pharmaceutically acceptable salt, isotopic derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite: in, U, V, W, E, X, Y, and Z are each independently N or CR3; B is selected from the following group: C and D are each independently selected from the following groups: Each R3 is independently selected from the following groups: 1) Substituted or unsubstituted groups selected from the following group: C3-C 12 Saturated or unsaturated carbon rings, 3-12 membered saturated or unsaturated heterocycles, 7-12 membered fused heterocycles, 7-12 membered spirocyclic heterocycles, 7-12 membered bridged heterocycles, C6-C 10 Aromatic rings, 5-12 quinary aromatic rings; 2) Hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 heteroalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, -(CH2) m R4、-NH(CH2) m R4, -NR5(CH2) m R4、-O(CH2) m R4; Where m is 0, 1, 2 or 3; R4 and R5 are each independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C. 12 Saturated or unsaturated carbocyclic rings, substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-12-membered heteroaromatic rings, C1-C8 alkyl groups, C1-C8 alkoxy groups, C3-C8 cycloalkyl groups, C1-C8 azaalkyl groups, C1-C8 haloalkyl groups, C1-C8 haloalkoxy groups, C3-C8 halocycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C2-C8 ester groups, C1-C8 amide groups, -S(O)C1-C8 alkyl groups, -S(O)2C1-C8 alkyl groups, or R4, R5 and the atoms they are attached to form substituted or unsubstituted groups selected from the group consisting of: 4-12-membered monoheterocycles, 7-12-membered fused heterocycles, 7-12-membered spiroheterocycles or 7-12-membered bridged heterocycles; L is selected from the following group: chemical bond, C1-C4 straight-chain alkylene, C1-C3 alkylene-C(O)O-C1-C3 alkylene. Ring A is selected from the following group: C 6-10 Aromatic rings, 5-12 membered heterocyclic rings, 3-8 membered heterocyclic rings; R1 and R2 are each independently selected from the following groups: 1) by 1, 2, 3 or 4 R a Replaced or not replaced Where L2 is C 0-4 Alkylene, cyclic B is selected from the following group: C3-C 12 Saturated or unsaturated carbon rings, 3-12 membered saturated or unsaturated heterocycles, 7-12 membered fused heterocycles, 7-12 membered spirocyclic heterocycles, 7-12 membered bridged heterocycles, C6-C 10 Aromatic rings, 5-12 heterocyclic aromatic rings; 2) Hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, -SF5, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, -(CH2) m R6、-NH(CH2) m R6, -NR7(CH2) m R6, -O(CH2) m R6; R6 and R7 are selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C. 12 Saturated or unsaturated carbocyclic rings, substituted or unsubstituted 3-12 membered saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-12 membered heteroaromatic rings, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, -CR 6a R 6b R 6c -OR8, -NR 7a R 7b ; Among them, R 6a R 6b R 6c R8, R 7a and R 7b Each is independently selected from the group consisting of: hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, halogen, hydroxyl, cyano, amino, C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -S(O)2C1-C8 alkyl, or R 6a R 6b R 6c Together with the carbon atom to which it is attached, they form substituted or unsubstituted groups selected from the group consisting of: 4-12 membered monoheterocycles, 7-12 membered fused heterocycles, 7-12 membered spiroheterocycles, and 7-12 membered bridged heterocycles; or R 7a R 7b Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted group selected from the group consisting of: 5-12-membered heteroaromatic rings, 4-12-membered monoheterocyclic rings, 7-12-membered fused heterocyclic rings, 7-12-membered spiroheterocyclic rings, and 7-12-membered bridged heterocyclic rings. R a Selected from the following groups: hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C8 ester, C1-C8 amide, -S(O)C1-C8 alkyl, -OS(O)2-halogen, -S(O)2C1-C8 alkyl, -CONR 12 R 13 -C 0-4 alkylene-4-10-membered heterocyclic group, -C 0-4 Alkylene-C 6-10 Aromatic ring, -C 0-4 alkylene-5-9 membered heteroaryl rings, or two Rs on adjacent atoms a Together with the atoms they are attached to, they form 5-9 membered heteroaromatic rings or 4-8 membered heterocycles; R 12 and R 13 Each is independently selected from the following group: hydrogen, deuterium, C1-C8 alkyl, -C 0-4 alkylene-C1-C8 alkylamino; Unless otherwise specified, "substitution" as used above refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, oxo, unsubstituted or halogenated C1-C6 sulfone, unsubstituted or halogenated C1-C6 sulfoxide, unsubstituted or halogenated C1-C6 sulfinyl, unsubstituted or halogenated C1-C6 sulfonylimide, unsubstituted or halogenated C1-C6 alkyl, Unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C1-C6 acyl, unsubstituted or halogenated C1-C6 amide, unsubstituted or halogenated C1-C6 alkylamine, unsubstituted or halogenated C1-C6 alkyl-hydroxy, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic groups; The heterocycle refers to a cyclic group containing one, two, or three heteroatoms selected from N, O, or S, which is saturated or partially unsaturated and non-aromatic. It can be a monocyclic, fused, bridged, or spirocyclic ring. The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, The ring A is selected from the group consisting of: phenyl, naphthyl, 5-7 membered heteroaromatic ring, benzene ring with 5-7 membered heteroaromatic ring, 5-7 membered heteroaromatic ring with 5-7 membered heteroaromatic ring, and 3-8 membered heterocycle; Ring A is selected from the following group: pyrazole, imidazole, pyrrole, triazole, phenyl, pyridine, diazine, triazine, thiophene, thiazole, isothiazine, furan, oxazole, isoxazole, indole, isoindole, benzopyrazole, benzimidazole, benzothiophene, benzofuran, quinoline, isoquinoline, benzodiazine, benzotriazine, 3-8 membered heterocycles; Preferably, ring A is selected from the group consisting of: pyrazole, imidazole, pyrrole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1,3,4-triazine, indole, isoindole, benzopyrazole, benzimidazole, quinoline, isoquinoline, benzodiazine, and benzotriazine. The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, The L is selected from the following group: The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, R1 is selected from the following group: 1) by 1, 2 or 3 R 1a Substituted or unsubstituted groups selected from the group consisting of: C3-C 10 Cycloalkyl, 4-10 membered saturated or unsaturated heterocycles, C6-C 10 Aromatic rings, 5-9 quintile aromatic rings; 2) Hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, cyano, amino, -SF5, C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -NHR6, -NR7R6; R6 and R7 are each independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, or R6 and R7 together with the atoms they are attached to form substituted or unsubstituted groups selected from the following group: 4-7 membered monoheterocycles, 7-12 membered fused heterocycles, 7-12 membered spiroheterocycles, 7-12 membered bridged heterocycles; R 1a Selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, 4-7 membered heterocyclic group, C 6-10 Aromatic rings, 5-7 quintile aromatic rings; Preferably, R1 is selected from the group consisting of: 1) by 1, 2 or 3 R 1a Substituted or unsubstituted groups selected from the group consisting of: C3-C8 cycloalkyl, 4-7 membered saturated or unsaturated heterocycles, C6-C 10 Aromatic rings, 5-7 quintile aromatic rings; 2) Hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, halogen, hydroxyl, cyano, amino, -SF5, C2-C4 ester, C1-C4 amide, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, -NHR6, -NR7R6; R6 and R7 are each independently selected from the following group: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, or R6 and R7 together with the atoms they are attached to form substituted or unsubstituted groups selected from the following group: 4-7 membered monoheterocycles, 7-10 membered fused heterocycles, 7-10 membered spiroheterocycles, 7-10 membered bridged heterocycles; R 1a Selected from the following groups: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C 2-4 Ester group, C1-C4 amide group, -S(O)C1-C4 alkyl group, -S(O)2C1-C4 alkyl group, 4-7 membered heterocyclic group, phenyl, naphthyl, 5-7 membered heteroaromatic ring. The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, R2 is selected from the following group: 1) by 1, 2, 3 or 4 R 2a Replaced or not replaced Where L2 is C 0-4 Alkylene, cyclic B is selected from the following group: C3-C 10 Cycloalkyl, 4-10 fused or unsaturated heterocycles, 7-10 fused heterocycles, 7-10 spirocyclic heterocycles, 7-10 bridged heterocycles, C6-C 10 Aromatic rings, 5-12 heterocyclic aromatic rings; 2) Hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxyl, cyano, amino, C2-C6 ester, C1-C6 amide, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -(CH2) m R 10 -NH(CH2) m R 10 -NR 11 (CH2) m R 10 -O(CH2) m R 10 ; Where m is 0, 1, 2 or 3; R 10 and R 11 Each is independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C. 10 Saturated or unsaturated carbocyclic rings, substituted or unsubstituted 4-10 member saturated or unsaturated heterocycles, substituted or unsubstituted C6-C 10 Aromatic rings, substituted or unsubstituted 5-9 membered heteroaromatic rings, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, or R 10 R 11 It forms, together with the atoms it is attached to, a substituent or unsubstituent group selected from the following group: 5-9 membered heteroaromatic rings, 4-7 membered monoheterocyclic rings, 7-10 membered fused heterocyclic rings, 7-10 membered spiroheterocyclic rings, and 7-10 membered bridged heterocyclic rings; R 2a Selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C6 ester, C1-C6 amide, -OS(O)2-halogen, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -CONR 12 R 13 -C 0-4 alkylene-4-7-membered heterocyclic group, -C 0-4 Alkylene-C 6-10 Aromatic ring, -C 0-4 alkylene-5-7-membered heteroaryl ring, or two R atoms on adjacent atoms 2a Together with the atoms they are attached to, they form 5-7 membered heteroaromatic rings or 4-8 membered heterocycles; R 12 and R 13 Each is independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, -C 0-4 alkylene-C1-C6 alkylamino; Preferably, R2 is selected from the group consisting of: 1) by 1, 2 or 3 R 2a Replaced or not replaced Where L2 is C 0-4 Alkylene, ring B is selected from the following group: C3-C8 cycloalkyl, 4-7 saturated or unsaturated heterocycles, 7-10 fused heterocycles, 7-10 spiroheterocycles, 7-10 bridged heterocycles, benzene rings, naphthalene rings, 5-7 heteroaromatic rings, benzo5-7 heteroaromatic rings; 2) Hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, halogen, hydroxyl, cyano, amino, C2-C4 ester, C1-C4 amide, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, -(CH2) m R 10 -NH(CH2) m R 10 -NR 11 (CH2) m R 10 -O(CH2) m R 10 ; Where m is 0, 1, 2 or 3; R 10 and R 11 Each is independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C3-C8 saturated or unsaturated carbon rings, substituted or unsubstituted 4-7 membered saturated or unsaturated heterocycles, substituted or unsubstituted benzene rings, substituted or unsubstituted 5-9 membered heteroaromatic rings, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, or R 10 R 11 It forms, together with the atoms it is attached to, a substituent or unsubstituent group selected from the following groups: 5-7 membered heteroaromatic rings, 4-7 membered monoheterocyclic rings, 7-10 membered fused heterocyclic rings, 7-10 membered spiroheterocyclic rings, and 7-10 membered bridged heterocyclic rings; R 2a Selected from the following groups: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 halocycloalkyl, carboxylic acid, halogen, hydroxyl, cyano, nitro, amino, oxo (=O), C2-C4 ester, C1-C4 amide, -OS(O)2-F, -S(O)C1-C4 alkyl, -S(O)2C1-C4 alkyl, -CONR 12 R 13 -C 0-4 alkylene-4-7-membered heterocyclic group, -C 0-4 alkylene ring, -C 0-4 alkylene-5-7-membered heteroaryl ring, or two R atoms on adjacent atoms 2a Together with the atoms they are attached to, they form 5-7 membered heteroaromatic rings or 4-8 membered heterocycles; R 12 and R 13 Each is independently selected from the following group: hydrogen, deuterium, C1-C4 alkyl, -C 0-4 Alkylene-C1-C4 alkylamino. The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, The Selected from the following group: Preferably, the Selected from the following group: Among them, R 3a R 3u and R 3w The definitions are the same as for R3; the definitions of B and D are as described in claim 1. More preferably, the Selected from the following group: The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, The compound has the structure shown in formula (II): The definitions of U, V, W, E, X, Y, Z, B, R3, L, ring A, R1, and R2 are as described in claim 1. The compound according to claim 1, its pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite is characterized in that, The compounds are selected from the group consisting of: A pharmaceutical composition, characterized in that, The composition comprises: (i) the compound according to any one of claims 1-8, its pharmaceutically acceptable salt, isotopic derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule, or metabolite, and (ii) Pharmaceutically acceptable carriers, excipients or excipients. The use of the compound according to any one of claims 1-8, its pharmaceutically acceptable salt, isotopic derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule or metabolite, or the pharmaceutical composition according to claim 9, is characterized in that, Used for the preparation of drugs for the prevention and / or treatment of DDR1 / 2-mediated diseases; Preferably, the diseases mediated by DDR1 / 2 are selected from the group consisting of: inflammatory diseases, cardiovascular diseases, fibrotic diseases, and cancer; More preferably, the diseases mediated by DDR1 / 2 are selected from the group consisting of: pulmonary fibrosis, renal fibrosis, acute lung injury, lung cancer, breast cancer, and pancreatic cancer.

Images