TWI750403B - Fibroblast growth factor receptor inhibitors, pharmaceutical preparations containing them, and uses thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and particularly relates to an irreversible inhibitor of fibroblast growth factor receptor (FGFR) represented by formula I, a pharmaceutically acceptable salt and a stereoisomer thereof. The present invention also relates to pharmaceutical formulations, pharmaceutical compositions and uses of these compounds. R ₁ , R ₂ , R ₃ , R ₄ , m, X, warhead ₁ , warhead ₂ are as defined in the specification. The compounds of the present invention have efficient and highly selective inhibitory effects on fibroblast growth factor receptors, and can be applied to the treatment of related diseases mediated by abnormal FGF/FGFR, especially the treatment of cancer diseases.

Description

Fibroblast growth factor receptor inhibitor, pharmaceutical preparation containing same and use thereof 【Cross reference to related applications】

This application claims the priority of the Chinese patent application filed on August 8, 2017 with the application number 201710672089.X of the invention titled "Fibroblast Growth Factor Receptor Inhibitor and Its Use", all of which The contents are incorporated by reference in this application.

The invention belongs to the technical field of medicine, and relates to irreversible inhibitors of fibroblast growth factor receptor (FGFR), or pharmaceutically acceptable salts, stereoisomers and applications thereof.

Tyrosine kinase receptors play an important role in tumor angiogenesis, proliferation, migration and infiltration of tumor cells. Currently, more than 100 tyrosine kinase inhibitor drugs have been launched or entered into clinical trials. These small-molecule tyrosine kinase inhibitors (TKIs) mostly work in a reversible way, which brings some disadvantages: ①the selectivity is not good enough, ②the drug effect is not strong and durable enough, ③ susceptible to drug resistance. Therefore, scientists are urged to focus their research on the development of irreversible TKIs.

Irreversible TKIs are usually based on the backbone structure of reversible TKIs, and an electrophilic functional group is attached at a suitable position, and the electrophilic functional group can interact with cysteine residues near the ATP-binding domain of tyrosine kinases. (electron-rich nucleophilic structure) undergoes an electrophilic reaction to form a covalent bond, thereby irreversibly inhibiting kinase activity. Compared with reversible TKIs, irreversible TKIs have many unique advantages: (1) Irreversible TKIs act in a way of permanent inactivation, and this way of inhibiting enzyme activity makes their effects more intense and lasting, even if drug molecules It is completely eliminated from the circulatory system, and its efficacy is still maintained. ②Because there is no ATP competition for its binding with kinase, it also reduces the possibility of kinase mutation and reduces or avoids the generation of drug resistance. ③ Because the electrophilic functional group on the molecular structure can selectively react with the sulfhydryl group on the cysteine residue, the selectivity of irreversible TKI is very high. Based on the above characteristics, the development of irreversible TKIs is gradually becoming a hot research direction.

Fibroblast growth factor receptor (FGFR) is an important member of the tyrosine kinase receptor family, FGFR contains four members, namely FGFR-1, FGFR-2, FGFR-3 and FGFR- 4. They are mostly single-chain glycoprotein molecules with a molecular mass of 110-150kd, and their structures are divided into extracellular, transmembrane and intracellular domains. Under normal physiological conditions, FGFR binds to its ligand fibroblast growth factor (FGF), FGFR undergoes dimerization and self-phosphorylation, and activates downstream signaling pathways, such as JAK/STAT pathway, phospholipase C pathway, phosphoinositide-3-kinase PI3K, and MAPK signaling pathways play important roles in tumor growth and angiogenesis. Abnormal FGFR is closely related to the occurrence of various tumors, such as bladder cancer (including urothelial cancer, etc.), breast cancer, bile duct cancer, gastric cancer, ovarian cancer, salivary gland cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, etc. Liver cancer, liver cancer, endometrial cancer, cervical cancer, pancreatic cancer, rhabdomyosarcoma, multiple myeloma, prostate cancer, esophageal cancer, glioma, myelodysplastic syndrome, dwarf syndrome, renal pelvis tumor, chondrosarcoma, melanoma Wait.

Although a series of patent applications for irreversible inhibitors of FGFR have been published, for example, the WO2015120049 patent discloses the compound PRN1371, which is currently in clinical phase I, and its chemical structure is as follows:

At present, there are no irreversible inhibitors of FGFR, especially irreversible inhibitors with high selectivity for pan (FGFR) pan-FGFR.

An object of the present invention is to provide a new class of irreversible pan-FGFR inhibitors, which have good inhibitory activity on pan-FGFR, and provide a possibility for the treatment of diseases mediated by pan-FGFR abnormality. The present invention also provides the use of the above-mentioned FGFR inhibitor.

The technical solution adopted in the present invention is as follows: an irreversible inhibitor of fibroblast growth factor receptor (FGFR) represented by general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

代表雙鍵，當X為N時，

代表單鍵；當warhead₁存在時，R₁選自C_1-6亞烷基、C_2-8亞烯基、C_2-8亞炔基、鹵代C_1-6亞烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-；當warhead₁不存在時，R₁選自氫、C_1-6烷基、C_2-8烯基、C_2-8炔基、鹵代C_1-6烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p；當warhead₂存在時，R₂選自C_1-6亞烷基、C_2-8亞烯基、C_2-8亞炔基、鹵代C_1-6亞烷基或-(L₃)q-Cy₃-；當warhead₂不存在時，R₂選自氫、C_1-6烷基、C_2-8烯基、C_2-8炔基、鹵代C_1-6烷基或-(L₃)q-Cy₃；Cy₁、Cy₂分別獨立地選自如下基團或其二價基：經一至多個R_a取代，或未經取代的3-12員環烷基、3-12員環烯基、3-12員雜環基、芳基或5-10員雜芳基，成環碳原子可任選被氧化為C(O)，成環硫原子可任選被氧化為S(O)、S(O)₂或S(O)(N)；Cy₃選自如下基團或其二價基：經一至多個R_b取代的，或未經取代的3-12員環烷基、3-12員環烯基、3-12員雜環基、芳基或5-10員雜芳基，成環碳原子可任選被氧化為C(O)，成環硫原子可任選被氧化為S(O)、S(O)₂或S(O)(N)； R_a、R_b分別獨立地選自：(i)氫；(ii)羥基、氨基、羧基、氰基、硝基、鹵素、C_2-6烯基羰基氨基或=CH₂；(iii)任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6烷氧C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、C_1-6烷基羰基氨基、C_1-6烷基磺醯氨基或3-8員雜環基取代的C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_2-8烯基、C_2-8炔基、C_1-6烷基磺醯基或C_1-6烷基硫基，所述的3-8員雜環基可任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基或(C_1-6烷基)₂氨基取代；(iv)任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基或(C_1-6烷基)₂氨基取代的3-8員環烷基、5-8員環烯基或3-8員雜環基；或(v)氨基-羰基、氰基-羰基、C_1-6烷基-羰基、C_1-6烷基氨基-羰基、(C_1-6烷基)₂氨基-羰基、C_1-6烷氧基-羰基、3-8員環烷基-羰基或3-8員雜環基-羰基；R₃選自氫、C_1-6烷基、C_1-6烷基氨基C_1-6烷基、(C_1-6烷基)₂氨基C_1-6烷基、鹵代C_1-6烷基、鹵代C_2-8烯基、C_2-8炔基，或任選被取代基Q₁取代的3-12員環烷基、3-12員環烯基、3-12員雜環基、芳基或5-10員雜芳基，所述取代基Q₁選自：羥基、氨基、氰基、硝基、鹵素、羧基、 醯胺基、氨基羰基、氨基磺醯基、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_2-8烯基、C_2-8炔基、C_1-6烷基磺醯基、C_1-6烷基羰基氨基、(C_1-6烷基)₂羰基氨基、C_1-6烷基氨基羰基、(C_1-6烷基)₂氨基羰基、C_1-6烷基氨基磺醯基、(C_1-6烷基)₂氨基磺醯基或C_1-6烷氧基C_1-6烷氧基；R₄選自氫、羥基、氨基、氰基、硝基、鹵素、羧基、醯胺基、氨基羰基、氨基磺醯基、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_2-8烯基、C_2-8炔基、C_1-6烷基磺醯基、C_1-6烷基羰基氨基、(C_1-6烷基)₂羰基氨基、C_1-6烷基氨基羰基、(C_1-6烷基)₂氨基羰基、C_1-6烷基氨基磺醯基、(C_1-6烷基)₂氨基磺醯基、C_1-6烷氧基C_1-6烷氧基，或任選被取代基Q₂取代的3-12員環烷基、3-12員環烯基、3-12員雜環基、芳基或5-10員雜芳基，所述取代基選自：羥基、氨基、氰基、硝基、鹵素、羧基、醯胺基、氨基羰基、氨基磺醯基、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_2-8烯基、C_2-8炔基、C_1-6烷基磺醯基、C_1-6烷基羰基氨基、(C_1-6烷基)₂羰基氨基、C_1-6烷基氨基羰基、(C_1-6烷基)₂氨基羰基、C_1-6烷基氨基磺醯基、(C_1-6烷基)₂氨基磺醯基或C_1-6烷氧基C_1-6烷氧基；或者，兩個相鄰的R₄與它們分別連接的原子一起形成3-8員環烷基、3-8員環烯基、3-8員雜環基、芳基或5-6員雜芳基； L₁、L₂、L₃分別獨立地為鍵、-N(Rc)-、-O-、-S-、-S(O)-、-S(O)₂-、-S(O)₂NH-、-C(O)-、-NHC(O)-、-OC(O)-、C_1-6亞烷基、C_2-8亞烯基或C_2-8亞炔基，Rc選自氫或C_1-6烷基；n、t、p、q分別獨立地為0或1；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Among them, warhead ₁ and warhead ₂ refer to the part that can form a covalent bond with a nucleophile, and warhead ₁ and warhead ₂ do not exist at the same time; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

represents a single bond; when warhead _{1 is} present, R _{1 is} selected from C _1-6 alkylene, C _2-8 alkenylene, C _2-8 alkynylene, halogenated C _1-6 alkylene or -( L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent, R _{1 is} selected from hydrogen, C _1-6 alkyl, C _2-8 alkenyl, C _{2 -8} alkynyl, halogenated C _1-6 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p; when warhead _{2 is} present, R _{2 is} selected from C _1-6 Alkylene, C _2-8 alkenylene, C _2-8 alkynylene, halogenated C _1-6 alkylene, or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R ₂ selected from hydrogen, C _1-6 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogenated C _1-6 alkyl or -(L ₃ )q-Cy ₃ ; Cy ₁ and Cy ₂ are respectively Independently selected from the following groups or their divalent groups: _{substituted with one to more R a} , or unsubstituted 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, Aryl or 5-10 membered heteroaryl, ring carbon atoms can be optionally oxidized to C(O), ring sulfur atoms can be optionally oxidized to S(O), S(O) ₂ or S(O ) (N); Cy _{3 is} selected from the following groups or their divalent groups: _{substituted with one to more R b} , or unsubstituted 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3- 12-membered heterocyclic group, aryl group or 5-10-membered heteroaryl group, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S(O), S(O) ) ₂ or S(O)(N); R _a , R _b are independently selected from: (i) hydrogen; (ii) hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-6 alkenyl Carbonylamino or =CH ₂ ; (iii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _{1 -6} alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino or 3-8 membered heterocycle substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkyl, halogenated C _{1 -6} alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl or C _1-6 alkylthio, the 3-8 membered heterocyclic group can be optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl) ₂ amino substituted; (iv) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _{1-6 alkyl)} amino Substituted 3-8 membered cycloalkyl, 5-8-membered cycloalkenyl, or 3-8 membered heterocyclyl group; or (v) amino - carbonyl group, a cyano - carbonyl, C _1-6 alkyl - carbonyl group, C _{1 -6} alkylamino-carbonyl, (C _1-6 alkyl) ₂ amino-carbonyl, C _1-6 alkoxy-carbonyl, 3-8 membered cycloalkyl-carbonyl or 3-8 membered heterocyclyl-carbonyl ; R _{3 is} selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, (C _1-6 alkyl) ₂ amino C _1-6 alkyl, halogenated C _{1- 6-} alkyl, halogenated C _2-8 alkenyl, C _2-8 alkynyl, or 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered optionally substituted by substituent Q ₁ Heterocyclic group, aryl group or 5-10 membered heteroaryl group, the substituent Q _{1 is} selected from: hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkyl Oxy group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _{1 -6} alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy base C _1-6 alkoxy; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl , C _2-8 alkynyl, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkyl aminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl, C _1-6 alkoxy C _1-6 alkoxy, or a 3-12-membered cycloalkyl group, a 3-12-membered cycloalkenyl group, a 3-12-membered heterocyclic group, an aryl group or a 5-10-membered heteroaryl group optionally substituted by a substituent Q _{2 , the substituents are selected from} From: hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino , (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkoxy Sulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _{1- 6} alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy C _{1- 6} alkoxy; alternatively, two adjacent R ₄ together with the atoms to which they are attached respectively form a 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, aryl or 5-membered -6-membered heteroaryl; L ₁ , L ₂ , L ₃ are each independently a bond, -N(Rc)-, -O-, -S-, -S(O)-, -S(O) ₂ - , -S(O) ₂ NH-, -C(O)-, -NHC(O)-, -OC(O)-, C _1-6 alkylene, C _2-8 alkenylene or C _{2- 8} alkynylene, Rc is selected from hydrogen or C _1-6 alkyl; n, t, p, q are independently 0 or 1; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups.

、

，warhead₁和warhead₂不同時存在； R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅分別獨立地選自氫、鹵素、C_1-6烷基或鹵代C_1-6烷基；Cy₄選自如下基團的二價基：3-12員環烷基、3-12員環烯基、3-12員雜環基、芳基或5-10員雜芳基；z為0-4的整數；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；當warhead₁存在時，R₁選自C_1-6亞烷基、鹵代C_1-6亞烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-；當warhead₁不存在 時，R₁選自氫、C_1-6烷基、鹵代C_1-4烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p；當warhead₂存在時，R₂選自C_1-6亞烷基、鹵代C_1-6亞烷基或-(L₃)q-Cy₃-；當warhead₂不存在時，R₂選自氫、C_1-6烷基、鹵代C_1-6烷基或-(L₃)q-Cy₃；Cy1、Cy2分別獨立地選自如下基團或其二價基：經一至多個Ra取代的，或未經取代的3-8員單雜環基、6-11員橋雜環基、7-12員螺雜環基或6-11員并雜環基、芳基或5-10員雜芳基，成環碳原子可任選地被氧化為C(O)，成環硫原子可任選被氧化為S(O)或S(O)2；Cy₃選自如下基團或其二價基：經一至多個R_b取代的，或未經取代的3-8員單雜環基、6-11員橋雜環基、7-12員螺雜環基或6-11員并雜環基、芳基或5-10員雜芳基，成環碳原子可任選地被氧化為C(O)，成環硫原子可任選被氧化為S(O)或S(O)₂；R_a、R_b分別獨立地選自：(i)氫、羥基、氨基、羧基、氰基、硝基、鹵素、C_2-8烯基羰基氨基或=CH₂，(ii)任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6烷氧C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、C_1-6烷基羰基氨基、C_1-6烷基磺醯氨基或3-8員雜環基取代的C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_2-8烯基、C_2-8炔基、C_1-6烷基磺醯基或C_1-6烷 基硫基，(iii)任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基或(C_1-6烷基)₂氨基取代的3-8員環烷基或3-8員雜環基，或(iv)氨基-羰基、氰基-羰基、C_1-6烷基-羰基、C_1-6烷基氨基-羰基、(C_1-6烷基)₂氨基-羰基、C_1-6烷氧基-羰基、3-8員環烷基-羰基或3-8員雜環基-羰基；R₃選自氫或C_1-6烷基；R₄選自氫、羥基、氨基、氰基、硝基、鹵素、羧基、醯胺基、氨基羰基、氨基磺醯基、C_1-6烷基、C_1-6烷氧基、C_1-6烷基氨基、(C_1-6烷基)₂氨基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_2-8烯基、C_2-8炔基、C_1-6烷基磺醯基、C_1-6烷基羰基氨基，(C_1-6烷基)₂羰基氨基、C_1-6烷基氨基羰基、(C_1-6烷基)₂氨基羰基、C_1-6烷基氨基磺醯基、(C_1-6烷基)₂氨基磺醯基或C_1-6烷氧基C_1-64烷氧基；L₁、L₂、L₃分別獨立地為鍵、-N(R_c)-、-O-、-S-、-S(O)-、-S(O)₂-、-C(O)-、-NHC(O)-、-OC(O)-或C_1-6亞烷基，R_c選自氫或C_1-6亞烷基；n、t、p、q分別獨立地為0或1；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當R₁為-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-，t和p為0，且Cy₁為經一至多個R_a取代的，或未經取代的3-8員單雜環基或苯基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多 個R_b取代，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ and warhead ₂ are independently selected from

,

, warhead ₁ and warhead ₂ do not exist at the same time; R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkane Cy ₄ is a divalent group selected from the following groups: 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, aryl or 5-10-membered heteroaryl; z is an integer from 0 to 4; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

represents a single bond; when warhead _{1 is} present, R _{1 is} selected from C _1-6 alkylene, halogenated C _1-6 alkylene, or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ ) p-; when warhead ₁ is absent, R _{1 is} selected from hydrogen, C _1-6 alkyl, haloC _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t- (Cy ₂ )p; when warhead _{2 is} present, R _{2 is} selected from C _1-6 alkylene, haloC _1-6 alkylene, or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent , R _{2 is} selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or -(L ₃ )q-Cy ₃ ; Cy1 and Cy2 are independently selected from the following groups or their divalent groups : substituted with one to more Ra, or unsubstituted 3-8-membered monoheterocyclyl, 6-11-membered bridged heterocyclyl, 7-12-membered spiroheterocyclyl or 6-11-membered heterocyclyl, Aryl or 5-10 membered heteroaryl, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S(O) or S(O)2; Cy ₃ Selected from the following groups or their divalent groups: _{substituted with one to more R b} , or unsubstituted 3-8-membered monoheterocyclic group, 6-11-membered bridged heterocyclic group, 7-12-membered spiro heterocyclic group base or 6-11-membered heterocyclic group, aryl or 5-10-membered heteroaryl group, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S( O) or S(O) ₂ ; R _a , R _b are independently selected from: (i) hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-8 alkenylcarbonylamino or =CH ₂ , (ii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy , C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkoxy group , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl or C _1-6 alkylthio, (iii) optionally by hydroxyl, amino, carboxyl, cyano, nitro group, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl) ₂ amino substituted 3-8 membered cycloalkyl or 3-8 Member heterocyclyl, or (iv) amino-carbonyl, cyano-carbonyl, C _1-6 alkyl-carbonyl, C _1-6 alkylamino-carbonyl, (C _1-6 alkyl) ₂ amino-carbonyl, C _1-6 alkoxy-carbonyl, 3-8 membered cycloalkyl-carbonyl or 3-8 membered heterocyclyl-carbonyl; R _{3 is} selected from hydrogen or C _1-6 alkyl; R _{4 is} selected from hydrogen, hydroxyl , amino, cyano , nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl ) ₂ amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkyl sulfonyl, C _{1- 6} alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy C _1-64 alkoxy; L ₁ , L ₂ , L ₃ are each independently a bond, -N(R _c )- , -O-, -S-, -S(O)-, -S(O) ₂ -, -C(O)-, -NHC(O)-, -OC(O)- or C _1-6 sub Alkyl, R _{c is} selected from hydrogen or C _1-6 alkylene; n, t, p, q are independently 0 or 1; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups; when R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy _{When 1} is a divalent group substituted with one or more R _a , or an unsubstituted 3-8-membered monoheterocyclic group or phenyl group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is 7-12 membered spiroheterocyclyl substituted with one to more R _{b, or unsubstituted.}

、

、

、

，warhead₁和warhead₂ 不同時存在；R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；當warhead₁存在時，R₁選自C_1-4亞烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-；當warhead₁不存在時，R₁選自氫、C_1-4烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p；當warhead₂存在時，R₂選自C_1-4亞烷基、鹵代C_1-4亞烷基或-(L₃)q-Cy₃-；當warhead₂不存在時，R₂選自氫、C_1-4烷基或-(L₃)q-Cy₃；Cy₁、Cy₂分別獨立地選自如下基團或其二價基：經一至多個R_a取代的，或未經取代的3-8員單雜環基、7-12員螺雜環基或芳基；Cy₃選自如下基團或其二價基：經一至多個R_b取代的，或未經取代的3-8員單雜環基或7-12員螺雜環基；R_a、R_b分別獨立地為氫、C_1-4烷基或羥基C_1-4烷基； R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；L₁、L₂、L₃分別獨立地為鍵或C_1-4亞烷基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當R₁為-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-，t和p為0，且Cy₁為經一至多個R_a取代的，或未經取代的3-8員單雜環基或苯基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ and warhead ₂ are independently selected from

,

,

,

, warhead ₁ and warhead ₂ do not exist at the same time; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead _{1 is} present, R _{1 is} selected from C _1-4 alkylene or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent _{When warhead 2} exists, R _{1 is} selected from hydrogen, C _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p; when warhead 2 exists, R _{2 is} selected from C _{1- 4} alkylene, halogenated C _1-4 alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ ) q-Cy ₃ ; Cy ₁ , Cy ₂ are independently selected from the following groups or their divalent groups: _{substituted with one to multiple R a} , or unsubstituted 3-8-membered monoheterocyclic group, 7- 12-membered spiro heterocyclyl or aryl; Cy _{3 is} selected from the following groups or their divalent radicals: _{substituted with one to more R b} , or unsubstituted 3-8-membered monoheterocyclyl or 7-12-membered Spiroheterocyclyl; R _a , R _b are independently hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, Halogen, C _1-4 alkyl or C _1-4 alkoxy; L ₁ , L ₂ , L ₃ are each independently a bond or C _1-4 alkylene; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups; when R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy _{When 1} is a divalent group substituted with one or more R _a , or an unsubstituted 3-8-membered monoheterocyclic group or phenyl group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is 7-12 membered spiroheterocyclyl substituted with one to more R _{b, or unsubstituted.}

、

、

、

，warhead₁和warhead₂ 不同時存在；R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；當warhead₁存在時，R₁選自C_1-4亞烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-；當warhead₁不存在時，R₁選自氫、C_1-4烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p；當warhead₂存在時，R₂選自C_1-4亞烷基或 -(L₃)q-Cy₃-；當warhead₂不存在時，R₂選自氫、C_1-4烷基或-(L₃)q-Cy₃；Cy₁、Cy₂分別獨立地選自如下基團或其二價基：經一至多個R_a取代的，或未經取代的3-8員單雜環基、6-11員橋雜環基、7-12員螺雜環基或6-11員并雜環基；Cy₃選自如下基團或其二價基：經一至多個R_b取代的，或未經取代的3-8員單雜環基、6-11員橋雜環基、7-12員螺雜環基、6-11員并雜環基；R_a、R_b分別獨立地選自：(i)氫、羥基、氨基、氰基或鹵素，或(ii)C_1-4烷基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、羥基C_1-4烷基、氰基C_1-4烷基或鹵代C_1-4烷基；L₁、L₂、L₃分別獨立地為鍵或C_1-4亞烷基；n、t、p、q分別獨立地為0或1；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當R₁為-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-，t和p為0，且Cy₁為經一至多個Ra取代的，或未經取代的3-8員單雜環基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ and warhead ₂ are independently selected from

,

,

,

, warhead ₁ and warhead ₂ do not exist at the same time; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead _{1 is} present, R _{1 is} selected from C _1-4 alkylene or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent _{When warhead 2} exists, R _{1 is} selected from hydrogen, C _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p; when warhead 2 exists, R _{2 is} selected from C _{1- 4} alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy ₁ , Cy ₂ are independently selected from the following groups or their divalent groups: _{substituted with one to more R a} , or unsubstituted 3-8-membered mono-heterocyclic group, 6-11-membered bridged heterocyclic group, 7-12-membered heterocyclic group membered spiro heterocyclyl or 6-11 membered heterocyclyl; Cy _{3 is} selected from the following groups or their divalent radicals: _{substituted with one to more R b} , or unsubstituted 3-8 membered monoheterocyclyl , 6-11-membered bridged heterocyclyl, 7-12-membered spiro heterocyclyl, 6-11-membered heterocyclyl; R _a and R _b are independently selected from: (i) hydrogen, hydroxyl, amino, cyano or halogen, or (II) C _1-4 alkyl, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, hydroxy C _1-4 alkyl, cyano C _1-4 alkyl or Halogenated C _1-4 alkyl; L ₁ , L ₂ , L ₃ are each independently a bond or C _1-4 alkylene; n, t, p, q are each independently 0 or 1; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups; when R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy _{When 1} is a divalent group of a 3-8-membered monoheterocyclic group substituted with one or more Ra, or an unsubstituted 3-8 membered monoheterocyclic group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is one or more R _b substituted, or unsubstituted 7-12 membered spiroheterocyclyl.

、

、

、

，warhead₁和warhead₂ 不同時存在；R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；當warhead₁存在時，R₁選自C_1-4亞烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-；當warhead₁不存在時，R₁選自氫、C_1-4烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p；當warhead₂存在時，R₂選自C_1-4亞烷基或-(L₃)q-Cy₃-；當warhead₂不存在時，R₂選自氫、C_1-4烷基或-(L₃)q-Cy₃；Cy₁、Cy₂分別獨立地選自如下基團或其二價基：經一至多個R_a取代的，或未經取代的3-8員單雜環基或7-12員螺雜環基；Cy₃選自如下基團或其二價基：經一至多個R_b取代的，或未經取代的3-8員單雜環基或7-12員螺雜環基；R_a為氫或C_1-4亞烷基；R_b為氫、C_1-4亞烷基或羥基C_1-4烷基；L₁、L₂、L₃分別獨立地為鍵或C_1-4亞烷基；n、t、p、q分別獨立地為0或1； R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當R₁為-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-，t和p為0，且Cy₁為經一至多個Ra取代的，或未經取代的3-8員單雜環基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ and warhead ₂ are independently selected from

,

,

,

, warhead ₁ and warhead ₂ do not exist at the same time; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead _{1 is} present, R _{1 is} selected from C _1-4 alkylene or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent _{When warhead 2} exists, R _{1 is} selected from hydrogen, C _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p; when warhead 2 exists, R _{2 is} selected from C _{1- 4} alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy ₁ , Cy ₂ are independently selected from the following groups or their divalent groups: _{substituted with one to more R a} , or unsubstituted 3-8-membered monoheterocyclic group or 7-12-membered spiro heterocyclic group; Cy ₃ options From the following groups or their divalent groups: _{substituted with one to more R b} , or unsubstituted 3-8-membered monoheterocyclic group or 7-12-membered spiroheterocyclic group; R _a is hydrogen or C _{1- 4} alkylene; R _b is hydrogen, C _1-4 alkylene or hydroxy C _1-4 alkyl; L ₁ , L ₂ , L ₃ are each independently a bond or C _1-4 alkylene; n, t, p, q are independently 0 or 1; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups; when R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy _{When 1} is a divalent group of a 3-8-membered monoheterocyclic group substituted with one or more Ra, or an unsubstituted 3-8 membered monoheterocyclic group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is one or more R _b substituted, or unsubstituted 7-12 membered spiroheterocyclyl.

、

、

、

，warhead₁和warhead₂ 不同時存在；R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；當warhead₁存在時，R₁選自C_1-4亞烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-；當warhead₁不存在時，R₁選自氫、C_1-4烷基或-(L₁)n-Cy₁-(L₂)t-(Cy₂)p；當warhead₂存在時，R₂選自C_1-4亞烷基或-(L₃)q-Cy₃-；當warhead₂不存在時，R₂選自氫、C_1-4烷基 或-(L₃)q-Cy₃；Cy₁和Cy₂分別獨立地選自如下結構的一價基或二價基：經一至多個R_a取代的，或未經取代的

Cy₃選自如下如結構的一價基或二價基：經一至多個R_b取代的，或未經取代的

R_a、R_b分別獨立的選自氫、C_1-4烷基或羥基C_1-4烷基；L₁、L₂、L₃分別獨立地為鍵或C_1-4亞烷基；n、t、p、q分別獨立地為0或1；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素原子、C_1-4烷基或C_1-4烷氧基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當R₁為-(L₁)n-Cy₁-(L₂)t-(Cy₂)p-，t和p為0，且Cy₁ 為經一至多個R_a取代的，或未經取代的

、

、

、

或

的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至 多個R_b取代的，或未經取代的

或

的一價基。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ and warhead ₂ are independently selected from

,

,

,

, warhead ₁ and warhead ₂ do not exist at the same time; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead _{1 is} present, R _{1 is} selected from C _1-4 alkylene or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent _{When warhead 2} exists, R _{1 is} selected from hydrogen, C _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p; when warhead 2 exists, R _{2 is} selected from C _{1- 4} alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy ₁ and Cy ₂ are independently selected from the monovalent or divalent groups of the following structures: _{substituted with one to more R a} , or unsubstituted

Cy _{3 is} selected from the following monovalent or divalent groups of the structure: _{substituted with one to more R b} , or unsubstituted

R _a , R _b are independently selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl; L ₁ , L ₂ , L ₃ are each independently a bond or C _1-4 alkylene; n , t, p, q are independently 0 or 1; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen atom, C _1-4 alkyl or C _1-4 alkoxy ; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups; when R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy ₁ is by one to the plurality of R _a substituted or unsubstituted

,

,

,

or

In the case of the divalent group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is substituted with one to more R _b , or unsubstituted

or

's one price basis.

，warhead₂不存在； R₁₂、R₁₃分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；R₁為-(L₁)_n-Cy₁-；Cy₁為經一至多個R_a取代的，或未經取代的7-12員亞螺雜環基，較佳7-12員含N亞螺雜環基，warhead₁與Cy₁中任意的成環N雜原子相連；L₁為鍵或C_1-4亞烷基；R_a選自氫或C_1-4烷基；R₂選自氫或C_1-4烷基；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；n為0或1；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ is

, warhead ₂ does not exist; R ₁₂ and R ₁₃ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R ₁ is -(L ₁ ) _n -Cy ₁ -; Cy ₁ is a 7-12-membered spiroheterocyclyl group substituted with one to multiple R _{a, or unsubstituted, preferably 7-12} The member contains N spiro heterocyclic group, warhead _{1 is} connected with any ring-forming N heteroatom in _{Cy 1 ; L 1} is a bond or C _1-4 alkylene group; R _{a is} selected from hydrogen or C _1-4 alkyl group; R _{2 is} selected from hydrogen or C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; n is 0 or 1; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups.

、

、

、

、

、

或

， warhead₁與Cy₁中任意的成環N雜原子相連。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Cy ₁ is a bivalent with the following structure Radical: substituted with one or more R _a , or unsubstituted

,

,

,

,

,

or

, warhead _{1 is} connected to any ring-forming N heteroatom in _{Cy 1.}

Another embodiment of the present invention relates to the aforementioned irreversible inhibitor of fibroblast growth factor receptor or a pharmaceutically acceptable salt, stereoisomer thereof, the irreversible inhibitor of fibroblast growth factor receptor such as the general formula ( IA) shows:

或

； R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；R₂選自氫、C_1-4烷基、鹵代C_1-4烷基或-(L₃)q-Cy₃；Cy1、Cy2分別獨立地選自如下基團的二價基：經一至多個Ra取代的，或未經取代的3-8員單雜環基、6-11員橋雜環基、7-12員螺雜環基或6-11員并雜環基； Cy₃選自如下基團：經一至多個R_b取代的，或未經取代的3-8員單雜環基、6-11員橋雜環基、7-12員螺雜環基或6-11員并雜環基；R_a、R_b分別獨立地選自氫、羥基、氨基、羧基、氰基、硝基、鹵素、C_2-4烯基羰基氨基、=CH₂或任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-4烷基、C_1-4烷氧基、C_1-4烷氧C_1-4烷氧基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、C_1-4烷基羰基氨基、C_1-4烷基磺醯氨基或3-8員雜環基取代的C_1-4烷基、C_1-4烷氧基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、鹵代C_1-4烷基、鹵代C_1-4烷氧基、C_2-4烯基、C_2-4炔基、C_1-4烷基磺醯基或C_1-4烷基硫基；R₃選自氫或C_1-4烷基；R₄選自氫、羥基、氨基、氰基、硝基、鹵素、羧基、醯胺基、氨基羰基、氨基磺醯基、C_1-4烷基、C_1-4烷氧基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、鹵代C_1-4烷基、鹵代C_1-4烷氧基、C_2-8烯基、C_2-8炔基、C_1-4烷基磺醯基、C_1-4烷基羰基氨基，(C_1-4烷基)₂羰基氨基、C_1-4烷基氨基羰基、(C_1-4烷基)₂氨基羰基、C_1-4烷基氨基磺醯基、(C_1-4烷基)₂氨基磺醯基或C_1-4烷氧基C_1-4烷氧基；L₁、L₂、L₃分別獨立地為鍵、-N(R_c)-、-O-、-S-或C_1-4亞烷基，R_c選自氫或C_1-4烷基；n、t、p、q分別獨立地為0或1；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團； 當t和p為0，且Cy₁為經一至多個R_a取代的，或未經取代的3-8員單雜環基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代，或未經取代的7-12員螺雜環基。 Among them, warhead _{1 is} selected from

or

; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R _{2 is} selected from hydrogen, C _1-4 alkyl, halogenated C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy1 and Cy2 are independently selected from the following divalent groups Base: substituted with one to more Ra, or unsubstituted 3-8-membered monoheterocyclyl, 6-11-membered bridged heterocyclyl, 7-12-membered spiroheterocyclyl or 6-11-membered heterocyclyl ; Cy _{3 is} selected from the following groups: _{substituted with one to more R b} , or unsubstituted 3-8-membered mono-heterocyclic group, 6-11-membered bridged heterocyclic group, 7-12-membered spiro heterocyclic group or 6-11-membered heterocyclic group; R _a , R _b are independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-4 alkenylcarbonylamino, =CH ₂ or optional hydroxy, amino, carboxyl, cyano, nitro, halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkyl Amino, (C _1-4 alkyl) ₂ amino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C _1-4 alkyl, C _{1 -4} alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, C _2-4 alkenyl , C _2-4 alkynyl, C _1-4 alkylsulfonyl group or C _1-4 alkylthio group; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, (C _{1-4 alkyl)} amino, halo-C _1-4 alkyl, halo C _1-4 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkylsulfonyl group, C _1-4 alkylcarbonylamino, (C _1-4 alkyl) ₂ carbonylamino, C _1-4 alkylaminocarbonyl, (C _1-4 alkyl) ₂ aminocarbonyl, C _1-4 alkylaminosulfonic acid group, (C _1-4 alkyl) ₂ aminosulfonyl group or C _1-4 alkoxy C _1-4 alkoxy; L ₁ , L ₂ , L ₃ are each independently a bond, -N(R _c )-, -O-, -S- or C _1-4 alkylene, R _{c is} selected from hydrogen or C _1-4 alkyl; n, t, p, q are independently 0 or 1; m is 0 an integer of -5 when m

2, R ₄ may be selected from the same group or different; and when p is 0 and t, and Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 3-8 membered heteromonocyclic group II In the case of a valent group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is a 7-12 membered spiroheterocyclyl group substituted with one to more R _{b s, or unsubstituted.}

或

； R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；R₂選自氫、C_1-4烷基、鹵代C_1-4烷基或-(L₃)q-Cy₃；Cy1、Cy2分別獨立地選自如下基團的二價基：經一至多個Ra取代的，或未經取代的3-8員單雜環基或7-12員螺雜環基；Cy₃選自如下基團：經一至多個R_b取代的，或未經取代的3-8員單雜環基或7-12員螺雜環基；R_a、R_b分別獨立地選自氫、C_1-4烷基或羥基C_1-4烷基；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；L₁、L₂、L₃分別獨立地為鍵、或C_1-4亞烷基；n、t、p、q分別獨立地為0或1； m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當t和p為0，且Cy₁為經一至多個R_a取代的，或未經取代的3-8員單雜環基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the aforementioned general formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead _{1 is} selected from the group consisting of

or

; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R _{2 is} selected from hydrogen, C _1-4 alkyl, halogenated C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy1 and Cy2 are independently selected from the following divalent groups Base: substituted with one to more Ra, or unsubstituted 3-8-membered monoheterocyclic group or 7-12-membered spiro heterocyclic group; Cy _{3 is} selected from the following groups: substituted _{with one to more R b,} or unsubstituted 3-8 membered monoheterocyclic group or 7-12 membered spiroheterocyclic group; R _a and R _b are independently selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; L ₁ , L ₂ , L ₃ are each independently a bond, or C _1-4 alkylene; n, t, p, q are independently 0 or 1; m is an integer of 0-5, when m

2, R ₄ may be selected from the same group or different; and when p is 0 and t, and Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 3-8 membered heteromonocyclic group II In the case of a valent group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is a 7-12 membered spiroheterocyclyl group substituted with one to more R _{b s, or unsubstituted.}

、

； R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；Cy₁、Cy₂分別獨立的選自如下基團的二價基：經一至多個R_a取代的，或未經取代的3-8員含氮單雜環基、6-11員含氮橋雜環基或7-12員含氮螺雜環基；R₂選自氫、C_1-4烷基或-(L₃)q-Cy₃；Cy₃為經一至多個R_b取代的，或未經取代的7-12員螺雜環基；R_a、R_b、R₃分別獨立地選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；L₁、L₂、L₃分別獨立地為鍵或C_1-4亞烷基；n、t、p、q分別獨立地為0或1； m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當t和p為0，且Cy₁為經一至多個R_a取代的，或未經取代的3-8員含氮單雜環基的二價基時，R₂為-(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代的，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to the fibroblast growth factor receptor irreversible inhibitor represented by the aforementioned general formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead _{1 is} selected from

,

; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; Cy ₁ , Cy ₂ are independently selected from the following divalent groups: _{substituted with one to multiple R a} , or unsubstituted 3-8-membered nitrogen-containing monoheterocyclic group, 6-11 A nitrogen-containing bridged heterocyclic group or a 7-12-membered nitrogen-containing spiro heterocyclic group; R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy ₃ is through one to more R _b substituted or unsubstituted 7-12-membered spiro heterocyclyl; R _a , R _b , R ₃ are independently selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _{1 -4} alkyl or C _1-4 alkoxy; L ₁ , L ₂ , L ₃ are each independently a bond or C _1-4 alkylene; n, t, p, q are each independently 0 or 1; m is an integer from 0 to 5, when m

2, R ₄ may be selected from the same group or different; and when p is 0 and t, and Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 3-8 membered nitrogen-containing monocyclic heterocyclic group When the divalent group of , R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is a 7-12 membered spiroheterocyclyl group substituted with one to more R _{b s or unsubstituted.}

或

； R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；Cy₁、Cy₂分別獨立地選自如下結構的二價基：經一至多個R_a取代的，或未經取代的

R₂選自氫、C_1-4烷基或-(L₃)q-Cy₃；Cy₃為經一至多個R_b取代的，或未經取代的7-12員螺雜環基； R_a、R_b、R₃分別獨立地選自氫、C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；L₁、L₂、L₃分別獨立地為鍵或C_1-4亞烷基；n、t、p、q分別獨立地為0或1；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團；當t和p為0時，且Cy₁為經一至多個R_a取代的， 或未經取代的

、

、

或

的二價基時，R₂為 -(L₃)q-Cy₃，且Cy₃為經一至多個R_b取代的，或未經取代的7-12員螺雜環基。 Another embodiment of the present invention relates to the fibroblast growth factor receptor irreversible inhibitor represented by the aforementioned general formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead _{1 is} selected from

or

; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; Cy ₁ , Cy ₂ are independently selected from the divalent groups of the following structures: _{substituted with one to multiple R a} , or unsubstituted

R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; Cy ₃ is substituted with one to more R _b , or unsubstituted 7-12 membered spiroheterocyclyl; R _a , R _b and R ₃ are independently selected from hydrogen, C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; L ₁ , L ₂ , L _{3 is} each independently a bond or C _1-4 alkylene; n, t, p, q are each independently 0 or 1; m is an integer of 0-5, when m

When 2, R ₄ may be selected from the same group or different; and when p and t is 0, and Cy ₁ is by one to the plurality of R _a substituted or unsubstituted

,

,

or

When the divalent group of , R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is a 7-12 membered spiroheterocyclyl group substituted with one to more R _{b s or unsubstituted.}

； R₁₂、R₁₃分別獨立地選自氫或C_1-4烷基；Cy₁為如下結構的二價基：經一至多個R_a取代的，或未經取代 的

、

、

、

、

、

或

，warhead₁與Cy₁ 中任意的成環N雜原子相連；t、p分別為0； n為0；R_a選自氫或C_1-4烷基；R₂選自氫或C_1-4烷基；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the aforementioned general formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ is

; R ₁₂ , R ₁₃ are independently selected from hydrogen or C _1-4 alkyl; Cy ₁ is a divalent group of the following structure: _{substituted with one to multiple R a} , or unsubstituted

,

,

,

,

,

or

, warhead _{1 is} connected _{to any ring-forming N heteroatom in Cy 1} ; t and p are respectively 0; n is 0; R _{a is} selected from hydrogen or C _1-4 alkyl; R _{2 is} selected from hydrogen or C _1-4 Alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups.

或

； R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；Cy₁為如下結構的二價基：經一至多個R_a取代的，或 未經取代的

、

、

或

，warhead₁與Cy₁中 任意的成環N雜原子相連；t、p分別為0；R₂選自氫、C_1-4烷基或為-(L₃)q-Cy₃-；Cy₃為如下結構的一價基：經一至多個R_b取代的，或 未經取代的

或

； n、q分別獨立地為0或1；R_a、R_b分別獨立地選自氫或C_1-4烷基； R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；L₁、L₃分別獨立地為鍵、-CH₂-或-CH₂-CH₂-；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the aforementioned general formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ is

or

_{; R 12, R 13, R} 14 are each independently selected from hydrogen or C _1-4 alkyl; Cy ₁ is a divalent group of the structure: substituted by one to the plurality of R _a, or unsubstituted

,

,

or

, warhead _{1 is} connected with _{any ring-forming N heteroatom in Cy 1} ; t, p are 0 respectively; R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ -; Cy ₃ is a monovalent group of the following structure: _{substituted with one to more R b} , or unsubstituted

or

; n, q are independently 0 or 1; R _a , R _b are independently selected from hydrogen or C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, Halogen, C _1-4 alkyl or C _1-4 alkoxy; L ₁ and L ₃ are each independently a bond, -CH ₂ - or -CH ₂ -CH ₂ -; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups.

； R₁₂、R₁₃分別獨立地選自氫或C_1-4烷基；Cy₁、Cy₂分別獨立地為如下結構的二價基：任選被一 至多個R_a取代的，或未取代的

、

、

或

， warhead₁與Cy₂中任意的成環上N雜原子相連；n、t分別為0；p為1；R_a選自氫或C_1-4烷基；R₂選自氫或C_1-4烷基；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the aforementioned general formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: warhead ₁ is

; R _12, R ₁₃ are each independently selected from hydrogen or C _1-4 alkyl; Cy _1, Cy ₂ are each independently a divalent group of the structure: optionally substituted by one to the plurality of R _a, substituted or unsubstituted of

,

,

or

, warhead _{1 is} connected _{to any ring-forming N heteroatom in Cy 2} ; n and t are respectively 0; p is 1; R _{a is} selected from hydrogen or C _1-4 alkyl; R _{2 is} selected from hydrogen or C _{1- 4} alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups.

Another embodiment of the present invention relates to the fibroblast growth factor receptor irreversible inhibitor represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, the fibroblast growth factor receptor Irreversible inhibitors are represented by general formula (IB):

、

或

； R₁₀、R₁₁、R₁₂、R₁₃、R₁₄分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；R₁選自氫或C_1-4烷基；Cy₃為經一至多個R_b取代的，或未經取代的3-8員亞單雜環基；R_b選自：(i)氫、羥基、氨基、羧基、氰基、硝基、鹵素、C_2-4烯基羰基氨基或=CH₂；(ii)任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-4烷基、C_1-4烷氧基、C_1-4烷氧C_1-4烷氧基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、C_1-4烷基羰基氨基、C_1-4烷基磺醯氨基或3-8員雜環基取代的C_1-4烷基、C_1-4烷氧基、C_1-4 烷基氨基、(C_1-4烷基)₂氨基、鹵代C_1-4烷基、鹵代C_1-4烷氧基、C_2-4烯基、C_2-4炔基、C_1-4烷基磺醯基或C_1-4烷基硫基；(iii)任選被羥基、氨基、羧基、氰基、硝基、鹵素、C_1-4烷基、C_1-4烷氧基、C_1-4烷基氨基或(C_1-4烷基)₂氨基取代的3-8員環烷基或3-8員雜環基；或(1v)氨基-羰基、氰基-羰基、C_1-4烷基-羰基、C_1-4烷基氨基-羰基、(C_1-4烷基)₂氨基-羰基、C_1-4烷氧基-羰基、3-8員環烷基-羰基或3-8員雜環基-羰基；R₃選自氫或C_1-4烷基；R₄選自氫、羥基、氨基、氰基、硝基、鹵素、羧基、醯胺基、氨基羰基、氨基磺醯基、C_1-4烷基、C_1-4烷氧基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、鹵代C_1-4烷基、鹵代C_1-4烷氧基、C_2-8烯基、C_2-8炔基、C_1-4烷基磺醯基、C_1-4烷基羰基氨基，(C_1-4烷基)₂羰基氨基、C_1-4烷基氨基羰基、(C₁₄烷基)₂氨基羰基、C_1-4烷基氨基磺醯基、(C_1-4烷基)₂氨基磺醯基或C_1-4烷氧基C_1-4烷氧基；L₃分別為鍵、-N(R_c)-、-O-、-S-或C_1-4烷基，R_c選自氫或C_1-4烷基；q為0或1；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Among them, warhead _{2 is} selected from

,

or

; R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R _{1 is} selected from hydrogen or C _1-4 alkyl; Cy ₃ is substituted by one to more R _b , or an unsubstituted 3-8-membered monoheterocyclic group; R _{b is} selected from: ( i) hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-4 alkenylcarbonylamino or =CH ₂ ; (ii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, C _1-4 alkylcarbonylamino, _C1-4 alkylsulfonylamino or 3-8 membered heterocyclic substituted _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl Sulfonyl or C _1-4 alkylthio; (iii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _{1 -4} alkylamino or (C _1-4 alkyl) ₂ amino substituted 3-8 membered cycloalkyl or 3-8 membered heterocyclyl; or (1v) amino-carbonyl, cyano-carbonyl, C _{1- 4} alkyl-carbonyl, C _1-4 alkylamino-carbonyl, (C _1-4 alkyl) ₂ amino-carbonyl, C _1-4 alkoxy-carbonyl, 3-8 membered cycloalkyl-carbonyl or 3 -8-membered heterocyclyl-carbonyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, amino sulfo acyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkylsulfonyl, C _1-4 alkylcarbonylamino, (C _1-4 alkyl) ₂ carbonyl Amino, C _1-4 alkylaminocarbonyl, (C ₁₄ alkyl) ₂ aminocarbonyl, C _1-4 alkylaminosulfonyl, (C _1-4 alkyl) ₂ aminosulfonyl or C _1-4 Alkoxy C _1-4 alkoxy; L ₃ is a bond, -N(R _c )-, -O-, -S- or C _1-4 alkyl, respectively, R _{c is} selected from hydrogen or C _1-4 Alkyl; q is 0 or 1; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups.

； R₁₂、R₁₃分別獨立地選自氫或C_1-4烷基；X選自C或N，當X為C時，

代表雙鍵，當X為N時，

代表單鍵；R₁選自氫或C_1-4烷基；Cy₃為如下結構的二價基：經一至多個R_b取代的，或未經取代 的

、

、

或

，較佳

，warhead₂與Cy₃中任意成環 N雜原子相連；q為0；R_b選自氫、C_1-4烷基或羥基C_1-4烷基，較佳為羥基C_1-4烷基；R₃選自氫或C_1-4烷基；R₄選自氫、鹵素、C_1-4烷基或C_1-4烷氧基；m是0-5的整數，當m

2時，R₄可以選自相同或不同的基團。 Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the aforementioned general formula (IB) or a pharmaceutically acceptable salt or stereoisomer thereof: warhead ₂ is

; R ₁₂ and R ₁₃ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R _{1 is} selected from hydrogen or C _1-4 alkyl; Cy ₃ is a divalent group of the following structure: _{substituted with one to more R b} , or unsubstituted

,

,

or

, preferably

, warhead _{2 is} connected to any ring-forming N heteroatom in _{Cy 3 ; q is 0; R b is} selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl, preferably hydroxy C _1-4 alkyl ; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups.

In another preferred embodiment, the compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer is, and the compound is:

The present invention also provides a pharmaceutical preparation containing the aforementioned irreversible inhibitor of fibroblast growth factor receptor or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments of the invention, the pharmaceutical formulation comprises one or more pharmaceutically acceptable carriers.

The pharmaceutical carrier of the present invention can be one or more solid or liquid fillers or gel substances suitable for human use. The pharmaceutical carrier preferably has sufficient purity and sufficiently low toxicity, and is compatible with the active ingredient of the present invention (irreversible inhibitor of fibroblast growth factor receptor or a pharmaceutically acceptable salt or stereoisomer thereof). Compatible and does not significantly reduce the efficacy of the active ingredient. For example, pharmaceutically acceptable carriers can be fillers, binders, disintegrants, lubricants, aqueous or non-aqueous solvents, and the like.

The pharmaceutical preparations of the present invention can be prepared in any pharmaceutically acceptable dosage form and administered in any suitable mode of administration, such as oral, parenteral, rectal or pulmonary administration, etc., to patients in need of such treatment patient or subject. When used for oral administration, it can be made into tablets, capsules, pills, granules and the like. When used for parenteral administration, it can be prepared into injection solution, sterile powder for injection and the like.

In some specific embodiments of the present invention, the pharmaceutical preparations of the present invention further comprise one or more second therapeutically active agents, the second therapeutically active agents are antimetabolites, growth factor inhibitors, filamentous Classification inhibitors, anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint or tumor immunotherapy-related antibodies and small molecular drugs.

The present invention also provides the aforementioned irreversible inhibitor of fibroblast growth factor receptor or its pharmaceutically acceptable salts, stereoisomers, and the aforementioned pharmaceutical preparation in the preparation and treatment of FGF (fibroblast growth factor)/FGFR abnormality Medicinal applications of mediated diseases. The disease mediated by abnormal FGF/FGFR according to the present invention is cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer, Endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, nerve Fibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma, colorectal chorioadenoma, Melanoma, cell tumor and sarcoma and/or myelodysplastic syndrome.

The present invention also provides the aforementioned irreversible inhibitors of fibroblast growth factor receptors or their pharmaceutically acceptable salts, stereoisomers, and the use of the aforementioned pharmaceutical preparations in the treatment of diseases.

In some specific embodiments of the present invention, the disease includes a disease mediated by abnormal FGF/FGFR, and the disease mediated by abnormal FGF/FGFR is cancer; the cancer includes lung cancer, squamous cell carcinoma, Bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glial tumor, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharynx Carcinoma, multiple myeloma, leukemia, non-Hodgkin's lymphoma, chorioadenoma, melanoma, cell tumor and sarcoma and/or myelodysplastic syndrome.

The present invention also provides a method for treating a disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned irreversible inhibitor of fibroblast growth factor receptor or a pharmaceutically acceptable salt, stereoisomer thereof , or the aforementioned pharmaceutical preparation, wherein the disease includes a disease mediated by abnormal FGF/FGFR, and the disease mediated by an abnormal FGF/FGFR is cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder Cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma , prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer , multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma and/or myelodysplastic syndrome.

The "therapeutically effective amount" in the present invention refers to the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt or stereoisomer thereof that can at least alleviate the symptoms of the patient's condition when administered to a patient , and the amount of the aforementioned pharmaceutical preparation. The actual amount encompassing a "therapeutically effective amount" will vary depending on a variety of circumstances, including but not limited to the particular condition being treated, the severity of the condition, the patient's physical and medical condition, and the route of administration. A skilled medical practitioner can readily determine appropriate amounts using methods known in the medical art.

The "halogen" in the present invention refers to fluorine, chlorine, bromine and iodine, etc., preferably fluorine and chlorine.

The "halogenated" in the present invention means that any hydrogen atom in the substituent may be replaced by one or more same or different halogens. "Halogen" is as previously defined.

The "monovalent group" and "divalent group" in the description of the present invention refer to the group formed by the loss of one or two hydrogen atoms of the compound.

The "C _1-6 alkyl group" in the present invention refers to a straight or branched chain alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methylbutyl base-2-methylpropyl, etc. The "C _1-4 alkyl" refers to the above examples containing 1-4 carbon atoms.

The "C _1-6 alkylene group" referred to in the _{present invention refers to a linear or branched divalent alkyl group derived from the aforementioned "C 1-6} alkyl group" by further removing one hydrogen atom.

The "C _2-8 alkenyl" in the present invention refers to a straight-chain or branched-chain or cyclic alkene group derived from an alkene moiety of 2-8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as vinyl , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 1,4-hexadienyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl and the like.

The "C _2-8 alkenylene group" in the _{present invention refers to a linear or branched divalent alkene group derived from the aforementioned "C 2-8} alkenyl group" by further removing one hydrogen atom.

The "3-12-membered cycloalkenyl" in the present invention, unless otherwise specified, includes all possible monocyclic and condensed rings (including condensed in the form of condensate, spiro and bridge), such as 3-8-membered monocyclic alkene, 7-11-membered spirocyclic alkene, 7-11-membered cycloalkene, 6-11-membered bridged cyclic alkene, etc.

The "C _2-8 alkynyl" in the present invention refers to a straight-chain or branched alkynyl group derived from the alkynyl moiety of 2-8 carbon atoms containing a carbon-carbon triple bond by removing one hydrogen atom, such as ethynyl, propyl Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl and the like.

The "C _2-8 alkynylene group" referred to in the _{present invention refers to a linear or branched divalent alkynyl group derived from the aforementioned "C 2-8} alkynyl group" by further removing one hydrogen atom.

"C _1-6 alkylamino", "(C _1-6 alkyl) ₂ amino", "C _1-6 alkylcarbonylamino", "C _1-6 alkylsulfonylamino" in the present invention , "C _1-6 alkylaminocarbonyl", "(C _1-6 alkyl) ₂ amino-carbonyl", "C _1-6 alkoxy-carbonyl", "C _1-6 alkylsulfonyl" , "C _1-6 alkylthio", "C _1-6 alkyl-carbonyl", "3-8 membered cycloalkyl-carbonyl", "3-8 membered heterocyclyl-carbonyl" respectively refer to C _{1 -6} alkyl- _{NH-, (C 1-6} alkyl) (C _1-6 alkyl) N-, C _1-6 alkyl-C(O)-NH-, C _1-6 alkyl-S (O) ₂ -NH ₂ -, C _1-6 alkyl-NH-C(O)-, (C _1-6 alkyl) (C _1-6 alkyl) NC(O)-, C _1-6 Alkyl-OC(O)-, C _1-6 alkyl-S(O) _2- , C _1-6 alkyl-S-, C _1-6 alkyl-C(O)-, 3-8 members Cycloalkyl-C(O)-, 3-8-membered heterocyclyl-C(O)-; the "C _1-6 alkyl" is as defined above, preferably "C _1-4 alkyl" .

"C _1-6 alkoxy" refers to the present invention as hereinbefore defined "C _1-6 alkyl" group by an oxygen atom to the parent molecule, i.e., "C _1-6 alkyl -O -" groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, neopentyloxy, n-hexyloxy, and the like. Said "C _1-4 alkoxy" refers to the above-mentioned examples containing 1-4 carbon atoms, ie "C _1-4 alkyl-O-" groups.

The "fused ring" in the present invention refers to a polycyclic structure formed by two or more cyclic structures in the form of connection, spiro and bridge. The said cyclic ring refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms with each other (ie sharing one bond). The bridged ring refers to a condensed ring structure formed by two or more ring-mounted structures sharing two non-adjacent ring atoms with each other. The spiro ring refers to a condensed ring structure formed by two or more ring structures sharing one ring atom with each other.

The "cycloalkyl" in the present invention refers to a 3- to 12-membered cycloalkyl, which may be a monocyclic, bicyclic, or polycyclic cycloalkyl system (also referred to as a fused ring system). Unless otherwise specified, it includes all possible monocyclic and condensed rings (including condensed in the form of condensed, spiro and bridged).

A monocyclic ring system is a cyclic hydrocarbyl group containing 3-8 carbon atoms. Examples of 3-8 membered monocycloalkyl groups include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The fused-ring cycloalkyl group includes a cyclocycloalkyl group, a bridged cycloalkyl group, and a spirocycloalkyl group.

The paracyclocycloalkyl can be a 6-11 membered paracyclocycloalkyl, a 7-10 membered paracyclocycloalkyl, and representative examples thereof include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1 ]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

、

、

、

、

The spirocyclyl group can be a 7-12 membered spirocyclyl group or a 7-11 membered spirocyclyl group, examples of which include but are not limited to:

,

,

,

,

、

、

、

、

、

。 Described bridged ring base can be 6-11 member bridged ring base, 7-10 member bridged ring base, its examples include but are not limited to:

,

,

,

,

,

.

The "3-12 membered heterocyclic group" in the present invention refers to a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, N, preferably 1-3 heterocyclic groups. Atoms, including carbon atoms, nitrogen atoms and sulfur atoms, can be oxo.

"Heterocyclyl" means a monocyclic heterocyclyl, bicyclic heterocyclyl system, or polycyclic heterocyclyl system (also known as a fused ring system), including saturated, partially saturated heterocyclyls, but excluding aromatic rings . Unless otherwise specified, it includes all possible monocyclic rings, condensed rings (including condensed in the form of condensed, spiro, and bridged forms), saturated, and partially saturated.

The "mono-heterocyclic group" described in the present invention refers to the aforementioned "mono-heterocyclic group" in which at least one ring carbon atom derived from a hydrogen atom is further removed and replaced by a heteroatom selected from O, S, N. cyclic group. The monoheterocyclic group can be a 3-8 membered heterocyclic group, a 3-8 membered saturated heterocyclic group, a 3-6 membered heterocyclic group, a 4-7 membered heterocyclic group, a 5-7 membered heterocyclic group, a 5- 6-membered heterocyclic group, 5-6-membered oxygen-containing heterocyclic group, 3-8-membered nitrogen-containing heterocyclic group, 5-6-membered nitrogen-containing heterocyclic group, 5-6-membered saturated heterocyclic group, etc. "3-8" membered saturated heterocyclyl, examples of which include, but are not limited to, aziridine, oxiranyl, thiirane, azetidinyl, oxetanyl, sulfur Hetetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2- Thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, pyridyl, oxazinyl, pyrrolyl, morpholinyl, 1,4-di Oxanyl, 1,4-oxathiolanyl; "3-8" membered partially saturated heterocyclyl, examples of which include but are not limited to 4,5-dihydroisoxazolyl, 4, 5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrole base, 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazole base, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl and the like. Condensed heterocycles include hexa-, spiro-, and bridged-heterocycles, which may be saturated, partially saturated, or unsaturated, but are not aromatic. Fused heterocyclyl is fused to a benzene ring, 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic cycloalkenyl, 5-6 membered monocyclic heterocyclyl, or 5-6 membered monocyclic heteroaryl 5-6 membered monocyclic heterocyclyl ring of the base. The said heterocyclyl group can be a 6-11-membered cyclyl group, a 7-10-membered cyclyl group, a 6-10-membered cyclyl group, a 6-12-membered saturated cyclyl group, and representative examples include but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro benzofuran-3-yl, indoline-1-yl, indoline-2-yl, indoline 3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro- 1H-indolyl, octahydrobenzofuranyl.

、

、

、

The spiro heterocyclyl group can be a 6-12 membered spiro heterocyclyl group, a 7-12 membered spiro heterocyclyl group, a 7-12 membered N-containing spiro heterocyclyl group, a 6-12 membered saturated spirocyclic group, examples of which include But not limited to:

,

,

,

The "spiroheterocyclic group" described in the present invention refers to the divalent spiro group in which at least one ring carbon atom derived from the aforementioned "spiroheterocyclic group" is further removed from a hydrogen atom and replaced by a heteroatom selected from O, S and N. cyclic group.

、

The bridged heterocyclyl group can be a 6-11-membered bridged heterocyclyl group, a 7-11-membered bridged heterocyclyl group, and a 6-12-membered bridged heterocyclyl group, examples of which include but are not limited to:

,

The "aryl group" in the present invention refers to a cyclic aromatic group containing 6-14 carbon atoms, including a 6-8 membered monocyclic aryl group and an 8-14 membered fused-ring aryl group, preferably a 6-8 membered aryl group A monocyclic aryl group. The 6-8 membered monocyclic aryl group may be phenyl, pyrazole, cyclooctatetraenyl and the like. The 8-14-membered fused-ring aryl group can be naphthalene, phenanthrene and the like.

The "heteroaryl group" in the present invention may be a 5-10 membered heteroaryl group, which refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S and N, preferably 1 -3 heteroatoms, including the case where carbon atoms and sulfur atoms are oxo, for example, carbon atoms are replaced by C(O), and sulfur atoms are replaced by S(O), S(O) ₂ . Heteroaryl groups include monoheteroaryl groups and fused heteroaryl groups, and unless otherwise specified, include all possible monocyclic, condensed, fully aromatic, and partially aromatic situations. Monoheteroaryl can be 5-7 membered heteroaryl, 5-6 membered heteroaryl, examples of which include but are not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl , oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl. In certain embodiments, the fused heteroaryl is fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocycle 5- or 6-membered monocyclic heteroaromatic ring of 5- or 6-membered monocyclic heteroaryl, wherein fused cycloalkyl, cycloalkenyl and heterocyclyl are used as independent oxo or thio groups One or two groups are selectively substituted. The fused heteroaryl can be 8-12 membered heteroaryl, 9-10 membered heteroaryl, examples include but are not limited to benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl , benzothiadiazolyl, benzothiazolyl, cinnoline, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridyl, indium azolyl, indolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydro Quinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridyl, 4,5,6, 7-Tetrahydro[c][1,2,5]oxadiazolyl and 6,7-dihydro[c][1,2,5]oxadiazol-4(5H)keto.

"Pharmaceutically acceptable salts" in the present invention refer to pharmaceutically acceptable addition salts of acids and quinines or solvates thereof. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfurous, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic , hydriodic acid, alkanoic acid (such as acetic acid, HOOC-(CH ₂ )n-COOH (where n is 0~4)) and the like. Sodium salt: sodium salt, potassium salt, calcium salt, ammonium salt, etc. Those skilled in the art are aware of a wide variety of non-toxic pharmaceutically acceptable addition salts.

The "stereoisomer" of the compound of formula (I) of the present invention means that when there is an asymmetric carbon atom in the compound of formula (I), (IA), (IB), an enantiomer will be produced; when the compound has a carbon-carbon When there is a double bond or a cyclic structure, cis-trans isomers are generated; when a ketone or oxime exists in the compound, tautomers are generated, all enantiomers of compounds of formula (I), (IA), (IB) All isomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof are included within the scope of the present invention.

A "warhead" as used herein refers to a moiety capable of forming a covalent bond with a nucleophile. A "nucleophile" is a substance that donates an electron pair to an electrophile to form a chemical bond in a reaction. In some embodiments, the nucleophile can be an oxygen nucleophile, eg, water or a hydroxyl group; a nitrogen nucleophile, eg, an amine; or a sulfur nucleophile, eg, a sulfhydryl group, such as a cystine residue Sulfhydryl in the side chain.

R₁₁、R₁₂、R₁₃、R₁₄、R₁₅分別獨立的選自氫、鹵素、氰基、C_1-4烷基、鹵代C_1-4烷基、Cy₄或任選被取代基取代的C_1-4烷基、鹵代C_1-4烷基、Cy₄、C_2-8烯基、C_2-8炔基，所述取代基選自：羥基、氨基、羧基、氰基、硝基、鹵素、C_1-4烷基、C_1-4烷氧基、C_1-4烷氧C_1-4烷氧基、C_1-4烷基氨基、(C_1-4烷基)₂氨基、C_1-4烷基羰基氨基、C_1-4烷基磺醯氨基、3-12員雜環基；Cy₄選自3-12員環烷基、3-12員環烯基、3-12員雜環基、芳基或5-10員雜芳基。 "Warhead" as used in the present invention refers to the portion of the inhibitor that reversibly or irreversibly participates in the reaction of a donor (eg, a protein) with a substrate. Warhead can, for example, form covalent bonds with proteins, or can generate stable transition states, or can be reversible and irreversible alkylating agents. For example, the warhead can be a functional group on the inhibitor that can participate in a bond-forming reaction in which a new covalent bond is formed between a portion of the warhead and a donor (eg, an amino acid residue of a protein). The warhead is an electrophile and the "donor" is a nucleophile, such as a cysteine residue side chain. Suitable structures for warhead include but are not limited to the following structures:

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are each independently selected from hydrogen, halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, Cy ₄ or optionally substituted Substituted C _1-4 alkyl, halogenated C _1-4 alkyl, Cy ₄ , C _2-8 alkenyl, C _2-8 alkynyl, the substituents are selected from: hydroxyl, amino, carboxyl, cyano , nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl ) ₂ amino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamino, 3-12-membered heterocyclic group; Cy _{4 is} selected from 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl , 3-12 membered heterocyclyl, aryl or 5-10 membered heteroaryl.

z is an integer from 0-4.

A better specific example is:

The irreversible inhibitor of fibroblast growth factor receptor (FGFR) provided by the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, has efficient and highly selective inhibitory effect on fibroblast growth factor receptor, It can be applied to the treatment of related diseases mediated by abnormal FGF/FGFR, especially in the treatment of cancer diseases.

detailed description

The abbreviation "NMP" as used herein refers to N-methylpyrrolidone; "DIPEA" refers to N,N-diisopropylethylamine; "TLC" refers to thin layer chromatography; "PE:EA" refers to petroleum ether : ethyl acetate; "TFA" means trifluoroacetic acid; "THF" means tetrahydrofuran; "EA" means ethyl acetate; "DCM:MeOH" means dichloromethane:methanol; "DCM" means dichloromethane Methane; "MTBE" means methyl tert-butyl ether; "TFAA" means trifluoroacetic anhydride; "TEA" means triethylamine; "LAN" means lithium tetrahydroaluminum; "Boc" means tertiary Butoxycarbonyl; "MsCl" is methylsulfonyl chloride; "DEAD" means diethyl azodicarboxylate; "PPh ₃ " means triphenylphosphorus; "mCPBA" means m-chloroperoxybenzoic acid; "LC-MS" refers to liquid chromatography-mass spectrometry.

The present invention can be better understood from the following examples and experimental examples. However, those with ordinary knowledge in the technical field to which this case belongs can easily understand that the contents described in the embodiments are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the scope of the patent application. In addition, the materials, instruments, etc. involved in the following examples and experimental examples can be purchased from commercial sources unless otherwise specified.

Preparation Example 1: Synthesis of Intermediate 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde

Step 1: Synthesis of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate

The raw material ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15g, 64.4mmol, 1.0eq) was dissolved in tetrahydrofuran (100mL), and triethylamine (19.6g, 193.4mmol, 3.00eq) was added. ), cooled to 0°C, slowly added ammonia water (7.8g, 1288mmol, 20.0eq), after adding, the reaction was raised to room temperature overnight, LC-MS detected that the reaction was complete, stood for separation, and the aqueous phase was extracted once with ethyl acetate, The organic phases were combined, dried, and concentrated. The crude product was washed with methyl tert-butyl ether to obtain a white solid product (11.8 g, yield: 87%).

Step 2: Synthesis of (4-amino-2-(methylthio)pyrimidin-5-yl)methanol

The raw material ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (11.8g, 55.3mmol, 1.0eq) was dissolved in tetrahydrofuran (100mL), cooled to 0°C, and tetrahydroaluminum was added in batches Lithium (4.8 g, 127.4 mmol, 2.3 eq) was added, and the reaction was naturally raised to room temperature for 2 hours. LC-MS detected that the reaction was complete, tetrahydrofuran (100 mL) was added to the system, the temperature was lowered to 0 °C, and water (10 mL) was slowly added in turn. ) and 15% NaOH (10 mL), filtered, the filtrate was dried, and concentrated to give a yellow solid product (10.0 g, crude).

Step 3: Synthesis of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde

The raw material (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (10.0 g, crude product, 1.0 eq) was dissolved in tetrahydrofuran (100 mL), and manganese dioxide (40.6 g, 467.2 mmol, 8.4 g) was added. eq), reacted at room temperature overnight, LC-MS detected that the reaction was complete, filtered, dried the filtrate, concentrated, and the crude product was washed with ethyl acetate to obtain a yellow solid product (7.7 g, two-step yield: 82.3%).

Preparation Example 2: Synthesis of Intermediate 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Step 1: Synthesis of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

The raw material 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (1.1 g, 5 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), triethylamine (1.5 g, 15mmol, 3.0eq) and methanesulfonyl chloride (573mg, 5mmol, 1.0eq), react at room temperature for 2 hours. LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, the organic phases were combined, washed twice with saturated brine, dried, and concentrated to obtain a white solid product (1.2 g, yield: 82%).

Preparation Example 3: Synthesis of Intermediate 4-(3-((methylsulfonyl)oxy)propyl)oxazine-1-carboxylate tert-butyl ester

Step 1: Synthesis of tert-butyl 4-(3-hydroxypropyl)oxazine-1-carboxylate

The raw material tert-butyloxazine-1-carboxylate (7g, 0.0376mol, 1.0eq) was dissolved in acetonitrile (50mL), 3-bromopropan-1-ol (5.2g, 0.0376mol, 1.0eq) and carbonic acid were added Potassium (15.5g, 0.1127mol, 3.0eq). After four hours of reaction, TLC detected that the reaction was complete, concentrated under reduced pressure, poured the residue into water (200 mL), added dichloromethane (200 mL×3) for extraction, dried the organic phase, and concentrated to obtain a yellow liquid product (8.82 g, Yield: 96%).

Step 2: Synthesis of tert-butyl 4-(3-((methylsulfonyl)oxy)propyl)oxazine-1-carboxylate

The raw material 4-(3-hydroxypropyl)oxazine-1-carboxylate tert-butyl ester (8.82g, 0.0361mol, 1.0eq) was dissolved in dichloromethane (80mL), and triethylamine (16.4g, 0.1623mol) was added. , 4.5eq) and methanesulfonic acid chloride (6.28g, 0.0541mol, 1.5eq) in dichloromethane (20mL) solution, react for 12 hours, TLC detection reaction is complete. Water (100 mL) was added to the reaction flask, extracted with dichloromethane (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain a yellow color Liquid product (6.58 g, yield: 57%).

Example 1: 1-(1-(1-Propenylpyridin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxy Synthesis of phenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (Compound 1)

Step 1: Synthesis of ethyl 4-((1-(tert-butoxycarbonyl)azetidine-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate

4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (5.0 g, 21.5 mmol, 1.0 eq) was dissolved in 1,4-dioxane (30 mL), triethylamine (7.6 g, 75.3mmol, 3.5eq) and tert-butyl 3-aminoazetidine-1-carboxylate (4.4g, 25.8mmol, 1.2eq), heated at 95°C for 10h, TLC monitored the completion of the reaction, and the reaction solution was cooled After reaching room temperature, concentrated, added water (50 mL), extracted with ethyl acetate (50 mL×2), combined the organic phases, concentrated, and the crude product was subjected to silica gel column chromatography (PE:EA=10:1~3:1) to obtain 4 -((1-(tert-butoxycarbonyl)azetidine-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate ethyl ester (7.5 g, yield: 95%) .

Step 2: Synthesis of tert-butyl 3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate

Lithium aluminum tetrahydrogen (1.2g, 31.6mmol, 1.5eq) was dissolved in THF (50mL), cooled to 0°C, and 4-((1-(tert-butoxycarbonyl)azepine) dissolved in THF (20mL) was added Cyclobutan-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate ethyl ester (7.5g, 20.4mmol, 1.0eq), react at 0°C for 2.5h, monitor the completion of the reaction by TLC, ice bath Water (1.2mL) was added, stirred for 10min, 15% sodium hydroxide aqueous solution (1.2g) was added, stirred for 15min, water (3.5mL) was added, stirred for 10min, suction filtered, and the filter cake was washed several times with a small amount of THF , the filtrate was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain 3-((5-(hydroxymethyl)-2-( Methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate tert-butyl ester (3.09 g, yield: 47%).

Step 3: Synthesis of tert-butyl 3-((5-carbamoyl-2-(methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate

tert-butyl 3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate (3.1 g, 9.5 mmol, 1.0 eq ) was dissolved in THF (60 mL), manganese dioxide (6.6 g, 75.7 mmol, 8.0 eq) was added, and the reaction was stirred at 45 °C for 12 h. TLC monitored the completion of the reaction, filtered through celite, and the filter cake was washed with a small amount of THF for several times. The filtrate was concentrated to give tert-butyl 3-((5-carbamoyl-2-(methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate (2.76 g, yield: 90 %).

Step 4: 3-((5-(((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidine- Synthesis of tert-butyl 1-carboxylate

Dissolve tert-butyl 3-((5-carbamoyl-2-(methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate (1.0 g, 3.1 mmol, 1.0 eq) In DCM (15 mL), acetic acid (0.5 mL) and 3,5-dimethoxyaniline (0.7 g, 4.6 mmol, 1.5 eq) were added, the reaction was stirred for 15 min, and sodium triacetoxyborohydride (3.3 g) was added. , 15.4mmol, 5.0eq), the reaction was stirred for 8h, the completion of the reaction was monitored by TLC, the pH of the solution was adjusted to 7~8 with saturated sodium bicarbonate solution, extracted with DCM (3×50mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, Concentrated, the crude product was subjected to silica gel column chromatography (DCM:MeOH=100:1~60:1) to obtain 3-((5-(((3,5-dimethoxyphenyl)amino)methyl)-2 -(Methylthio)pyrimidin-4-yl)amino)azetidine-1-carboxylate tert-butyl ester (973 mg, yield: 70%).

Step 5: 3-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidine Synthesis of -1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester

3-((5-(((3,5-dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidine-1- Tert-butyl carboxylate (1.0g, 2.2mmol, 1.0eq) was dissolved in THF (20mL), cooled to 0°C, added with triethylamine (657.5mg, 6.5mmol, 3.0eq) and solid triphosgene (771.5mg, 2.6mmol, 1.2eq), stirred at room temperature for 2h, 75°C for 1.5h, monitored by LC-MS for complete reaction, cooled to room temperature, added saturated aqueous ammonium chloride (50mL), extracted with DCM (3×50mL), combined The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=100:1~60:1) to obtain 3-(3-(3,5-dimethoxyphenyl) -7-(Methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylic acid tert-butyl Ester (845 mg, yield: 80%).

Step 6: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester

3-(3-(3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidine-1 ( 2H )-yl) tert-butyl azetidine-1-carboxylate (1.9 g, 3.9 mmol, 1.0 eq) was dissolved in DCM (20 mL), cooled to 0°C, and sulfonic acid dissolved in DCM (2 mL) was added Acrylic chloride (1.3g, 9.6mmol, 2.5eq) was stirred at 0°C for 15min, the reaction was added dropwise to saturated aqueous sodium bicarbonate solution (50mL), extracted with DCM (3×50mL), the organic phases were combined and dried over anhydrous sodium sulfate , filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=100:1~60:1) to obtain 3-(3-(2,6-dichloro-3,5-dimethoxyphenyl) -7-(Methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylic acid tert. Butyl ester (1.67 g, yield: 61%).

Step 7: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5- d ]Pyrimidine-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester (800.0 mg, 1.4 mmol, 1.0 eq) was dissolved in DCM (20 mL), cooled to 0 °C, m-chloroperoxybenzoic acid (496.2 mg, 2.8 mmol, 2.0 eq) was added, and the reaction was stirred at 0 °C for 2 h. LC-MS monitored the reaction to complete the reaction, and the reaction solution was directly carried out to the next step without purification.

Step 8: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[ 4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester The reaction solution in the previous step was added to the honeycomb, and methylamine aqueous solution (10mL) was added, and the reaction was sealed at 45°C 2h, LCMS monitored the completion of the reaction, cooled to room temperature, separated the layers, the aqueous phase was extracted with DCM (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=100: 1~60:1) to obtain 3-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4- Dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester (600 mg, two-step yield: 77%).

Step 9: 1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4 Synthesis of -Dihydropyrimido[4,5- d ]pyrimidin-2( 1H)-one

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5- d ]Pyrimidine-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester (600.0 mg, 1.1 mmol, 1.0 eq) was dissolved in EtOH (10 mL), and ethanolic hydrogen chloride solution was added ( 25%, 10 mL), the reaction was stirred at room temperature for 3 h, monitored by LC-MS, the reaction was complete, saturated aqueous sodium bicarbonate solution (50 mL) was added, extracted with DCM (3×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, yielded 1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-di Hydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (460 mg, yield: 94%).

Step 10: 4-(3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydro Synthesis of pyrimido[4,5- d ]pyrimidin-1( 2H )-yl)azetidin-1-yl)quamidine-1-carboxylate tert-butyl ester

The tert-butyl 1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3, 4-Dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (460.0 mg, 1.0 mmol, 1.0 eq) was dissolved in DCM (125 mL), acetic acid (0.5 mL) and 4-oxo were added tert-butyl pyridine-1-carboxylate (330mg, 1.6mmol, 1.5eq), stirred for 2h, added sodium triacetoxyborohydride (665.7mg, 3.1mmol, 3.0eq), stirred for 8h, monitored by TLC The reaction was completed, the pH of the solution was adjusted to 7~8 with saturated sodium bicarbonate solution, the solution was separated, extracted with DCM (2×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM: MeOH=100:1~20:1), get 4-(3-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2- Oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)azetidin-1-yl)quamidine-1-carboxylate tert-butyl ester (406.3 mg, yield: 62%).

Step 11: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(1-(guaidin-4-yl)azetidine Synthesis of Alk-3-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

4-(3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido [4,5- d ]Pyrimidine-1( 2H )-yl)azetidin-1-yl)quaridine-1-carboxylate tert-butyl ester (406.3 mg, 0.7 mmol, 1.0 eq) was dissolved in EtOH In (15 mL), ethanolic hydrogen chloride solution (10 mL) was added, and the reaction was stirred at room temperature for 3 h. LC-MS monitored the completion of the reaction, and concentrated to obtain 3-(2,6-dichloro-3,5-dimethoxyphenyl) -7-(methylamino)-1-(1-(guaidin-4-yl)azetidin-3-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidine- 2( 1H )-keto hydrochloride (364.8 mg, yield: 100%).

Step 12: 1-(1-(1-Propenylpyridin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxy Synthesis of Phenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(1-(guaidin-4-yl)azetidine- 3-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (364.8 mg, 0.7 mmol, 1.0 eq) in THF (10 mL) , add triethylamine (198.1mg, 2.0mmol, 3.0eq), stir the reaction for 10min, slowly add acrylonitrile chloride (70.9mg, 0.8mmol, 1.2eq) dissolved in THF (2mL) dropwise, stir the reaction at room temperature for 2h, TLC Monitor the completion of the reaction, add saturated sodium bicarbonate solution (20 mL), extract with EA (2×50 mL), dry over anhydrous sodium sulfate, filter, concentrate, and the crude product is subjected to silica gel column chromatography (DCM:MeOH=100:1~20:1) , to give 1-(1-(1-propenylpyridin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxybenzene yl)-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (200 mg, yield: 53%).

Molecular formula: C ₂₆ H ₃₁ C ₁₂ N ₇ O ₄ Molecular weight: 576.48 LC-MS ( m/z )=576.18 [M+H ⁺ ].

: ¹ HNMR (400MHz, DMSO) δ (ppm): 8.00 (s, 1H), 6.98-7.07 (m, 2H), 6.74-6.81 (m, 1H), 6.03-6.08 (m, 1H), 5.62-5.65 (m,1H),4.39(m,2H),4.28(s,1H),3.82-3.95(m,10H),3.14-3.20(m,1H),2.87-2.98(m,3H),2.77-2.78 (s, 3H), 2.26 (m, 1H), 1.63 (m, 2H), 1.10 (m, 2H).

Example 2: 1-(7-Propenyl-7-azaspiro[3.5]nonan-2-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (Compound 2)

Step 1: tert-Butyl 2-((5-(ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate Synthesis

4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (3.4g, 14.55mmol, 1.0eq) was dissolved in 1,4-dioxane (30mL), and the system was added to the system at room temperature. 2-Amino-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (4.2g, 17.47mmol, 1.2eq) and triethylamine (4.4g, 43.69mmol, 3.0eq) were added, After the temperature was raised to 98°C, the mixture was refluxed and stirred overnight. TLC monitored the completion of the reaction. After the reaction solution was concentrated and cooled, saturated aqueous ammonium chloride solution (100 mL) was added, and after stirring for 5 minutes, dichloromethane (150 mL×3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (200-300 mesh silica gel; petroleum ether:ethyl acetate=40:1) to obtain 2-((5-(ethoxycarbonyl)-2-(methylthio)pyrimidine-4- (yl)amino)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (6.49 g, yield: 100%).

Step 2: Synthesis of tert-butyl 2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate

At 0 °C, lithium tetrahydroaluminum (842.5 mg, 22.2 mmol, 1.5 eq) was added to tetrahydrofuran (10 mL), and 2-((5-(ethoxycarbonyl)-2-(methylthio) was slowly added dropwise with stirring base)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (6.49g, 14.8mmol, 1.0eq) in tetrahydrofuran (30mL), the temperature of the system was controlled at Below 5°C, the dripping was completed, and the mixture was slowly raised to room temperature and stirred overnight. TLC showed that the reaction was complete, the system was cooled to 0 °C, water (842.4 mg) was added, and after stirring for 20 minutes, 15% aqueous sodium hydroxide solution (842.5 mg) was added dropwise at this temperature, and after stirring for 20 minutes, the temperature was again heated to 0 Water (2.5 g) was added dropwise at ℃, stirred for 40 minutes, and then filtered with suction. The filtrate was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (200-300 mesh silica gel; dichloromethane and methanol = 150:1). ~40:1) to give tert-2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylic acid Butyl ester (3.14 g, yield: 57.0%).

Step 3: Synthesis of 2-((5-Carboxyl-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester

2-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3.12 g , 7.9mmol, 1.0eq) was dissolved in tetrahydrofuran (20mL), manganese dioxide (6.8g, 79mmol, 10.0eq) was added at room temperature with stirring, the addition was completed, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was complete, the system was filtered with celite, the filtrate was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain 2-((5-carbamoyl-2-(methylthio)pyrimidin-4-yl)amino) -7-Azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3.56 g crude, yield: 100%).

Step 4: 2-((5-(((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro Synthesis of [3.5] Nonane-7-carboxylate tert-butyl ester

2-((5-Methylamino-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3.56 g, 9.0 mmol, 1.0eq) and 3,5-dimethoxyaniline (2.06g, 13.5mmol, 1.5eq) were dissolved in tetrahydrofuran (30mL), acetic acid (0.5mL) was added dropwise, stirred at room temperature for 1 hour, under an ice-water bath Sodium triacetoxyborohydride (9.5 g, 45 mmol, 5.0 eq) was added in portions, and the mixture was warmed to room temperature and stirred overnight. TLC showed that the reaction was complete, the system was cooled to 0°C, saturated aqueous sodium bicarbonate solution (60 mL) was added, extracted with dichloromethane (150×3 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography ( 200-300 mesh silica gel; dichloromethane and methanol = 200:1) to give 2-((5-(((3,5-dimethoxyphenyl)amino)methyl)-2-(methylthio) Pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (2.89 g, yield: 61.4%).

Step 5: 2-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidine Synthesis of -1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

2-((5-(((3,5-dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5 ] Nonane-7-carboxylate tert-butyl ester (2.89g, 5.45mmol, 1.0eq) was dissolved in tetrahydrofuran (20mL), stirred and lowered to 0°C, and triethylamine (1.65g, 16.35mmol, 3.0eq) was added dropwise ). After the dropping was completed, the mixture was stirred at this temperature for 10 minutes, and a tetrahydrofuran solution (5 mL) of triphosgene (1.46 g, 7.08 mmol, 1.3 eq) was added dropwise. After the dropping was completed, the mixture was slowly raised to room temperature and stirred for 1 hour, and then heated to 72 °C and refluxed for 2 Hour. LC-MS showed no raw material, the system was cooled to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added to the system, extracted with dichloromethane (150 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated , the crude product was separated by silica gel column chromatography (200-300 mesh silica gel; dichloromethane and methanol = 200:1) to obtain 2-(3-(3,5-dimethoxyphenyl)-7-(methylthio) )-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl Ester (1.76 g, 58.6% yield).

Step 6: 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

2-(3-(3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidine-1 ( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (1.76g, 3.16mmol, 1.0eq) was dissolved in dichloromethane (15mL), cooled to 0°C , sulfonyl chloride (1.06g, 7.9mmol, 2.5eq) in dichloromethane solution (10mL) was added dropwise. After the dropping was completed, the mixture was stirred at this temperature for 15 minutes, the reaction was added dropwise to saturated aqueous sodium bicarbonate solution (50 mL), the layers were separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 2-(3-(2,6-dichloromethane). -3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl )-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (1.71 g crude, yield: 89.4%).

Step 7: 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (1.71 g, 2.73 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL) ), cooled to 0 °C and stirred for 30 minutes, added m-chloroperoxybenzoic acid (1.17 g, 6.82 mmol, 2.5 eq) in methylene chloride suspension (10 mL) in batches, and stirred at this temperature for 15 minutes after the addition. , the system was added dropwise to saturated aqueous sodium bicarbonate solution (50 mL), the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 2-(3-(2,6-dichloro-3,5). -Dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)- 7-Azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (1.52 g, yield: 84.9%).

Step 8: 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[ 4,5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (1.52g, 2.31mmol, 1.0eq) was added to aqueous methylamine solution (30 mL), heated at 45°C for 3 hours. TLC showed that the reaction was complete, it was cooled to room temperature, extracted with dichloromethane (150 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the crude product was separated by silica gel column chromatography (200-300 mesh silica gel; dichloromethane) Methane and methanol=200:1~80:1) to obtain 2-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo -3,4-Dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (574.1 mg, received rate 41.3%).

Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5]nonan-2-yl )-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5- d ]pyrimidin-1( 2H )-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (574.1 mg, 0.94 mmol, 1.0 eq) was added to ethanol (4 mL) , cooled to 0° C., added dropwise an ethanolic hydrogen chloride solution (15 mL), and after the addition was completed, the mixture was warmed to room temperature and stirred overnight. TLC showed that the reaction was complete, and the system was concentrated to give 3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5] Nonan-2-yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (569.8 mg crude, 100% yield).

Step 10: 1-(7-Propenyl-7-azaspiro[3.5]nonan-2-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- Synthesis of 7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5]nonan-2-yl)-3 ,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (569.8 mg crude product, 0.94 mmol) was added to tetrahydrofuran (15 mL), cooled to 0 °C, followed by dropwise addition of three Ethylamine (339.9 mg, 3.36 mmol) and acryl chloride (121.6 mg, 1.34 mmol) were added, and the mixture was warmed to room temperature and stirred for 2 hours. TLC showed that the reaction was complete, saturated aqueous ammonium chloride solution (20 mL) was added to the concentrated system, extracted with dichloromethane (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the crude product was separated by silica gel column chromatography (200-300 mesh silica gel; dichloromethane and methanol=200:1~80:1) to obtain 1-(7-propenyl-7-azaspiro[3.5]nonan-2-yl)-3-( 2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H )- Ketone (180.75 mg, 34.2% over 2 steps).

Molecular formula: C ₂₆ H ₃₀ Cl ₂ N ₆ O ₄ Molecular weight: 561.46 LC-MS (Pos, m/z )=562.2 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.98 (s, 1H), 6.97-7.01 (m, 1H), 6.73-6.83 (m, 1H), 6.03-6.07 (m, 2H), 5.62 -5.75(s, 1H), 4.81-4.85(m, 1H), 4.37(s, 2H), 3.95(s, 6H), 3.31-3.50(m, 4H), 2.78-2.79(s, 3H), 2.25 -2.35(m,4H),1.51-1.58(m,4H).

Example 3: 8-(7-Propenyl-7-azaspiro[3.5]nonan-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2- Synthesis of (Methylamino)pyrido[2,3- d ]pyrimidin-7( 8H )-one (Compound 3)

Step 1: 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3- d ]pyrimidine-8( synthesis of carboxylate-yl) -7-aza-spiro [3.5] nonane -7- - 7 H)

6- (2-chloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d] pyrimidin -7 (8 H) - one (726mg, 2mmol, 1.0eq), 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (483mg, 2mmol, 1.0eq) and triphenylphosphine (787mg, 3mmol, 1.5eq) were dissolved in tetrahydrofuran (10 mL), slowly add diethyl azodicarboxylate (522 mg, 3 mmol, 1.5 eq), and react at 25° C. for 4 h. TLC monitored the completion of the reaction, the reaction solution was poured into water, extracted with EA, the organic phases were combined, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=2:1) to obtain 2-(6-(2-chloro-3, 5-Dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3- d ]pyrimidin-8( 7H )-yl)-7-azaspiro[3.5] Nonane-7-carboxylate tert-butyl ester (1.1 g, 93% yield).

Step 2: 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3- d ]pyrimidine- Synthesis of 8( 7H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3- d ]pyrimidine-8( 7H )-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (587mg, 1mmol, 1.0eq) was dissolved in dichloromethane (10mL), m-chloroperoxybenzoic acid (246mg) was added , 1mmol, 1.0eq, mass fraction 70%), reacted at 25°C for 2h, TLC monitoring was completed, and the reaction solution was directly used in the next step without treatment.

Step 3: 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8( synthesis of carboxylate-yl) -7-aza-spiro [3.5] nonane -7- - 7 H)

The reaction solution obtained in the previous step was directly added to an aqueous methylamine solution (10 mL), and the reaction was carried out at 25 °C for 4 h. LC-MS detected that the reaction was complete, the reaction solution was statically separated, the organic phase was dried, concentrated, and the crude product was subjected to silica gel column chromatography (PE: EA=1:1) to obtain 2-(6-(2-chloro-3,5-diol). Methoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidin-8( 7H )-yl)-7-azaspiro[3.5]nonane- tert-Butyl 7-carboxylate (230 mg, 40% yield).

Step 3: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(7-azaspiro[3.5]nonan-2-yl)pyrido Synthesis of [2,3- d ]pyrimidin-8( 7H )-one

2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8( 7H )-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (230mg, 0.40mmol, 1.0eq) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, 25 ℃ reaction 2h. The reaction was completed as monitored by TLC, concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=10:1) to obtain 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)- 8-(7-Azaspiro[3.5]nonan-2-yl)pyrido[2,3- d ]pyrimidin-8( 7H )-one (100 mg, 53% yield).

Step 4: 8-(7-Propenyl-7-azaspiro[3.5]nonan-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-( Synthesis of Methylamino)pyrido[2,3- d ]pyrimidin-7( 8H )-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(7-azaspiro[3.5]nonan-2-yl)pyrido[2 , 3- d] pyrimidin--8 (7 H) - one (100mg, 0.213mmol, 1.0eq) was dissolved in dichloromethane (2mL) was added triethylamine (65mg, 0.639mmol), and Bing Xixi chloride (19.2 mg , 0.213 mmol). The reaction was carried out at 25°C for 2 h. TLC monitored the completion of the reaction. The reaction solution was poured into water, extracted with dichloromethane, and the organic phases were combined and concentrated. The crude product was subjected to silica gel column chromatography (elution with EA) to obtain 8-(7-propenyl-7 -Azaspiro[3.5]nonan-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3- d ] Pyrimidine-7( 8H )-one (60 mg, 54% yield).

Molecular formula: C ₂₇ H ₃₀ ClN ₅ O ₄ Molecular weight: 524.02 LC-MS (Pos, m/z )=524.2 [M+H ⁺ ]

¹ H NMR (400MHz, CDCl ₃ )δ(ppm): 8.92(s, 1H), 7.96(s, 1H), 7.60(s, 1H), 6.76(s, 1H), 6.59-6.60(m, 1H), 6.04-6.08(m, 2H), 5.62-5.65(d, 1H), 5.37(s, 1H), 3.89(s, 3H), 3.80(s, 3H), 3.50(s, 2H), 3.40(s, 2H), 2.91-2.92(m, 3H), 2.43(m, 2H), 1.75-1.79(m, 2H), 1.59(s, 2H), 1.47(s, 2H).

Example 4 8-(2-Propenyl-2-azaspiro[3.3]heptan-6-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-( methylamino)pyrido Synthesis of [2,3- d ]pyrimidin-7-( 8H )-one (Compound 4)

Step 1: 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3- d ]pyrimidine-8( synthesis of carboxylate-yl) -2-aza-spiro [3.3] heptane -2- - 7 H)

The starting material 6- (2-chloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d] pyrimidin -7 (8 H) - one (300mg, 0.825 mmol, 1.2eq) was dissolved in THF (7.5mL), 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (49mg, 0.229mmol, 1eq) and triphenylphosphine were added (180mg, 0.687mmol, 3eq), cooled to 0°C, under nitrogen protection, added dropwise DEAD (120mg, 0.687mmol, 3eq), slowly warmed to room temperature and stirred overnight. TLC monitored the completion of the reaction, water (5 mL) was added to the reaction solution, stirred for 10 min, extracted with DCM, concentrated, and the crude product was separated by silica gel column chromatography (PE:EA=10:1~5:1) to obtain an off-white solid product ( 603 mg crude).

Step 2: 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3- d ]pyrimidine- Synthesis of 8( 7H )-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

The intermediate 6-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3- d ]pyrimidine-8( 7 H) - yl) -2-aza-spiro [3.3] heptane-2-carboxylate (crude 603mg, 0.971mmol by meter, 1 eq) was dissolved in DCM (5mL) cooled to below 0 ℃, mCPBA (263 mg, 1.068 mg, 1.1 eq) was added, and the reaction was carried out at 0°C for 1 hour. TLC monitored the completion of the reaction, and the reaction solution was directly dropped into the next step without treatment.

Step 3: 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8(7 Synthesis of H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester:

The reaction solution obtained in the previous step was added to methylamine solution (20 mL), the reaction was carried out at 50°C overnight in a sealed tube, extracted with DCM (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was passed through a silica gel column. Chromatographic separation (PE:EA=5:1~1:1) gave off-white solid product (187mg).

Step 4: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-azaspiro[3.3]heptan-6-yl)pyrido Synthesis of [2,3- d ]pyrimidin-7( 8H )-one trifluoroacetate:

The intermediate 6-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8(7 H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (187 mg) was dissolved in DCM (3 mL), cooled to 0°C, TFA (3 mL) was added, stirred to room temperature The reaction was warmed for 2 hours. TLC monitored the completion of the reaction, and concentrated under reduced pressure to obtain the product (109 mg crude product), which was directly added to the next step of the reaction.

Step 5: 8-(2-Propenyl-2-azaspiro[3.3]heptan-6-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-( Synthesis of methylamino)pyrido[2,3- d ]pyrimidin-7-( 8H )-one:

The intermediate 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-azaspiro[3.3]heptan-6-yl)pyrido [2,3- d] pyrimidin -7 (8 H) - one trifluoroacetate (109 mg of crude) was dissolved in THF (5mL) was added triethylamine (124mg, 1.23mmol, 5eq), cooled to -10 ℃ , slowly add acryl chloride (26.6 mg, 0.296 mmol, 1.2 eq) in DCM (5 mL) solution, stir the reaction for 1 hour, monitor the completion of the reaction by TLC, add saturated sodium bicarbonate solution, stir, DCM extraction (20 mL × 3), The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (DCM:MeOH=150:1~80:1) to obtain a white solid product (12 mg, yield: 9.8%).

Molecular formula: C ₂₅ H ₂₆ ClN ₅ O ₄ Molecular weight: 495.96 LC-MS(Pos, m/z )=496.2[M+H] ⁺ .

¹ HNMR (400MHz, DMSO- d ₆ )δ(ppm): 8.93(s,1H), 7.98(s,1H), 7.63(s,1H), 6.77(s,1H), 6.60(s,1H), 6.20-6.28(m, 1H), 6.05-6.10(d, 1H), 5.64-5.67(d, 1H), 5.33(s, 1H), 4.31(s, 1H), 4.16(s, 1H), 4.02( s,1H),3.81-3.90(m,7H),2.92(s,3H),2.72(s,3H),2.16-2.21(t,1H).

Example 5: 7 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -3- (2,6-dichloro-3 Synthesis of ,5-dimethoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (Compound 5)

Step 1: Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester

4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (22.0g, 94.55mmol, 1.0eq) was dissolved in THF (100mL), TEA (28.70g, 283.65mmol, 3.0eq) was added, Aqueous methylamine solution (100 mL) was slowly added dropwise at a temperature not exceeding 30°C. After the addition was completed, the reaction was carried out at room temperature (25°C) overnight, and monitored by TLC. TLC monitored the completion of the reaction, the reaction solution was spin-dried under reduced pressure, water (50 mL) was added, stirred at room temperature (25°C) for 10 min, the reaction solution was suction filtered, the filter cake was washed with water (a small amount of multiple washes), and the filter cake was air-dried to obtain a solid 4-(Methylamino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (16.98 g crude).

Step 2: Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol

Dissolve tetrahydroaluminum lithium (4.01g, 105.47mmol, 1.5eq) in THF (500mL), cool down to -10℃~-5℃ in an ice-salt bath, slowly add 4-(methylamino)-2-( Methylthio)pyrimidine-5-carboxylic acid ethyl ester (15.98 mg crude product, 70.31 mmol, 1.0 eq) in THF (120 mL) solution, control the temperature during the dropwise addition -10 ℃ ~ -5 ℃, after the dropwise addition, slowly rise To room temperature (25°C), the reaction was stirred at room temperature (25°C) overnight (12h), and monitored by TLC. TLC monitored the completion of the reaction, followed by adding water (4 mL), 10% aqueous sodium hydroxide solution (4 mL) and water (12 mL) to quench lithium tetrahydroaluminum, suction filtration, the filter cake was washed with THF, the filtrates were combined, and anhydrous magnesium sulfate was added to dry, Concentrated, the crude product was separated by silica gel column chromatography (eluent PE:EA=5:1, 2:1) to obtain (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol ( 11.24 g, yield: 86.33%).

Step 3: Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde

(4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (11.24g, 60.67mmol, 1.0eq) was dissolved in DCM (582mL), manganese dioxide (42.20g, 485.36mmol, 8.0eq), stirred at room temperature (25°C) overnight, monitored by TLC. TLC monitored the completion of the reaction, the reaction solution was suction filtered with celite, and the filtrate was concentrated to obtain 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (10.68 g, yield: 96.04%).

Step 4: Synthesis of 5-(((3,5-dimethoxyphenyl)amino)methyl) -N -methyl-2-(methylthio)pyrimidin-4-amine

4-(Methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (5.18 g, 28.27 mmol, 1.0 eq) was dissolved in DCM (173 mL), 3,5-dimethoxyaniline ( 5.20g, 33.92mmol, 1.2eq), stir until dissolved, add sodium triacetoxyborohydride (21.97g, 103.67mmol, 3.7eq), stir at room temperature (25°C) overnight (12h). TLC monitored the completion of the reaction, added saturated aqueous sodium bicarbonate solution to adjust pH=7-8, separated the layers, extracted the aqueous phase with DCM (20 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate. The crude product was passed through a silica gel column. Chromatographic separation (eluent PE: EA=10:1~4:1) gave 5-(((3,5-dimethoxyphenyl)amino)methyl) -N -methyl-2- (Methylthio)pyrimidin-4-amine (5.44 g, yield: 60.0%).

Step 5: 3-(3,5-Dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1 H )-ketone synthesis

5-(((3,5-dimethoxyphenyl)amino)methyl) -N -methyl-2-(methylthio)pyrimidin-4-amine (3.84g, 12.0mmol, 1.0eq) It was dissolved in THF (40.0 mL), cooled to 0 °C in an ice-water bath, TEA (3.64 g, 18.0 mmol, 1.5 eq) was added and stirred for 5 min, and triphosgene (5.64 g, 36.0 mmol) was slowly added at 0 °C under nitrogen protection. , 3.0eq) of THF (20.0mL) solution, the addition was completed, slowly warmed to room temperature (25°C), stirred for 2h, then heated to 70°C and refluxed overnight (12h). TLC monitored the completion of the reaction, added saturated aqueous ammonium chloride solution (20 mL) to the reaction solution for washing, a solid product was precipitated, filtered, and the filter cake was washed with ice water (10 mL×3), and the filter cake was dried to obtain 3-(3,5 -Dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (2.80 g, Yield: 67.5%).

Step 6: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5 - Synthesis of d ]pyrimidin-2( 1H)-one

3-(3,5-Dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H )-ketone (2.16g, 6.24mmol, 1.0eq) was dissolved in DCM (90mL), the ice-salt bath was cooled to 0°C, and sulfonyl chloride (2.10g, 15.60mmol, 2.5eq) in DCM (5mL) was slowly added dropwise After the addition was completed, the solution was stirred at 0 °C for 15 min. TLC monitored the completion of the reaction, and saturated aqueous sodium bicarbonate solution was added to quench the reaction solution. Separation, the aqueous phase was extracted with DCM (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (eluent MeOH:DCM=0~1:30), to give 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (620.00 mg, yield: 18.5%).

Step 7: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4 Synthesis of ,5- d ]pyrimidin-2( 1H )-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5- d ] Pyrimidine-2( 1H )-one (620.00mg, 1.49mmol, 1.0eq) was dissolved in DCM (18mL), cooled to 0°C in an ice-salt bath, m-chloroperoxybenzoic acid (70%) was slowly added (737.70 mg, 2.98 mmol, 2.0 eq), the addition was completed, slowly warmed to room temperature (25° C.) and stirred overnight (12 h). TLC monitored the completion of the reaction, added saturated aqueous sodium thiosulfate solution (5 mL), added saturated aqueous sodium bicarbonate solution to adjust pH=7-8, separated the layers, the aqueous phase was extracted with DCM (10 mL×3), the organic phases were combined, anhydrous sodium sulfate Dry, filter, concentrate the filtrate, and separate the crude product by silica gel column chromatography (eluent MeOH:DCM=0~1:100) to obtain 3-(2,6-dichloro-3,5-dimethoxyphenyl) )-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (280.00 mg, yield: 42.0% ).

Step 8: ( 2S , 4S )-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-5,6 Synthesis of ,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5 - d] pyrimidin -2 (1 H) - one (280.00mg, 0.63mmol, 1.0eq) was dissolved in N - methyl-2-pyrrolidinone (10mL), was added (2 S, 4 S) -4- amino - 2-(Hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (545.00mg, 2.52mmol, 4.0eq), TEA (318.40mg, 3.15mmol, 5.0eq), after the addition, the reaction was warmed to 100°C overnight ( 12h). TLC monitored the completion of the reaction, added saturated aqueous ammonium chloride solution (10 mL), water (10 mL), extracted with EA (15 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate. The crude product was separated by silica gel column chromatography ( Eluent MeOH: DCM=0~1:50) to give ( 2S , 4S )-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8 -Methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl acid (83.70 mg, yield: 22.8%).

Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino )-1-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

( 2S , 4S )-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-5,6,7 ,8-tetrahydropyrimido[4,5- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (83.00mg, 0.142mmol, 1.0eq) Dissolve in ethanol (2.0 mL), add hydrogen chloride/ethanol solution (5 mL), and stir at room temperature (25° C.) overnight (12 h). The completion of the reaction was monitored by TLC and concentrated under reduced pressure to obtain 3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrole Alk-3-yl)amino)-1-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (84.88 mg crude).

Step 10: 7 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -3- (2,6-dichloro-3, Synthesis of 5-dimethoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)- 1-Methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (84.88 mg crude, 0.142 mmol) was dissolved in THF (18 mL) and TEA was added (49.48mg, 0.489mmol), stirred at room temperature (25°C) for 15min, cooled to 0°C in an ice-salt bath, slowly added acrylonitrile chloride (14.75mg, 0.163mmol) in THF (1mL) solution, after the addition was completed, slowly rose to Stir at room temperature (25°C) for 30 min. The completion of the reaction was monitored by TLC, saturated aqueous sodium bicarbonate solution (5 mL) was added, extracted with EA (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (eluent MeOH). : DCM = 0 ~ 3: 100 ) to give 7 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -3- (2, 6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (34.00 mg, Two-step yield 44.6%).

Molecular formula: C ₂₃ H ₂₆ Cl ₂ N ₆ O ₅ , molecular weight: 537.40, LC-MS (Pos, m/z )=538.9 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.01 (s, 1H), 7.40-7.52 (d, 1H), 6.99 (s, 1H), 6.55-6.69 (m, 1H), 6.10-6.17 (m,1H),5.64-5.67(m,1H),5.00-5.07(m,1H),4.46(s,2H),4.35-4.36(m,2H),4.28-4.29(m,3H),3.83 -3.87(m,6H),3.57-3.69(m,3H),3.25-3.26(m,3H).

Example 6: 2 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -6- (2-chloro-3,5 Synthesis of Dimethoxyphenyl)-8-methylpyrido[2,3- d ]pyrimidin-7( 8H )-one (Compound 6)

Step 1: 6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3- d ]pyrimidine-7( 8H ) -Synthesis of ketones

6- (2-chloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d] pyrimidin -7 (8 H) - one (600mg, 1.65mmol , 1.0eq) was dissolved in tetrahydrofuran (10mL), cooled to 0°C, added sodium hydride (125mg, 3.63mmol, 2.2eq), stirred for two hours, added iodomethane (703mg, 4.96mmol, 3.0eq), stirred at room temperature overnight . LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, the organic phases were combined, dried, concentrated, and the crude product was added to dichloromethane and beaten to obtain 6-(2-chloro-3,5-dimethoxyphenyl) )-8-methyl-2-(methylthio)pyrido[2,3- d ]pyrimidin-7( 8H )-one (400 mg, 60% yield).

Step 2: 6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3- d ]pyrimidine-7(8 Synthesis of H )-ketones

6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3- d ]pyrimidin-7( 8H )-one (400mg, 1.06mmol, 1.0eq) was dissolved in DMF (6mL), mCPBA (mass fraction 70%, 183mg, 1.06mmol, 1.0eq) was added, and the reaction was carried out at room temperature for two hours. TLC detected that the reaction was complete, and the reaction solution was directly used in the following step.

Step 3: ( 2S , 4S )-4-((6-(2-chloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydro Synthesis of pyrido[2,3- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The reaction solution in the previous step was added to ( 2S , 4S )-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 1.06 mmol, 1.0 eq), add triethylamine (537mg, 5.30mmol, 3.0eq), react at 50°C for 4h, TLC monitors the completion of the reaction, pour the reaction solution into water, add EA for extraction, combine the organic phases, wash once with water and saturated brine each, dried, concentrated, and the crude product was subjected to silica gel column chromatography (PE:EA=1:1)( 2S , 4S )-4-((6-(2-chloro-3,5-dimethoxyphenyl)- 8-Methyl-7-oxo-7,8-dihydropyrido[2,3- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl Ester (140 mg, 25% yield).

Step 4: 6- (2-Chloro-3,5-dimethoxyphenyl) -2 - (((3 S , 5 S) -5- ( hydroxymethyl) pyrrolidin-3-yl) amino) Synthesis of -8-methylpyrido[2,3- d ]pyrimidin-7( 8H )-one

( 2S , 4S )-4-((6-(2-chloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido [2,3- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (140 mg, 0.26 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) In the solution, trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for two hours. After the reaction was detected by LC-MS, the reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=10:1) to obtain 6-(2-chloro-3,5-dimethoxyphenyl)-2-( ((3 S, 5 S) -5- ( hydroxymethyl) pyrrolidin-3-yl) amino) -8-methyl pyrido [2,3- d] pyrimidin -7 (8 H) - one (80 mg of , the yield is 70%).

Step 5: 2 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -6- (2-chloro-3,5- Synthesis of Methoxyphenyl)-8-methylpyrido[2,3- d ]pyrimidin-7( 8H )-one

6- (2-chloro-3,5-dimethoxyphenyl) -2 - (((3 S , 5 S) -5- ( hydroxymethyl) pyrrolidin-3-yl) amino) -8 - methyl-pyrido [2,3- d] pyrimidin -7 (8 H) - one (80mg, 0.18mmol, 1.0eq) was dissolved in DMF (1mL) and THF mixed solution (2mL), was added triethylamine ( 55mg, 0.54mmol, 3.0eq) and acryl chloride (16mg, 0.18mmol, 1.0eq), react at room temperature for 2h. TLC monitoring the reaction was complete, the reaction solution was poured into water, EA was added for extraction, the organic phases were combined, washed once with water and saturated brine, dried, concentrated, and the crude product was subjected to silica gel column chromatography (EA) to obtain 2-((( 3S , 5 S )-1-propenyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-methyl pyrido [2,3- d] pyrimidin -7 (8 H) - one (34mg, yield 38%).

Molecular formula: C ₂₄ H ₂₆ ClN ₅ O ₅ Molecular weight: 499.95 LC-MS(Pos, m/z )=500.1[M+H ⁺ ].

¹ HNMR (400MHz, CDCl ₃ )δ(ppm): 8.47(s, 1H), 7.53(s, 1H), 6.85(s, 1H), 6.57(s, 1H), 6.50-6.51(d, 1H), 6.43-6.45(m, 2H), 5.74-5.77(m, 1H), 4.72-4.77(m, 1H), 4.42(s, 1H), 4.13-4.17(m, 2H), 4.10(s, 3H), 3.92(s, 3H), 3.73-3.82(m, 3H), 3.58(s, 1H), 2.59-2.64(m, 1H), 1.90(s, 1H).

Example 7: 2 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -6- (2-chloro-3,5 Dimethoxyphenyl)pyrido[2,3- d ]pyrimidine Synthesis of Pyridin-7( 8H )-one (Compound 7)

Step 1: Reduction of 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one synthesis

The starting material 6- (2-chloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin -7 (8 H) - one (300mg, 0.825 mmol, 1.0eq) was added to THF and heated to dissolve. The temperature was lowered to 0° C., and mCPBA (318.8 mg, 0.907 mmol, 1.1 eq) dissolved in THF was added dropwise. After adding and stirring the reaction for 2 h, TLC monitored the completion of the reaction, adding saturated sodium bicarbonate solution, extracting with DCM (20 mL×3), combining the organic phases, drying, and concentrating to obtain 6-(2-chloro-3,5-dimethoxy) phenyl) -2- (methyl-sulfo acyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (390mg).

Step 2: ( 2S , 4S )-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2, Synthesis of 3- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

6- (2-chloro-3,5-dimethoxyphenyl) -2- (methyl-sulfo acyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (270mg, 0.682mmol, 1.0eq), (2 S , 4 S) -4- amino-2- (hydroxymethyl) pyrrolidine-carboxylate -1- (295mg, 1.364mmol, 2.0eq) and DIPEA (176.3mg , 1.364mmol, 2.0eq) was dissolved in NMP (5mL) and reacted at 90°C for 5h. The completion of the reaction was monitored by TLC. The reaction solution was poured into water (30 mL), DCM (30 mL) was added, and the layers were separated by stirring. The aqueous phase was extracted with DCM (20 mL), and the organic phases were combined and washed with saturated sodium chloride solution (20 mL). The phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=10:1~5:1) to obtain ( 2S , 4S )-4-((6-(2-chloro-3, 5-Dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3- d ]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1 - tert-butyl carboxylate (76 mg, yield: 21%).

Step 3: 6- (2-Chloro-3,5-dimethoxyphenyl) -2 - (((3 S , 5 S) -5- ( hydroxymethyl) pyrrolidin-3-yl) amino) Synthesis of pyrido[2,3- d ]pyrimidin-7( 8H )-one hydrochloride

( 2S , 4S )-4-((6-(2-chloro-3,5-dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3- d ] pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (76mg, 0.143mmol, 1.0eq) was dissolved in ethanol (5mL), cooled to 0°C, Hydrogen chloride ethanol solution (5 mL) was added dropwise, and after 6 h of reaction, TLC monitoring was completed, and the reaction was concentrated. The crude product was dissolved in THF, concentrated, and repeated three times. The obtained crude product was directly put into the next step.

Step 4: 2 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -6- (2-chloro-3,5- Synthesis of Methoxyphenyl)pyrido[2,3- d ]pyrimidin-7( 8H)-one

6- (2-chloro-3,5-dimethoxyphenyl) -2 - (((3 S , 5 S) -5- ( hydroxymethyl) pyrrolidin-3-yl) amino) pyridine and [2,3- d] pyrimidin -7 (8 H) - one hydrochloride (crude, 0.143 mmol, 1.0 eq) was dissolved in THF (10mL) was added triethylamine (72.35mg, 0.715mmol, 5.0eq) Cool to 0°C, slowly add acryl chloride (12.94mg, 0.143mmol, 1.0eq), after the reaction for 1h, monitor the remaining raw material by TLC, add acryl chloride (12.94mg, 0.143mmol, 1.0eq), and react for 2h after TLC A small amount of starting material remained, saturated sodium bicarbonate solution (10 mL) and DCM (10 mL) were added, the layers were separated, the aqueous phase was extracted with DCM (10 mL), the organic phases were combined, concentrated, and the crude product was separated by preparative thin layer chromatography (DCM:MeOH= 20: 1) to give 2 - (((3 S, 5 S) -1- Bingxi Xi-5- (hydroxymethyl) pyrrolidin-3-yl) amino) -6- (2-chloro-3,5 - dimethoxyphenyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (32mg, yield: 46%).

Molecular formula: C ₂₃ H ₂₄ ClN ₅ O ₅ Molecular weight: 485.93 LC-MS (Pos, m/z )=486.2 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 12.12 (m, 1H), 8.61 (s, 1H), 7.91-8.13 (m, 1H), 7.70-7.74 (s, 1H), 6.58-6.68 (m,1H),6.53-6.54(m,1H),6.23-6.24(m,1H),6.05-6.10(s,1H),5.05-5.12(m,1H),4.10(m,1H),4.09 (m,1H),4.02(m,2H),3.87(m,3H),3.79(m,3H),3.18(m,1H),3.16(m,1H),2.32(m,1H),2.05( s, 2H).

Example 8: 1-(2-Propenyl-2-azaspiro[3.3]heptan-6-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (Compound 9)

Step 1: tert-Butyl 6-((5-(ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate Synthesis

The raw material 6-amino-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (5.0 g, 23.55 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL), and 4-chlorine was added successively at room temperature -2-(Methylthio)pyrimidine-5-carboxylic acid ethyl ester (8.2g, 35.32mmol, 1.5eq) and triethylamine (7.1g, 70.65mmol, 3.0eq) were added and stirred at room temperature overnight. TLC monitored the completion of the reaction, added saturated aqueous ammonium chloride solution (100 mL), stirred for 5 minutes, added dichloromethane (150 mL×3) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the crude product was subjected to silica gel column chromatography Purification (silica gel specification: 200-300 mesh, dichloromethane: methanol = 200: 1~90: 1) to obtain the product (8.15 g, yield: 84.8%).

Step 2: Synthesis of tert-butyl 6-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

Lithium tetrahydroaluminum (2.26g, 59.7mmol, 3.0eq) was added to tetrahydrofuran (50mL) and stirred, cooled to 0°C, and 6-((5-(ethoxycarbonyl)-2-(methylthio) was slowly added dropwise with stirring (yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (8.15g, 19.9mmol, 1.0eq) in tetrahydrofuran (30mL), the temperature was controlled at 5 ℃ or less for 6 hours. TLC showed that the reaction was complete. After adding water (2.26g) at 0°C and stirring for 20 minutes, 15% aqueous sodium hydroxide solution (2.26g) was added dropwise, stirring for 20 minutes, and water (6.78g) was added dropwise, stirring for 2 hours, and suction filtration. , the filtrate was dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (silica gel specification: 200-300 mesh, petroleum ether: ethyl acetate=10:1~3:1) to obtain the product (2.2g, Yield: 30.5%).

Step 3: Synthesis of tert-butyl 6-((5-carbamoyl-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

6-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.03 g, 8.26mmol, 1.0eq) was dissolved in tetrahydrofuran (60mL), manganese dioxide (7.18g, 82.6mmol, 10.0eq) was added with stirring, the addition was completed, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was complete, filtered through celite, the filtrate was dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the crude product was subjected to silica gel column chromatography (silica gel specification: 200-300 mesh, petroleum ether: ethyl acetate = 20: 1~5 : 1) The product (2.70 g, yield: 90.0%) was isolated and obtained.

Step 4: 6-((5-(((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro [3.3] Synthesis of tert-butyl heptane-2-carboxylate

6-((5-Carboxyl-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.6 g, 7.13 mmol , 1.0eq) was dissolved in dichloromethane (50mL), stirred to dissolve, added 3,5-dimethoxyaniline (1.63g, 10.69mmol, 1.5eq) and acetic acid (0.6mL), the drop was completed, stirred at room temperature For 2 hours, sodium triacetoxyborohydride (7.55 g, 35.65 mmol, 5.0 eq) was added in portions under an ice-water bath, and the addition was completed, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was complete, saturated aqueous sodium bicarbonate solution (150 mL) was added, extracted with dichloromethane (150×3 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (silica gel specification: 200-300 mesh) , petroleum ether: ethyl acetate = 10: 1) to obtain the product (2.68 g, yield: 72.4%).

Step 5: 6-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidine Synthesis of -1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-((5-(((3,5-dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3 ] Heptane-2-carboxylate tert-butyl ester (2.68g, 5.34mmol, 1.0eq) was dissolved in tetrahydrofuran (33mL), cooled to 0°C, triethylamine (1.62g, 16.02mmol, 3.0eq) was added dropwise, After dropping, stirring for 10 minutes, adding triphosgene (2.06 g, 6.94 mmol, 1.3 eq) in tetrahydrofuran solution (10 mL) dropwise, after dropping, slowly warming to room temperature, stirring for 1 hour, heating to 70 °C and reacting for 3.5 hours. LC-MS showed no raw material, cooled to room temperature, added saturated aqueous ammonium chloride solution (60 mL), extracted with dichloromethane (100 mL×3), dried the organic phase over anhydrous sodium sulfate, filtered with suction, concentrated the filtrate, and passed the crude product through a silica gel column Purification by chromatography (silica gel specification: 200-300 mesh, petroleum ether: ethyl acetate=10:1~5:1) to obtain the product (1.69 g, yield: 60.3%).

Step 6: 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidine-1 ( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (1.69g, 3.2mmol, 1.0eq) was dissolved in dichloromethane (12mL), cooled to 0°C After stirring for 30 minutes, a solution of sulfonyl chloride (1.08 g, 8.0 mmol, 2.5 eq) in dichloromethane (5 mL) was added dropwise. The system was added dropwise to saturated aqueous sodium bicarbonate solution (50 mL), stirred and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (silica gel specification: 200-300 mesh, dichloromethane: methanol =200:1) to obtain the product (702.3 mg, yield: 36.9%).

Step 7: 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5- d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5- d ]pyrimidin-1( 2H )yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (448.1 mg, 0.75 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) , cooled to 0 °C, stirred for 30 minutes, added m-chloroperoxybenzoic acid (323.9 mg, 1.87 mmol, 2.5 eq) in batches, and after the addition was completed, stirred for 3 hours, and TLC monitored the completion of the reaction. Saturated aqueous sodium thiosulfate solution (20 mL) was added to the reaction solution, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain the product (589.6 mg crude product, yield: 100.0%).

Step 8: 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[ 4,5- d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (335.7mg crude, 0.42mmol, 1.0eq) was added to methylamine The aqueous solution (15 mL) was heated and stirred at 45°C for 4 hours, and TLC showed that the reaction was complete. Cool to room temperature, extract with dichloromethane (150 mL×3), dry the organic phase over anhydrous sodium sulfate, filter with suction, concentrate the filtrate, and purify the crude product by silica gel column chromatography (silica gel specification: 200-300 mesh, dichloromethane: methanol =200:1~100:1) to obtain the product (105.5 mg, yield: 43.3%).

Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(2-azaspiro[3.3]heptan-6-yl )-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5- d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (105.5 mg, 0.182 mmol, 1.0 eq) was added to ethanol (3 mL) , cooled to 0 ℃, the ethanolic solution of hydrogen chloride (3mL) was added dropwise, the dropping was completed, the temperature was raised to room temperature and stirred for 2 hours, TLC showed that the reaction was complete, and the reaction solution was concentrated to obtain the product (128.6mg crude product, yield: 100.0%).

Step 10: 1-(2-Propenyl-2-azaspiro[3.3]heptan-6-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- Synthesis of 7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(2-azaspiro[3.3]heptan-6-yl)- 3,4-Dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (128.6mg crude product, 0.18mmol, 1.0eq) was added to tetrahydrofuran (4mL), cooled to 0°C, Triethylamine (81.3 mg, 0.804 mmol, 4.4 eq) and acryl chloride (29.1 mg, 0.321 mmol, 1.7 eq) were successively added dropwise, and the drop was completed, and the mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. Saturated aqueous ammonium chloride solution (10 mL) was added to the concentrated system, extracted with dichloromethane (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was purified by preparative thin layer chromatography (dichloromethane: methanol=30 : 1) The product (11.1 mg, yield: 11.5%) was obtained.

Molecular formula: C ₂₄ H ₂₆ Cl ₂ N ₆ O ₄ Molecular weight: 533.41 LC-MS ( m/z )=533.0[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.98 (s, 1H), 6.97 (s, 1H), 6.24-6.28 (m, 1H), 6.08-6.09 (m, 1H), 5.63 (m) ,1H),5.31(m,1H),4.37(s,2H),4.29(s,1H),4.16(s,1H),3.95(s,6H),3.86(s,1H),2.79-2.80( m,3H),2.66-2.68(m,2H),1.98-2.03(m,2H),1.10(s,1H),0.83-0.86(m,1H).

Example 9: 1-(1'-Propenyl[1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl )-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (Compound 10)

Step 1: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5- d ]pyrimidin-1( 2H )yl)azetidine-1-carboxylate tert-butyl ester (700.0 mg, 1.3 mmol, 1.0 eq) was dissolved in DCM (20 mL), cooled to 0 °C, added m-chloroperoxybenzoic acid (434.2 mg, 2.5 mmol, 2.0 eq) was stirred at 0 °C for 2 h, and LC-MS monitored the completion of the reaction, and the reaction solution was directly carried out to the next step without purification.

Step 2: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester

The reaction solution in the previous step was put into a sealed tube, and methylamine aqueous solution (10 mL) was added, and the reaction was carried out at 45 °C for 2 h. The reaction was completed by LC-MS monitoring, cooled to room temperature, and the layers were separated. The aqueous phase was extracted with DCM (20 mL), and the organic phases were combined. , dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=100:1~60:1) to obtain 3-(3-(2,6-dichloro-3,5-dimethylformaldehyde) oxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)azetidine- 1-Carboxylic acid tert-butyl ester (470 mg, two-step yield: 69%).

Step 3: 1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4 Synthesis of -Dihydropyrimido[4,5- d ]pyrimidin-2( 1H)-one

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5- d ]Pyrimidine-1( 2H )-yl)azetidine-1-carboxylate tert-butyl ester (470.0 mg, 0.9 mmol, 1.0 eq) was dissolved in EtOH (10 mL), and ethanolic hydrogen chloride solution was added ( 10 mL), the reaction was stirred at room temperature for 3 h, and the reaction was completed under LCMS monitoring. Saturated aqueous sodium bicarbonate solution (50 mL) was added, extracted with DCM (3×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1-(nitrogen Hetetan-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido[4 ,5- d ]pyrimidin-2( 1H )-one (340 mg, yield: 89%).

Step 4: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5- d ]pyrimidin-1( 2H )-yl)-[-1,3'-biazetidine]-1'-carboxylate tert-butyl ester

1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-di Hydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (340.0 mg, 0.8 mmol, 1.0 eq) was dissolved in DCM (125 mL), acetic acid (0.5 mL) and 3-oxoazepine were added Cyclobutane-1-carboxylate tert-butyl ester (198.7mg, 1.2mmol, 1.5eq), stirred for 2h, added sodium triacetoxyborohydride (492.1mg, 2.3mmol, 3.0eq), stirred for 8h, The completion of the reaction was monitored by TLC, the pH of the solution was adjusted to 7~8 with saturated sodium bicarbonate solution, the layers were separated, extracted with DCM (2×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography ( DCM:MeOH=100:1~20:1) to obtain 3-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo Substituted-3,4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)-[-1,3'-biazetidine]-1'-carboxylate tert-butyl ester ( 240 mg, yield: 52%).

Step 5: 1-([1,3'-Diazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methyl Synthesis of amino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5- d ]pyrimidin-1( 2H )-yl)-[-1,3'-biazetidine]-1'-carboxylate tert-butyl ester (240.0 mg, 0.4 mmol, 1.0 eq) was dissolved in EtOH ( 15mL), add hydrogen chloride ethanol solution (10mL), stir the reaction at room temperature for 3h, monitor the reaction by LC-MS, and concentrate to obtain 1-([1,3'-biazetidine]-3-yl)-3- (2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidine-2( 1H ) - Ketone hydrochloride (320 mg, yield: 100%).

Step 6: 1-(1'-Propenyl[-1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl )-7-(methylamino)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one

1-([1,3'-Diazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino) -3,4-Dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (320.0 mg, 0.6 mmol, 1.0 eq), dissolved in THF (15 mL), added triethyl Amine (244.1 mg, 2.4 mmol, 4.0 eq), stirred for 10 min, slowly added dropwise acryl chloride (81.8 mg, 0.9 mmol, 1.5 eq) dissolved in THF (1 mL), stirred at room temperature for 2 h, TLC monitored the completion of the reaction, Saturated sodium bicarbonate solution (20 mL) was added, extracted with EA (2×50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain 1-( 1'-Propenyl[-1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methyl) yl) -3,4-dihydro-pyrimido [4,5- d] pyrimidin -2 (1 H) - one (100mg, yield: 30%).

Molecular formula: C ₂₄ H ₂₇ Cl ₂ N ₇ O ₄ Molecular weight: 548.43 LC-MS ( m/z )=548.1 [M+H ⁺ ].

¹ HNMR (400MHz, DMSO)δ(ppm): 8.00(s, 1H), 7.05(m, 1H), 6.97(m, 1H), 6.25-6.29(m, 1H), 6.05-6.09(m, 1H) ,5.63-5.67(m,1H),4.39(m,3H),4.16-4.18(m,1H),3.86-3.95(m,10H),3.62-3.64(m,2H),3.01(m,2H) ,2.77-2.78(s,3H).

Example 10: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-propenyloxazin-1-yl)propyl)-6- Synthesis of (2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one (Compound 12)

Step 1: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfinyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one Synthesis

6- (2-chloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d] pyrimidin -7 (8 H) - 580mg -one (, 1.754mmol , 1.0eq) was dissolved in tetrahydrofuran (15mL), cooled to 0°C, 70% mCPBA (616.3mg, 1.754mmol, 1.1eq) in tetrahydrofuran (2mL) was added dropwise, and the mixture was stirred at 0°C-5°C for 3h. TLC monitored the completion of the reaction, added saturated sodium carbonate solution (10 mL), saturated brine (10 mL), and sodium thiosulfate solution (10 mL) to the reaction solution in sequence, stirred for 10 min, extracted with dichloromethane (50 mL×3), and combined them The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylsulfinyl)pyrido[2, 3- d] pyrimidin -7 (8 H) - one (605.7mg, yield: 100%).

Step 2: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- Synthesis of d ]pyrimidin-7( 8H)-one

6- (2-chloro-3,5-dimethoxyphenyl) -2- (methylsulfinyl acyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (605.7 mg, 1.594mmol, 1.0eq), 2-oxaspiro[3.3]heptane-6-amine hydrochloride (475.5mg, 3.188mmol, 2.0eq) and triethylamine (806mg, 7.970mmol, 5.0eq) were dissolved In 1,4-dioxane (10 mL), the temperature was raised to 95° C. for 2 h after the addition. No raw material was monitored by TLC, concentrated under reduced pressure, the crude product was slurried with water (10 mL×1) for 10 min, the filter cake was then slurried with ethyl acetate (50 mL×2), filtered, and the filter cake was dried at 60°C to obtain 2-((2-oxaspiro) [3.3]Heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one ( 220 mg, yield: 32%).

Step 3: 4-(3-(2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)- Synthesis of 7-oxopyrido[2,3- d ]pyrimidin-8( 7H )-yl)propyl)oxazine-1-carboxylate tert-butyl ester

2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- d ] pyrimidin -7 (8 H) - one (220mg, 0.5129mmol, 1.0eq) was dissolved in DMF (5mL) was added 4- (3 - ((meth sulfo acyl) oxy) propyl) piperazine -1 - tert-butyl formate (248 mg, 0.769 mmol, 1.5 eq) and potassium carbonate (212.3 mg, 1.539 mmol, 3.0 eq). After the addition was completed, the temperature was increased to 90 °C and stirred for 0.5 h. No raw material was detected by TLC, the temperature was lowered to 30 °C, the reaction solution was poured into ice water, extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was passed through a silica gel column. Purification by chromatography (EA:PE=1:2, MeOH:DCM=1:30) gave 4-(3-(2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6 -(2-Chloro-3,5-dimethoxyphenyl)-7-oxopyrido[2,3- d ]pyrimidin-8( 7H )-yl)propyl)oxazine-1-carboxylate tert-butyl acid (288 mg, yield: 78.6%).

Step 4: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-( Synthesis of oxazin-1-yl)propyl)pyrido[2,3- d ]pyrimidin-7( 8H )one

4-(3-(2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-7- oxo-pyrido [2,3- d] pyrimidin--8 (7 H) - yl) propyl) piperazine-1-carboxylate (288mg, 0.440mmol, 1.0eq) was dissolved in dichloromethane (5mL ), cooled to 0 °C, added trifluoroacetic acid (1.5 mL) dropwise, the dropping was completed, the reaction was carried out at 0 °C for 3 h, the solvent was concentrated under reduced pressure, the crude product was dissolved in tetrahydrofuran (50 mL), concentrated, and repeated three times to obtain an oily liquid, Water was added, extracted with ethyl acetate (20 mL×2), the aqueous phase was adjusted to pH=8-9 with sodium carbonate solution, extracted with dichloromethane (50 mL×3), the organic phases were combined, dried, filtered, and concentrated to obtain 2-( (2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-(oxazin-1-yl) ) propyl) pyrido [2,3- d] pyrimidin -7 (8 H) -one (129mg, yield: 52.8%).

Step 5: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-propenyloxazin-1-yl)propyl)-6-( Synthesis of 2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one

2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-(oxazine) 1-yl) propyl) pyrido [2,3- d] pyrimidin -7 (8 H) -one (129mg, 0.2323mmol, 1.0eq) was dissolved in tetrahydrofuran (5mL) was added triethylamine (117.5 mg, 1.162mmol, 5.0eq), cooled to 0°C, and acrylonitrile chloride (21mg, 0.232mmol, 1.0eq) was added dropwise. After the addition was completed, the mixture was stirred at 0 °C for 1 h. TLC monitored the completion of the reaction, added saturated sodium carbonate solution (10 mL), stirred for 20 min, extracted with dichloromethane (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to preparative thin layer chromatography Purification to give 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-propenyloxazin-1-yl)propyl)-6-(2 - chloro-3,5-dimethoxyphenyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (56mg, yield: 39.6%).

Molecular formula: C ₃₁ H ₃₇ ClN ₆ O ₅ Molecular weight: 609.13 LC-MS (Pos, m/z )=609.3 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.62 (s, 1H), 8.16-8.17 (s, 1H), 7.72-7.73 (m, 1H), 7.68-7.70 (m, 2H), 6.73 -6.78(s,1H),6.06-6.10(m,1H),5.64-5.67(m,1H),4.63(m,2H),4.53(m,2H),4.32(m,2H),4.23(m ,1H),3.87(s,3H),3.78(s,3H),3.31-3.50(m,4H),2.67(m,2H), 2.31-2.51(m,6H),1.26(m,2H), 1.24(m,1H),0.92(m,1H).

Example 11: 8-(2-Propenyl-2-azaspiro[3.3]heptan-6-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl )-2-(methylamino)pyrido[2,3-d]pyrimidin-7( 8H )-one (Compound 15)

Step 1: Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate

Dissolve 2-(3,5-dimethoxyphenyl)acetic acid (25g, 0.13mol, 1.0eq) in methanol (250mL), add DMF (0.5mL) and thionite chloride (5mL), and react at room temperature After 2 hours, concentrated, water was added, extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated sodium bicarbonate, dried and concentrated to give a pale yellow oily product (28 g, yield: 100%).

Step 2: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3- d ]pyrimidin-7( 8H )-one

Combine methyl 2-(3,5-dimethoxyphenyl)acetate (14.3g, 68.25mmol, 1.5eq) and 4-amino-2(methylthio)pyrimidine-5-carbaldehyde (7.7g, 45.5mmol) , 1.0eq) was dissolved in DMF (50mL), potassium carbonate (12.5g, 91mmol, 3.0eq) was added, the temperature was raised to 70°C and reacted for 5 hours, the reaction was detected by LC-MS, the reaction solution was poured into water, extracted with ethyl acetate , washed twice with saturated brine, combined the organic phases, dried and concentrated, the crude product was washed with ethyl acetate slurry to obtain a yellow solid product (3.8 g, yield: 26%).

Step 3: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3- d ]pyrimidin-7( 8H )-one

6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d] pyrimidin -7 (8 H) - 3.8g -one (, 11.54mmol, 1.0eq ) was dissolved in DMF (30mL), cooled to 0°C, 70% m-chloroperoxybenzoic acid (2.84g, 11.54mmol, 1.0eq) was added, and after 2 hours of reaction, the reaction solution was added to methylamine aqueous solution (30mL) During the reaction, the temperature was raised to 50° C. and reacted for 1 hour. There was solid precipitation in the reaction system, which was filtered, and the filter cake was rinsed twice with dichloromethane and dried to obtain the product (1.9 g, yield: 53%).

Step 4: 6-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8( 7H )- Synthesis of tert-butyl)-2-azaspiro[3.3]heptane-2-carboxylate

6- (3,5-dimethoxyphenyl) -2- (methylamino) pyrido [2,3- d] pyrimidin -7 (8 H) - one (313mg, 1mmol) and 6- ( (Methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (437mg, 1.5mmol, 1.5eq) was dissolved in DMF (15mL), potassium carbonate ( 414mg, 3mmol, 3.0eq), warmed to 100°C and reacted for 12 hours. LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed twice with saturated brine, the organic phases were combined, dried, concentrated, and the crude product was subjected to silica gel column chromatography (PE:EA=1:1) to obtain pale Product as a yellow solid (230 mg, yield: 45%).

Step 5: (6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8 Synthesis of ( 7H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester

6-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidin-8( 7H )-yl) -2-Azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (230mg, 0.45mmol, 1.0eq) was dissolved in dichloromethane (5mL), cooled to 0°C, added sulfonyl chloride (135mg, 1 mmol), reacted at room temperature for 2 hours, LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, washed twice with saturated brine, the organic phases were combined, dried, concentrated, and the crude product was subjected to silica gel column chromatography (PE : EA=1:1) to obtain a pale yellow solid product (110 mg, yield: 42.4%).

Step 6: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-aza-spiro[3.3]hept-6-yl ) Synthesis of pyrido[2,3- d ]pyrimidin-7( 8H)one

(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8(7 H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (110 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, room temperature After 2 hours of reaction, LC-MS detected that the reaction was complete, and concentrated to obtain a pale yellow oily product (150 mg crude product, yield: 100%), which was directly used in the next reaction according to the theoretical amount.

Step 7: 8-(2-Propenyl-2-azaspiro[3.3]heptan-6-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -2-(methylamino)pyrido[2,3-d]pyrimidin-7( 8H )-one

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-aza-spiro[3.3]hept-6-yl)pyridine Hemo[2,3- d ]pyrimidin-7( 8H )one (150mg, 0.19mmol, 1.0eq) was dissolved in dichloromethane (3mL), triethylamine (160mg, 1.57mmol, 8.0eq) and propylene were added Acrylic chloride (28.5mg, 0.31mmol, 1.6eq) was reacted at 25°C for 2h, TLC monitoring was completed, the reaction solution was poured into water, extracted with dichloromethane, the organic phases were combined and concentrated, and the crude product was subjected to silica gel column chromatography (EA) The product was purified as a pale yellow solid (40 mg, yield: 40%).

¹ H NMR (400MHz, CDCl ₃ )δ(ppm): 8.94(s, 1H), 7.94(s, 1H), 7.67(s, 1H), 7.00(s, 1H), 6.18-6.29(m, 1H), 6.04-6.09(d,1H), 5.63-5.66(d,1H), 5.33(s,1H), 4.29(s,1H), 4.12(s,1H), 3.98(s,7H), 3.84(s, 1H), 2.92(s, 3H), 2.70(m, 2H), 2.01-2.12(m, 2H).

Molecular formula: C ₂₅ H ₂₅ Cl ₂ N ₅ O ₄ Molecular weight: 530.41 LC-MS(Pos, m/z )=530.9[M+H] ⁺ .

Example: 12: N- (4-(2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3] heptane-6-yl) amino) -7-oxo-pyrido [2,3- d] pyrimidin--8 (7 H) - synthesis yl) ethyl) phenyl) acrylamide (compound 17)

Step 1: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(4-nitrobenzene)pyrido[2,3- d ]pyrimidine- Synthesis of 7( 8H)-ketone

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3- d ]pyrimidin-7( 8H )-one (3.0 g, 8.25 g mmol), 4-nitrophenethyl methanesulfonate (5.67 _{g, 23.1 mmol) and K 2} CO ₃ (2.28 g, 16.5 mmol) were successively added to DMF (40 mL), and reacted at 50° C. for 2 h. The reaction solution was cooled and poured into water (60 mL), then EA (10 mL) was added, and after stirring for 2 min, suction filtration was performed, and the filter cake was dried to obtain a white solid product (3.2 g, yield: 75.6%).

Step 2: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-8-(4-nitrophenethyl)pyrido[2,3- d Synthesis of ]pyrimidin-7( 8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(4-nitrobenzene)pyrido[2,3- d ]pyrimidine-7( 8 H) - one (400mg, 0.78mmol, 1.0eq) was dissolved in dichloromethane (5mL), a cooled 0 ℃. 70% mCPBA (301.4 mg, 0.86 mmol, 1.1 eq) in dichloromethane (3 mL) was added dropwise, the addition was completed, and the mixture was stirred at room temperature for 2 h. TLC monitored the completion of the reaction. Saturated sodium bicarbonate solution (10 mL) and brine (10 mL) were sequentially added to the reaction solution, stirred for 10 min, extracted with dichloromethane (50 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (PE:EA=5:1) to obtain 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl) 8- (4-ethyl-nitrophenyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (397mg, yield: 93.6%).

Step 2: 6-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyridine Synthesis of [2,3- d ]pyrimidin-2yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-8-(4-nitrobenzene)pyrido[2,3- d ]pyrimidine-7 (8 H) - one (397mg, 0.73mmol, 1.0eq), 6- amino-2-aza-spiro [3.3] heptane-2-carboxylate (618.5mg, 2.91mmol, 4.0eq) and tris Ethylamine (368.5 mg, 3.64 mmol, 5.0 eq) was dissolved in 1,4-dioxane (5 mL), and the temperature was raised to 95° C. to react overnight. No raw material was monitored by TLC, saturated aqueous ammonium chloride solution (10 mL) was added, extracted with dichloromethane (50 mL×3), the organic phases were combined, dried with anhydrous sulfuric acid, filtered, and the mother liquor was concentrated under reduced pressure to obtain 6-((6-(2 -Chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyrido[2,3- d ]pyrimidine-2 (280 mg, yield: 56.7%).

Step 3: 2-((2-Azaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(4-nitro Synthesis of phenylethyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one trifluoroacetate

6-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyrido[ 2,3- d ]pyrimidin-2yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (280 mg, 0.41 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) , the temperature was lowered to 0°C, trifluoroacetic acid solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. No starting material as monitored by TLC, concentrated, the crude product was dissolved in THF (50 mL), concentrated in vacuo, repeated three times to give 2-((2-azaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro) -3,5-Dimethoxyphenyl)-8-(4-nitrophenethyl)pyrido[2,3-d]pyrimidin-7(8H)-one trifluoroacetate, put in according to the theoretical amount Next step.

Step 4: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8 Synthesis of -(4-nitrophenethyl)pyrido[2,3- d ]pyrimidin-7( 8H)-one

The crude product obtained in the previous step was dissolved in methanol (10 mL), 37% aqueous formaldehyde solution (83.8 mg, 1.03 mmol, 2.5 eq) was added, and the mixture was stirred at room temperature for 1 h under nitrogen protection. The temperature was lowered to 0° C., sodium triacetoxyborohydride (318.8 mg, 1.24 mmol, 3.0 eq) was added in portions, and the mixture was stirred at room temperature overnight under nitrogen protection. TLC monitored the completion of the reaction, added saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), extracted with dichloromethane (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain solid 6-( 2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8-(4-nitro Phenethyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one (200 mg, yield: 80%).

Step 5: 8-(4-Aminophenethyl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3] Synthesis of heptan-6-yl)amino)pyrido[2,3- d ]pyrimidin-7( 8H )-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8-( ethyl 4-nitrophenyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (200mg, 0.338mmol, 1.0eq) was dissolved in methanol (10mL) was added saturated ammonium chloride solution ( 3mL), iron powder (378.9mg, 6.766mmol, 20eq) was added, and the temperature was heated and refluxed for 2h. The completion of the reaction was monitored by TLC, filtered while hot, the filter cake was rinsed with methanol, the filtrate was concentrated under reduced pressure to obtain a solid, which was slurried with dichloromethane (100 mL×3), filtered, and the filtrate was concentrated under reduced pressure to obtain 8-(4-aminophenethyl) )-6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)pyrido[ 2,3- d] pyrimidin -7 (8 H) - one (142mg, yield: 75%).

Step 6: N- (4-(2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptane- synthesis yl) ethyl) phenyl) acrylamide - a 6-yl) amino) -7-oxo-pyrido [2,3- d] pyrimidin--8 (7 H)

8-(4-Aminophenethyl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptane 6-yl) amino) pyrido [2,3- d] pyrimidin -7 (8 H) - one (142mg, 0.253mmol, 1.0eq) was dissolved in dichloromethane (5mL), the temperature was lowered to 0 deg.] C, dropwise Add allyl chloride (22.8 mg, 0.253 mmol, 1.0 eq), and stir at 0 °C for 2 h after the addition. The completion of the reaction was monitored by TLC, saturated sodium carbonate solution (10 mL) was added, stirred for 20 min, the layers were separated, the aqueous phase was extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative thin layer chromatography gave N- (4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[ 3.3] heptane-6-yl) amino) -7-oxo-pyrido [2,3- d] pyrimidin--8 (7 H) - yl) ethyl) phenyl) acrylamide (5mg, yield: 3%).

Molecular formula: C ₃₃ H ₃₅ ClN ₆ O ₄ Molecular weight: 615.13 LC-MS (Pos, m/z )=615.21 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.78 (s, 1H), 7.70-7.75 (s, 1H), 7.65-7.68 (d, 1H), 7.60 (s, 1H), 7.15-7.20 (m,2H),6.70-6.75(m,1H),6.50(m,1H),6.20-6.25(m,1H),5.73-5.75(m,1H),5.30(m,1H),4.30-4.45 (m,4H),4.25(m,1H),3.80-3.85(s,3H),3.75-3.78(s,3H),3.10(m,1H),2.80-2.85(s,3H),2.65-2.68 (m,2H), 2.20-2.50(m,1H), 1.90-2.00(m,2H), 1.40-1.45(m,2H).

Example 13: 1-(2-Propenyl-2-azaspiro[3.3]hept-6-yl)-7-amino-3-(2,6-dichloro-3,5-dimethoxy Synthesis of Phenyl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one (Compound 18)

Step 1: 6-(7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrimido[4,5- Synthesis of d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[ 4,5- d ]pyrimidin-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (169.8 mg, 0.21 mmol, 1.0 eq) was added to an aqueous amine solution ( 10 mL), heated at 60°C for 5 hours, TLC showed that the reaction was complete. The system was cooled to room temperature, extracted with dichloromethane (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (silica gel specification: 200-300 mesh, dichloromethane: Methanol=200:1~30:1) to obtain the product (59.2 mg, yield: 49.8%).

Step 2: 7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2-azaspiro[3.3]heptan-6-yl)-3, Synthesis of 4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride

6-(7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrimido[4,5- d ] Pyrimidine-1( 2H )-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester (59.2mg, 0.10mmol, 1.0eq) was added to ethanol (1mL), the system was cooled to At 0°C, ethanolic hydrogen chloride solution (2 mL) was added dropwise. After the dropping was completed, the temperature was raised to room temperature and stirred for 2 hours. TLC showed that the reaction was complete. The system was concentrated to obtain the product (57.2 mg crude product, yield: 100.0%).

Step 3: 1-(2-Propenyl-2-azaspiro[3.3]hept-6-yl)-7-amino-3-(2,6-dichloro-3,5-dimethoxybenzene yl)-3,4-dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one

7-amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2-azaspiro[3.3]heptan-6-yl)-3,4- Dihydropyrimido[4,5- d ]pyrimidin-2( 1H )-one hydrochloride (57.2 mg crude product, 0.10 mmol, 1.0 eq) was added to tetrahydrofuran (3 mL), cooled to 0 °C, followed by dropwise addition of three Ethylamine (37.3 mg, 0.36 mmol, 3.6 eq) and acryl chloride (13.6 mg, 0.13 mmol, 1.3 eq) were added dropwise, warmed to room temperature and stirred for 1 hour. TLC showed that the reaction was complete. Saturated aqueous ammonium chloride solution (10 mL) was added to the system, extracted with dichloromethane (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was purified by preparative thin layer chromatography (dichloromethane:methanol=30: 1) The product (1.8 mg, yield: 3.4%) was obtained.

Molecular formula: C ₂₃ H ₂₄ Cl ₂ N ₆ O ₄ Molecular weight: 519.38 LC-MS ( m/z )=520.08[M+H] ⁺ .

¹ HNMR (400MHz, DMSO- d ₆ ) δ(ppm): 7.72(s, 1H), 7.22(s, 1H), 6.99(m, 1H), 6.64-6.99(s, 1H), 6.21-6.30(m ,1H),6.04-6.08(m,1H),5.55-5.65(m,1H),5.31-5.33(m,1H),4.28-4.31(m,2H),4.15(m,1H),3.94-3.98 (s,6H),3.84-3.86(m,1H),2.63-2.66(m,2H),1.98-2.02(m,2H),0.83-0.86(m,2H).

Example 14: N- (4-(2-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3, Synthesis of 4-dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)ethyl)phenyl)acrylamide (Compound 19)

Step 1: Synthesis of 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester

4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (20.0g, 86.2mmol, 1.0eq), 2-(4-nitrophenyl)ethan-1-amine hydrochloride (20.9 g, 103.4mmol, 1.2eq) and triethylamine (26.2g, 258.6mmol, 3.0eq) were dissolved in tetrahydrofuran (200.0mL), stirred at room temperature for 2h, TLC showed that the reaction was complete. After filtration, the filtrate was concentrated under reduced pressure to obtain ethyl 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxylate (33.0 g) as a yellow solid, which was used directly in the next step.

Step 2: Synthesis of 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidin-5-yl)methanol

Lithium tetrahydroaluminum (4.9g, 129.3mmol, 1.5eq) was dissolved in tetrahydrofuran (200.0mL), and 2-(methylthio)-4-((4-nitrophenethyl) was slowly added dropwise at 0°C A solution of ethyl amino)pyrimidine-5-carboxylate (33.0 g) in tetrahydrofuran (100.0 mL) was stirred at 0° C. for 1 h, and TLC showed that the reaction was complete. Water (4.9 mL) was added under ice bath, stirred for 2 min, 10% aqueous sodium hydroxide solution (4.9 mL) was added under ice bath, stirred for 2 min, then water (15.0 mL) was added, stirred for 15 min, filtered through celite, and the filtrate was decompressed After concentration, the crude product was purified by silica gel column chromatography (DCM:MeOH=300:1~40:1) to obtain the product as a yellow solid (4.0 g, yield: 14.5%).

Step 3: Synthesis of 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carbaldehyde

2-(Methylthio)-4-((4-nitrophenethyl)amino)pyrimidin-5-yl)methanol (3.56g, 11.122mmol, 1.0eq) was dissolved in dichloromethane (70.0mL) and Manganese dioxide (7.74 g, 88.975 mmol, 8.0 eq) was added to a mixed solvent of tetrahydrofuran (10.0 mL), and the mixture was stirred at room temperature overnight. TLC detected that the reaction was complete, filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=300:1~150:1) to obtain a yellow solid product (2.78 g, yield: 78.1%) ).

Synthesis of (4-nitrophenyl) pyrimidin-4-amine - A 5 - (((3,5-dimethoxyphenyl) amino) methyl) -2- (methylthio) - N: Step 4

Dissolve 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carbaldehyde (2.78g, 8.732mmol, 1.0eq) in dichloromethane (50mL), add 3 , 5-Dimethoxyaniline (1.604g, 10.478mmol, 1.2eq) and sodium triacetoxyborohydride (4.627g, 21.830mmol, 2.5eq) were stirred at room temperature overnight. TLC detected the completion of the reaction, quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane (10.0 mL) three times, the organic phase was dried, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=250:1~100:1 ) was purified to obtain a yellow solid product (2.68 g, yield: 70%).

Step 5: 3-(3,5-Dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimido[4,5- Synthesis of d ]pyrimidin-2( 1H)-one

5 - (((3,5-dimethoxyphenyl) amino) methyl) -2- (methylthio) - N - (4- nitrophenyl) pyrimidin-4-amine (2.68g, 5.883mmol, 1.0eq) was dissolved in tetrahydrofuran (50.0mL), added triphosgene (1.89g, 6.471mmol, 1.1eq) at 0°C, stirred at room temperature for 1 h, cooled to 0°C, added triethylamine (1.79g, 17.649 g) mmol, 3.0eq), the temperature was raised to 70°C for 1.5h, and the reaction was complete as detected by TLC. The reaction solution was quenched by adding saturated ammonium chloride, extracted three times with ethyl acetate, washed with water, and washed with saturated sodium chloride solution, the organic phase was dried, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=300:1~ 200:1) was purified to obtain a white solid product (2.42 g, yield: 90.3%).

Step 6: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydro Synthesis of Pyrimido[4,5- d ]pyrimidin-2( 1H)-one

3-(3,5-Dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimido[4,5- d ] Pyrimidine-2( 1H )-one (500.0 mg, 1.038 mmol, 1.0 eq) was dissolved in dichloromethane (10.0 mL), cooled to 0 °C, and diluted with dichloromethane (2.0 mL). mg, 2.596mmol, 2.5eq), after the reaction for 15min, saturated sodium bicarbonate solution was added to quench, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, washed with methyl tert-butyl ether slurry to obtain a white solid as the product (478.0 mg, yield: 83.62%).

Step 7: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-1-(4-nitrophenyl)-3,4- Synthesis of Dihydropyrimido[4,5- d ]pyrimidin-2( 1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimido [4,5- d ]pyrimidin-2( 1H )-one (478.0 mg, 0.868 mmol, 1.0 eq) was dissolved in dichloromethane (15.0 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid ( 470.9mg, 1.910mmol, 2.2eq), reacted for 1h, TLC showed that the reaction was complete. Saturated sodium bicarbonate was added to quench, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=500:1~400:1) to give the product (360.0 mg, 360.0 mg, Yield: 75.7%).

Step 8: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(4-nitrophenyl)-3,4-dihydro Synthesis of Pyrimido[4,5- d ]pyrimidin-2( 1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-1-(4-nitrophenyl)-3,4-dihydro Pyrimido[4,5- d ]pyrimidin-2( 1H )-one (336.0mg, 0.6546mmol, 1.0eq), methylamine solution (286.7mg, 2.308mmol, 4.0eq) and triethylamine (350.3mg, 3.462mmol, 6.0eq) was dissolved in dioxane (5.0mL) and tetrahydrofuran (2.0mL), refluxed at 80°C for 3h, TLC showed that the reaction was complete. Water was added, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=300:1~200:1) to give the product (194.0 mg) as an off-white solid. , yield: 55.4%).

Step 9: 1-(4-Aminophenethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydro Synthesis of Pyrimido[4,5- d ]pyrimidin-2( 1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(4-nitrophenyl)-3,4-dihydropyrimido [4,5- d ]pyrimidin-2( 1H )-one (194.0mg, 0.364mmol, 1.0eq) was dissolved in ethanol (5.0mmol), iron powder (814.7mg, 14.549mmol, 40.0eq) and saturated chlorine were added Ammonium chloride solution (2.5 mL) was refluxed at 80 °C for 1.5 h. TLC showed that the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=300:1~200:1) to obtain the product (65.0 mg, yield: 33.5%).

Step 10: N- (4-(2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4 - Synthesis of Dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)ethyl)phenyl)acrylamidoamide

1-(4-Aminophenethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido [4,5- d ]pyrimidin-2( 1H )-one (20.0mg, 0.0377mmol, 1.0eq) was dissolved in tetrahydrofuran (1.0mL), triethylamine (11.4mg, 0.113mmol, 3.0eq) was added, 0 ℃ Add acryl chloride (5.1 mg, 0.0566 mmol, 1.5 eq), slowly warmed to room temperature, after 1 h TLC showed that the reaction was complete. Saturated sodium bicarbonate was added to quench, extracted three times with dichloromethane and three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (DCM:MeOH=90:1~50: 1) Purified white solid N- (4-(2-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo- 3,4-Dihydropyrimido[4,5- d ]pyrimidin-1( 2H )-yl)ethyl)phenyl)acrylamide (6.0 mg, yield: 30%).

Molecular formula: C ₂₆ H ₂₆ Cl ₂ N ₆ O ₄ Molecular weight: 557.43 LC-MS (Pos, m/z )=558.4[M+H] ⁺

¹ H NMR (400MHz, DMSO- d ₆ ) δ (ppm): 10.07(s, 1H), 7.99(s, 1H), 7.59-7.57(d, 2H), 7.20-7.18(d, 2H), 6.99(s) , 1H),6.46-6.39(m,1H),6.27-6.22(d,1H),5.76-5.73(d,1H),4.42(s,2H),4.14-4.13(m,2H),3.97(s ,6H),2.90-2.86(m,5H),2.02-1.99(m,1H).

Comparative Example 1: 8-(3-(4-Propenyloxazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2- (methylamino) pyrido [2,3- d] pyrimidin -7 (8 H) - -one (PRN1371, referred to as compound a)

Step 1: Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate

The raw material 2-(3,5-dimethoxyphenyl)acetic acid (50g, 0.26mol, 1.0eq) was dissolved in methanol (500mL), DMF (0.5mL) and thionite chloride (10mL) were added, room temperature After the reaction was completed for 12 hours, LC-MS detected that the reaction was complete, concentrated, added water, extracted twice with ethyl acetate, combined the organic phases, washed twice with saturated aqueous sodium bicarbonate solution, dried and concentrated to give a pale yellow oily product (53 g, Yield: 100%).

Step 2: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3- d ]pyrimidin-7( 8H )-one

Combine methyl 2-(3,5-dimethoxyphenyl)acetate (19.6g, 0.0931mol, 1.5eq) and 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (10.5g, 0.0621 mol, 1.0eq) was dissolved in NMP (20mL), potassium carbonate (17.1g, 0.124mol, 3.0eq) was added, the temperature was raised to 100°C and reacted for 12 hours, LC-MS detected the reaction was complete, the reaction solution was poured into water, acetic acid Extracted with ethyl ester, washed twice with saturated brine, combined the organic phases, dried and concentrated, the crude product was washed with ethyl acetate to obtain a white solid product (14.745 g, yield: 72%).

Step 3: Synthesis of 6-(3,5-Dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3- d ]pyrimidin-7( 8H )-one

6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [2,3- d] pyrimidin -7 (8 H) - one (4.0g, 0.0121mol, 1.0eq ) was dissolved in DMF (50mL), cooled to 0°C, added 70% m-chloroperoxybenzoic acid (3.5g, 0.0134mol, 1.1eq), reacted for 2 hours, LC-MS detected that the reaction was complete, and the reaction solution was directly used for next reaction.

Step 4: Synthesis of 6-(3,5-Dimethoxyphenyl)-2-(methylamino)pyrido[2,3- d ]pyrimidin-7( 8H )-one

6- (3,5-dimethoxyphenyl) -2- (methyl-sulfo acyl) pyrido [2,3- d] pyrimidin -7 (8 H) - one (4.178g, 0.0121mol, 1.0eq) was dissolved in methyl ammonia methanol solution (300mL), and after 12 hours at 50°C, LC-MS detected the reaction was complete, water (200mL) was added, stirred for 10min, filtered, and the filter cake was rinsed twice with dichloromethane , the product (2.75g, yield: 72.7%) was obtained after drying.

Step 5: 4-(3-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8( 7H )-yl)propyl)oxazine-1-carboxylate tert-butyl ester

6- (3,5-dimethoxyphenyl) -2- (methylamino) pyrido [2,3- d] pyrimidin -7 (8 H) - one (2.75g, 0.0088mol, 1.0eq ) and 4-(3-((methylsulfonyl)oxy)propyl)oxazine-1-carboxylate tert-butyl ester (4.256mg, 0.0132mol, 1.5eq) were mixed in DMF (50mL), added Potassium carbonate (3.645g, 0.0264mol, 3.0eq) was heated to 90°C and reacted for 3 hours. LC-MS detected that the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane, washed twice with saturated brine, and the organic phases were combined. It was dried and concentrated to give a pale yellow oily product (4.738 g, yield: 100%).

Step 5: 4-(3-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d Synthesis of tert-butyl ]pyrimidin-8( 7H )-yl)propyl)oxazine-1-carboxylate

4-(3-(6-(3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine-8( 7H )- (4.738g, 0.0088mol, 1.0eq) was dissolved in dichloromethane (100mL), cooled to 0°C, added with sulfonyl chloride (2.969g, 0.022mol, 2.5eq), react at room temperature for 2 hours. LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, washed twice with saturated brine, the organic phases were combined, dried, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain Product as pale yellow solid (5.432 g, yield: 100%). According to the theoretical amount, it is directly invested in the next reaction.

Step 6: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(oxazin-1-yl)propyl)pyridine Ipo[2,3- d ]pyrimidin-7( 8H )-one trifluoroacetate

4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3- d ]pyrimidine -8 (7 H) - yl) propyl) piperazine-1-carboxylate (5.346g, 0.0088mol, 1.0eq) was dissolved in dichloromethane (50mL), trifluoroacetic acid (50mL), at room temperature After 2 hours of reaction, LC-MS detected that the reaction was complete, and concentrated to obtain the product (4.465 g crude product), which was directly used in the next reaction according to the theoretical amount.

Step 7: 8-(3-(4-Propenyloxazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-( Synthesis of Methylamino)pyrido[2,3- d ]pyrimidin-7( 8H )-one

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(oxazin-1-yl)propyl)pyrido[ 2,3- d] pyrimidin -7 (8 H) - one trifluoroacetate in (4.465g, 0.0088mol, 1.0eq) was dissolved in tetrahydrofuran (50mL), was added in triethylamine (4.452g, 0.044mol, 5.0 eq), add acryl chloride (1.5g, 0.0088mol, 1.0eq) at 0°C, react at 0~5°C for 2h, monitor the completion of the reaction by LC-MS, pour the reaction solution into saturated aqueous sodium carbonate solution (50mL), stir for 20min After that, dichloromethane was added for extraction (100 mL×3), the organic phases were combined, dried, and concentrated. The crude product was first purified by silica gel column chromatography (MeOH:DCM=1:150), washed with methyl tert-butyl ether slurry, and extracted. The product was obtained by filtration as a yellow solid (600 mg, 3-step yield: 13%).

Molecular formula: C ₂₆ H ₃₀ Cl ₂ N ₆ O ₄ Molecular weight: 561.46 LC-MS (Pos, m/z )=561.11[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ(ppm): 8.618(s, 1H), 7.892(s, 1H), 7.675(s, 1H), 6.976(s, 1H), 6.732-6.800(m, 1H) ), 6.054-6.101(m, 1H), 5.633-5.665(m, 1H), 4.282-4.368(d, 2H), 3.951(s, 6H), 3.445-3.462(d, 4H), 2.910-2.921(d ,3H),2.301-2.389(d,6H),1.837(s,2H).

Compared with the prior art, the compound of the present invention has the following innovative points: ① The compound has stronger enzymatic inhibitory activity on each subtype of FGFR, and has better killing activity against cancer cells due to abnormal FGFR gene. ②The compound has stronger drugability in the in vitro and in vivo PK of animals and humans, which can ensure a better exposure in animals and humans after administration, which is beneficial to the manifestation of the anticancer effect of the drug. ③ The compound showed a better inhibitory effect on the animal pharmacodynamic model, so it is predicted that its clinical application effect in human body is better.

The present invention can be better understood from the following experimental examples. However, those with ordinary knowledge in the technical field to which this case belongs can easily understand that the contents described in the experimental examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the scope of the patent application.

Experimental Example 1 Cell activity test of the compounds of the present invention

Hep3B is abnormal FGFR cells in hepatocellular carcinoma, derived from ATCC

RT112/84 are bladder cancer cells with abnormal FGFR, derived from ECACC

SNU-16 is gastric cancer FGFR abnormal cells, derived from ATCC

Test substance: the compound of the present invention, the structure of which is shown above.

Test instrument: EnSpire ^TM or EnVision ^TM multifunctional microplate reader.

experiment method:

After the cells of each strain were inoculated in a 96-well plate and cultured overnight, different concentrations of compounds (12 dose groups, 3-fold gradient DMSO dilution) were added to make the final concentration 0.17-30000nM, and the final content of DMSO was 5‰(v /v). Negative control wells contain only 5‰ DMSO medium, and positive control wells contain cells and 5‰ DMSO medium. Incubate at 37°C, 5% CO ₂ , and 95% humidity for 72 h before testing. 30 μL of Cell titer-Glo ^TM reagent was added to each well, and after 30 min incubation at room temperature, the final chemiluminescence data was read by a microplate reader.

The cell viability inhibition rate was calculated according to the following formula:

Among them, the maximum luminescence value is obtained from the positive control well, the minimum luminescence value is obtained from the negative control well, and the IC50 value is obtained by XLFit regression, and the regression curve is fit=(A+((BA)/(1+((x/C)^D )))), where A is the minimum inhibition rate of the compound, B is the maximum inhibition rate of the compound, C is the IC50, and D is the slope.

The test results are shown in Table 2-3:

- means not tested.

From the results in Table 2-3, it can be seen that the compounds of the present invention have good inhibitory activity on the abnormal cell viability of FGFR such as Hep3B, RT112/84, SNU-16, etc., indicating that the compounds of the present invention can be used to treat the abnormal mediated by FGF/FGFR. Cancer such as liver cancer, stomach cancer, bladder cancer, has very good clinical value.

Experimental Example 2 Enzymatic activity test of the compounds of the present invention

The FAM-labeled polypeptide substrate P22 was derived from GL Biochem

Test substance: the compound of the present invention, the structure of which is shown above.

Test equipment: Caliper EZ Reader ^™ II drug screening platform was used.

experiment method:

1. Compound Plate Preparation

a) Set 10 dose groups of compounds on a 96-well plate, add DMSO to each well, and dilute with 3-fold gradient DMSO to obtain dilutions of each compound; the highest concentration of the compound is 500 μM; b) Each compound prepared in step a) The dilutions were transferred to 384-well plates and diluted with 1× Kinase Buffer (50 mM HEPES, Ph 7.5; 0.0015% Brij-35; 2 mM DTT) so that each well contained 5 μL of 5 μL dissolved in 10% DMSO (v/v). × Compound solution, resulting in a maximum final concentration of 10 μM. Negative control wells were 5 μL of 1X kinase buffer containing 10% DMSO.

2. Experimental steps

Add 10 μL of 2.5× enzyme solution to the 5× compound solution in step 1b). After reacting at room temperature for 10 min, add a total volume of 10 μL of FAM-labeled polypeptide substrate dissolved in 1× kinase buffer. After ATP started the reaction, 25 μL of stop solution (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) was added to stop the reaction after 30 minutes of incubation, and Caliper read the final data.

The test results are shown in Table 4:

- means not tested.

It can be seen from the experimental results in Table 4 that the compounds of the present invention have good inhibitory activity against FGFR, indicating that the compounds of the present invention have good clinical application potential in the treatment of diseases mediated by abnormal FGF/FGFR.

Experimental Example 3 Pharmacokinetic evaluation of the compounds of the present invention in mice 1. Purpose:

The pharmacokinetic parameters of the compounds of the present invention in BalbC female nude mice (Nanjing University-Nanjing Institute of Biomedicine) were evaluated, and their bioavailability was investigated.

2. Animal administration and sample collection:

Compound 9 was dispersed in 0.5% CMC-Na aqueous solution (containing 0.5% Tween-80) to prepare a suspension. The suspension of compound 9 was administered to BalbC nude mice (9 mice in total, divided into 3) at a dose of 10.0 mg/kg. group, 3 mice in each group) administered by gavage (suspension of compound 9), blood collection time points were after administration: 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, 30h.

Compound 9 was treated with dimethylacetamide (DMA): polyoxyethylene castor oil (EL): 10% hydroxypropyl-β-cyclodextrin (HP-β-CD) saline: 1M HCl=5:5 : 89.5: 0.5 (v/v/v/v) solution was prepared by dissolving, and the solution of compound 9 was administered to BalbC nude mice (9 mice in total, divided into 3 groups, 3 mice in each group) at a dose of 4.0 mg/kg by bolus injection Administration, blood collection time points are after administration (3 time points for each animal): 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h.

About 100 μL of blood was collected through the retro-orbital venous plexus, and placed in an anticoagulant tube _{containing EDTA-K 2 after blood collection.} Blood samples were centrifuged at 8000 rpm for 6 min at 4 °C to obtain plasma samples. Plasma must be prepared within 30 min after blood collection, and stored in -80 °C refrigerator before testing.

3. Sample analysis method:

The samples to be tested from 9 individual mice were taken out from the -80°C refrigerator, thawed at room temperature and vortexed for 5 min; 10 μL plasma samples of different individual mice at each time point were accurately drawn into 1.5 mL centrifuge tubes (precisely Aspirate 30 μL of standard curve plasma); add 200 μL of methanol solution of tolbutamide (internal standard working solution) with a concentration of 100 ng/mL, and mix well; after vortexing for 5 min, centrifuge at 12000 rpm for 5 min; In a 96-well plate with 150 μL/well of water; vortex and mix for 5 min, and perform LC-MS/MS measurement, and the injection volume is 10 μL.

4. Data processing method:

Compound concentrations were output using AB's Analyst 1.6.3. Microsoft Excel calculates parameters such as mean, standard deviation, coefficient of variation (the direct output of Analyst 1.6.3 does not need to be calculated), and the pharmacokinetic parameters are calculated using Pharsight Phoenix 6.1 software NCA.

The results are shown in Table 5:

Note T _max po : time to peak, AUC _inf iv/po: area under the drug-time curve, F%: bioavailability

Conclusion : The compounds of the present invention have good in vivo exposure and bioavailability.

Experimental Example 4 Evaluation of the stability of human liver microsomes of the compounds of the present invention

Objective: To evaluate the human liver microsomal stability of the compounds of the present invention.

experiment procedure:

(1) Take out liver microsomes (20 mg protein/mL) from the -80°C refrigerator, place them on a 37°C water bath constant temperature shaker for pre-incubation for 3 minutes, and thaw them for use.

(2). According to the ratio of "Constitution of the experimental incubation system" above, prepare the mixed solution of the incubation system (without compound and β-NADPH), and place it on a 37°C water bath constant temperature shaker for pre-incubation for 2 minutes.

(3). Control group (without β-NADPH): add 30 μL of water and 30 μL of compound working solution (10 μM) to 240 μL of the incubation system mixture described in step (2), vortex for 30 s, mix well, and react The total volume was 300 μL, and the sample was repeated. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing. The sampling time points are 0min and 60min.

(4). Sample group: 70 μL of β-NADPH solution (10 mM) and 70 μL of compound working solution (10 μM) were added to 560 μL of the mixed solution described in step (2). hole. Put it into a 37°C water bath constant temperature oscillator for incubation, and start timing. The sampling time points are 0min, 5min, 10min, 20min, 30min, and 60min after the timing.

(5). After vortexing for 3min, centrifuge at 12000rpm for 5min.

(6). Take 50 μL of the supernatant and add 150 μL of water, vortex to mix well, and analyze by LC/MS/MS.

ANALYSE information:

_{Half-life (t 1/2} ) and clearance (Cl) were calculated using the following first-order kinetic equations:

Ct=C0 * e ^-kt

t _1/2 =ln2/k=0.693/k

Cl _int =Vd * k

Vd=1/protein content in liver microsomes

Note: k is the slope of the plot of the logarithm of the remaining amount of the compound versus time, and Vd is the apparent volume of distribution.

The results are shown in Table 7:

Note: R ² : coefficient of determination; t _1/2 : elimination half-life; Cl _int : intrinsic clearance rate; E _h : liver extraction rate.

From the above results, it can be seen that our compound has a lower clearance rate in human liver microsomes than Compound A disclosed in the prior art.

Experimental Example 5 Canine plasma stability evaluation of the compounds of the present invention

Objective: To evaluate the stability of the compounds of the present invention in canine plasma.

Working solution preparation:

Test substance: take about 2 mg of the compound, first prepare a 5 mM stock solution with DMSO, then dilute it with DMSO to a 1 mM solution, and finally dilute with water to a 50 μM working solution of the tested compound, ready for use.

Stop solution: take about 2 mg of the compound tolbutamide, first prepare a 1 mg/mL stock solution with DMSO, and finally dilute it with acetonitrile to a 100 ng/mL stop solution, and store at 4°C until use.

experiment procedure:

1). The frozen Beagle dog plasma (purchased from Reed Liver Disease Research (Shanghai) Co., Ltd.) was pre-cultured and thawed in a 37°C water bath constant temperature shaker for use.

2). Take 10 μL of the test compound working solution (50 μM) and add it to 490 μL of Beagle dog plasma, the final concentration of the test compound is 1 μM, and two duplicate samples are obtained.

3). Vortex to mix well, and place in a 37°C water bath constant temperature shaker for incubation.

4). At the corresponding time points (T=0h, 0.5h, 1h, 2h, 4h; 0h samples are not incubated), take 40μL of the reaction solution, add 400μL of stop solution (100ng/mL of tolbutamide acetonitrile) solution), mix well and store at -80°C. .

6). After the culture experiment is completed, thaw the sample tubes at each time point, mix well, and centrifuge at 12000 rpm in a 4°C centrifuge for 5 minutes. .

7). Take a 96-well sample plate and add 150 μL of water, take 50 μL of the supernatant after centrifugation in step 6) into the sample well, mix well, and then perform sample injection analysis.

ANALYSE information:

The stability of the compound in plasma was evaluated by the retention percentage of the compound after incubation at each time point, and the concentration of the sample was expressed as the ratio of the peak area of the test compound to the peak area of the internal standard.

The calculation formula is as follows: retention rate (%)=C _Tn /C _T0

Wherein, C _Tn is the measured concentration of the compound in the final solution after each incubation time point, n=0.5h, 1h, 2h, 4h; C _T0 is the measured concentration of the compound in the final solution during the initial incubation.

The results are shown in Table 8:

Conclusion: From the above results it can be seen that our compound has better canine plasma stability than Compound A disclosed in the prior art

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the present invention. within the scope of protection.

Claims (21)

A fibroblast growth factor receptor (FGFR) irreversible inhibitor compound represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof,

Among them, warhead ₁ and warhead ₂ do not exist at the same time; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead ₂ does not exist, warhead _{1 is} selected from

, R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, when t and p are respectively 0, Cy ₁ and R _{2 are} selected from the following groups: (i) when Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 7-12 membered heterocyclyl spiro, ring carbon atoms may optionally be oxidized to C (O), a sulfur ring atom may optionally be oxidized When it is S(O), S(O) ₂ or S(O)(N), n is 0, and R _{2 is} selected from hydrogen, C _1-6 alkyl, C _2-8 alkenyl, C _2-8 alkyne group, halogenated C _1-6 alkyl or -(L ₃ )q-Cy ₃ , q is 0 or 1, Cy _{3 is} selected from 3-12 membered rings substituted with one to more R _{b , or unsubstituted} Alkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, aryl or 5-10-membered heteroaryl, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S (O), S (O ) 2 or S (O) (N); (ii) when Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 3-8 membered monocyclic heteroaryl Divalent radicals of cyclic or aryl groups, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S(O), S(O) ₂ or S(O) (N), n is 0 or 1, R ₂ is -(L ₃ )q-Cy ₃ , q is 0 or 1, Cy ₃ is a 7-12 member substituted with one or _{more R b or unsubstituted} Spiroheterocyclyl, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S(O), S(O) ₂ or S(O)(N); When warhead ₁ does not exist, warhead _{2 is} selected from

or

, R ₁ is hydrogen or C _1-6 alkyl, R ₂ is -(L ₃ )q-Cy ₃ -, q is 0, Cy ₃ is substituted by one or more R _b , or unsubstituted 3- 8-membered monoheterocyclic group; R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are each independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl; Cy ₄ is a divalent group selected from the following groups: 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, aryl or 5-10-membered heteroaryl; z is 0 An integer of -4; R _a , R _b are independently selected from: (i) hydrogen; (ii) hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-6 alkenylcarbonylamino or =CH ₂ ; (iii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C _{1- 6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl group, C _2-8 alkynyl group, C _1-6 alkylsulfonyl group or C _1-6 alkylthio group, the 3-8 membered heterocyclic group may be optionally replaced by hydroxyl, amino , carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl) ₂ amino substituted; (iv) any optionally substituted by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl) ₂ amino or (v) amino-carbonyl, cyano-carbonyl, C _1-6 alkyl-carbonyl, C _{1- 6} alkylamino-carbonyl, (C _1-6 alkyl) ₂ amino-carbonyl, C _1-6 alkoxy-carbonyl, 3-8 membered cycloalkyl-carbonyl or 3-8 membered heterocyclyl-carbonyl; R _{3 is} selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, (C _1-6 alkyl) ₂ amino C _1-6 alkyl, halogenated C _1-6 Alkyl, halogenated C _2-8 alkenyl, C _2-8 alkynyl, or 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heteroalkyl optionally substituted by substituent Q ₁ A cyclic group, an aryl group or a 5-10-membered heteroaryl group, the substituent Q _{1 is} selected from: hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, sulfamoyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy base, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkyl sulfonyl base, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkyl Sulfamoyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy C _1-6 alkoxy; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano, nitro, Halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, Halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonyl Amino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylaminosulfonyl, (C _{1- 6} alkyl) ₂ aminosulfonyl, C _1-6 alkoxy C _1-6 alkoxy, or 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl optionally substituted by substituent Q ₂ , 3-12-membered heterocyclic group, aryl group or 5-10-membered heteroaryl group, the substituent is selected from: hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl acyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halogeno C _{1 -6} alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino , C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _{1- 6} alkoxy C _1-6 alkoxy; alternatively, two adjacent R ₄ together with the atoms to which they are attached respectively form 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered hetero Cyclic group, aryl group or 5-6 membered heteroaryl group; L ₁ and L ₃ are each independently a bond, -N(Rc)-, -O-, -S-, -S(O)-, -S( O) ₂ -, -S(O) ₂ NH-, -C(O)-, -NHC(O)-, -OC(O)-, C _1-6 alkylene, C _2-8 alkenylene or C _2-8 alkynylene, Rc is selected from hydrogen or C _1-6 alkyl; m is an integer of 0-5, when m

2, R ₄ may be selected from the same group or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by general formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead ₂ does not exist, warhead _{1 is} selected from

, R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, when t and p are respectively 0, Cy ₁ and R _{2 are} selected from the following groups: (i) When Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 7-12 membered heterocyclyl spiro, ring carbon atoms may optionally be oxidized to C (O), a sulfur ring atom may optionally be oxidized When it is S(O) or S(O) ₂ , n is 0, and R _{2 is} selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or -(L ₃ )q-Cy ₃ , q is 0 or 1, Cy _{3 is} selected from 3-8-membered monoheterocyclyl, 6-11-membered bridged heterocyclyl, 7-12-membered spiroheterocyclyl or unsubstituted substituted with one to more R _b 6-11-membered heterocyclic group, aryl group or 5-10-membered heteroaryl group, the ring carbon atom can be optionally oxidized to C(O), and the ring sulfur atom can be optionally oxidized to S(O) or S(O) ₂ ; (ii) when Cy ₁ is a divalent group substituted with one or more R _a , or an unsubstituted 3-8-membered monoheterocyclic group or an aryl group, the ring carbon atom can be any It is optionally oxidized to C(O), and the ring-forming sulfur atom can be optionally oxidized to S(O) or S(O) ₂ , n is 0 or 1, and R ₂ is -(L ₃ )q-Cy ₃ , q is 0 or 1, Cy ₃ is a 7-12-membered spiro heterocyclic group substituted by one to more R _b , or unsubstituted, the ring carbon atom can be optionally oxidized to C(O), forming a ring The sulfur atom can be optionally oxidized to S(O) or S(O) ₂ ; when warhead ₁ is absent, warhead _{2 is} selected from

or

, R ₁ is hydrogen or C _1-6 alkyl, R ₂ is -(L ₃ )q-Cy ₃ -, q is 0, Cy ₃ is substituted by one or more R _b , or unsubstituted 3- 8-membered monoheterocyclic group; R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are each independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl; Cy ₄ is a divalent group selected from the following groups: 3-12-membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocyclyl, aryl or 5-10-membered heteroaryl; z is 0 An integer of -4; R _a , R _b are independently selected from: (i) hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-8 alkenylcarbonylamino or =CH ₂ , (ii) ) optionally substituted with hydroxyl, amino, carboxyl, cyano, nitro, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _{1- 6} alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, C _{1-6 alkylsulfonylamino or C 1-6} alkyl substituted by 3-8 membered heterocyclyl , C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _{2- 8} alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl or C _1-6 alkylthio, (iii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl) ₂ amino substituted 3-8 membered cycloalkyl or 3-8 membered heterocyclyl , or (iv) amino-carbonyl, cyano-carbonyl, C _1-6 alkyl-carbonyl, C _1-6 alkylamino-carbonyl, (C _1-6 alkyl) ₂ amino-carbonyl, C _1-6 Alkoxy-carbonyl, 3-8-membered cycloalkyl-carbonyl or 3-8-membered heterocyclyl-carbonyl; R _{3 is} selected from hydrogen or C _1-6 alkyl; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano base, nitro, halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkane yl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl groups, C _{1 -6} alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylaminosulfonyl , (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy C _1-6 alkoxy; L ₁ , L ₃ are each independently a bond, -N(R _c )-, - O-, -S-, -S(O)-, -S(O) ₂ -, -C(O)-, -NHC(O)-, -OC(O)- or C _1-6 alkylene , R _{c is} selected from hydrogen or C _1-6 alkylene; m is Integer from 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by general formula (I) according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead ₂ does not exist, warhead _{1 is} selected from

, R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, when t and p are respectively 0, Cy ₁ and R _{2 are} selected from the following groups: (i) when When Cy ₁ is a 7-12-membered spiroheterocyclic group substituted by one or more R _a , or unsubstituted, n is 0, and R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q -Cy ₃ , q is 0 or 1, Cy _{3 is} selected from 3-8-membered mono-heterocyclic group, 6-11-membered bridged heterocyclic group, 7-12-membered heterocyclic group substituted with one to more R _{b , or unsubstituted} Spiroheterocyclyl, 6-11-membered heterocyclyl; (ii) When Cy ₁ is a divalent group substituted with one to more R _a , or an unsubstituted 3-8-membered monoheterocyclyl, n is 0 or 1, R ₂ is -(L ₃ )q-Cy ₃ , q is 0 or 1, Cy ₃ is 7-12-membered spiroheterocyclyl substituted with one to more R _{b , or unsubstituted; when} warhead ₁ does not exist, warhead _{2 is} selected from

or

, R ₁ is hydrogen or C _1-4 alkyl, R ₂ is -(L ₃ )q-Cy ₃ -, q is 0, Cy ₃ is substituted by one or more R _b , or unsubstituted 3- 8-membered monoheterocyclic group; R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; R _a , R _b are independently selected from: (i) hydrogen, hydroxyl, amino, cyano or halogen, or (II) C _1-4 alkyl, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, hydroxy C _1-4 alkyl, cyano C _1-4 alkyl group or halogenated C _1-4 alkyl; L ₁ and L ₃ are each independently a bond or C _1-4 alkylene; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen , C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; when warhead ₂ does not exist, warhead _{1 is} selected from

, R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, when t and p are respectively 0, Cy ₁ and R _{2 are} selected from the following groups: (i) when Cy ₁ is selected from divalent group structure: by one to the plurality of R _a substituted or unsubstituted

or

, n is 0, R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ , q is 0 or 1, Cy ₃ is a monovalent group selected from the following structures: R _b substituted, or unsubstituted

(ii) when Cy ₁ is selected from divalent group structure: substituted by one to the plurality of R _a, or unsubstituted

or

, n is 0 or 1, R ₂ is -(L ₃ )q-Cy ₃ , q is 0 or 1, and Cy ₃ is a monovalent group selected from the following structures: _{substituted with one or more R b} , or not substituted

or

When warhead ₁ does not exist, warhead _{2 is} selected from

or

, R ₁ is hydrogen or C _1-4 alkyl, R ₂ is -(L ₃ )q-Cy ₃ -, q is 0, and Cy ₃ is a divalent group selected from the following structures: through one or more R _a substituted, or unsubstituted

or

R ₁₂ , R ₁₃ and R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; R _a and R _b are independently selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl; L ₁ and L ₃ are each independently a bond or C _1-4 alkylene; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen atom, C _1-4 alkyl or C _{1- 4} alkoxy; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein warhead ₁ is

, warhead ₂ does not exist; R ₁₂ and R ₁₃ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R ₁ is _{- (L 1) n -Cy 1} -; Cy 1 is by one to the plurality of R _a substituted or unsubstituted 7-12-membered spiro-heterocyclic group; n is 0; R _{a is} selected from hydrogen or C _1-4 alkyl; R _{2 is} selected from hydrogen or C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 Alkyl or C _1-4 alkoxy; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the aforementioned spiroheterocycle The base is an N-containing spiroheterocyclic group, and warhead _{1 is} connected to any ring-forming N heteroatom in _{Cy 1.} The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Cy ₁ has the following structure divalent group: substituted by one to the plurality of R _a, or unsubstituted

or

, warhead _{1 is} connected to any ring-forming N heteroatom in _{Cy 1.} The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said fibroblast The cell growth factor receptor irreversible inhibitor compound is represented by the general formula (IA),

Among them, warhead _{1 is} selected from

or

R ₁₂ , R ₁₃ and R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; t and p are respectively 0; when Cy ₁ is substituted by one to more R _a , or an unsubstituted 7-12 member spiroheterocyclic group, n is 0, and R _{2 is} selected from hydrogen, C _1-4 alkyl, halogenated C _1-4 alkyl or -(L ₃ )q-Cy ₃ , Cy _{3 is} selected from substituted with one to more R _b , or unsubstituted 3-8 membered monoheterocycle groups, 6-11 membered bridged heterocyclyl, spiro heterocyclyl or 7-12 membered and 6-11 membered heterocyclic group; and when Cy ₁ is by one to the plurality of R _a substituted or unsubstituted 3-8 membered When a divalent group of a monoheterocyclic group, n is 0 or 1, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is substituted by one or more R _b , or an unsubstituted 7-12 membered spiro Heterocyclyl; R _a , R _b are independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-4 alkenylcarbonylamino, =CH ₂ or optionally by hydroxyl, amino, carboxyl, cyano, nitro, halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _{1 -4} alkyl) ₂ amino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonyl amino, or 3-8 membered heterocyclic group-substituted C _1-4 alkyl, C _1-4 alkoxy , C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 Alkynyl, C _1-4 alkylsulfonyl or C _1-4 alkylthio; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano, nitro , halogen, carboxyl, amido, aminocarbonyl, aminosulfonyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino , halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl sulfonyl, C _1-4 alkyl Carbonylamino, (C _1-4 alkyl) ₂ carbonylamino, C _1-4 alkylaminocarbonyl, (C _1-4 alkyl) ₂ aminocarbonyl, C _1-4 alkylaminosulfonyl, (C _{1 -4} alkyl) ₂ aminosulfonyl or C _1-4 alkoxy C _1-4 alkoxy; L ₁ and L ₃ are each independently a bond, -N(R _c )-, -O-, - S- or C _1-4 alkylene, R _{c is} selected from hydrogen or C _1-4 alkyl; q is 0 or 1; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by general formula (I) according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein warhead _{1 is} selected from

R ₁₂ , R ₁₃ and R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; t and p are respectively 0; when Cy ₁ is a divalent group substituted with one to more R _a , or an unsubstituted 7-12-membered nitrogen-containing spiroheterocyclic group, n is 0, R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ; when Cy ₁ is substituted by one to more R _a , or unsubstituted 3-8-membered nitrogen-containing monoheterocyclic group When the divalent group of , n is 0 or 1, R ₂ is -(L ₃ )q-Cy ₃ ; Cy ₃ is substituted by one to more R _b , or unsubstituted 7-12 membered spiro heterocyclyl ; R _a , R _b , R ₃ are independently selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; L ₁ , L ₃ are each independently a bond or C _1-4 alkylene; q is 0 or 1; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein warhead _{1 is} selected from

or

R ₁₂ , R ₁₃ and R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; t and p are respectively 0; when Cy ₁ is a divalent group selected from the following structures: _{substituted with one to more R a} , or unsubstituted

or

n is 0, R ₂ is selected from hydrogen, C _1-4 alkyl or _{- (L 3) q-Cy} 3; Cy ₁ when the structure is selected from a divalent radical: by one to the plurality of R _a substituents, or unsubstituted

or

When n is 0 or 1, R ₂ is -(L ₃ )q-Cy ₃ ; Cy ₃ is a 7-12-membered spiro heterocyclic group substituted with one to more R _{b s, or unsubstituted; R a} , R _b , R ₃ are independently selected from hydrogen, C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; L ₁ , L ₃ are independently is a bond or C _1-4 alkylene; q is 0 or 1; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein warhead ₁ is

R _12, R ₁₃ are each independently selected from hydrogen or C _1-4 alkyl; Cy ₁ is a divalent group of the structure: substituted by one to the plurality of R _a, or unsubstituted

or

, warhead _{1 is} connected _{to any ring-forming N heteroatom in Cy 1} ; t and p are respectively 0; n is 0; R _{a is} selected from hydrogen or C _1-4 alkyl; R _{2 is} selected from hydrogen or C _1-4 Alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein warhead ₁ is

or

R _12, R _13, R ₁₄ are each independently selected from hydrogen or C _1-4 alkyl; Cy ₁ is a divalent group of the structure: substituted by one to the plurality of R _a, or unsubstituted

or

, warhead _{1 is} connected _{to any ring-forming N heteroatom in Cy 1} ; t and p are 0 respectively; R ₂ is -(L ₃ )q-Cy ₃ ; Cy ₃ is a monovalent group of the following structure: through one to more R _b substituted, or unsubstituted

or

n and q are independently 0 or 1; R _a and R _b are independently selected from hydrogen or C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, halogen , C _1-4 alkyl or C _1-4 alkoxy; L ₁ and L ₃ are each independently a bond, C _1-4 alkyl; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said fibroblast The cell growth factor receptor irreversible inhibitor compound is represented by the general formula (IB),

Among them, warhead _{2 is} selected from

or

R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R _{1 is} selected from hydrogen or C _1-4 alkyl; Cy ₃ is substituted by one to more R _b , or an unsubstituted 3-8-membered monoheterocyclic group; R _{b is} selected from: ( i) hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _2-4 alkenylcarbonylamino or =CH ₂ ; (ii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, C _1-4 alkylcarbonylamino, _C1-4 alkylsulfonylamino or 3-8 membered heterocyclic substituted _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl Sulfonyl or C _1-4 alkylthio; (iii) optionally by hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _{1 -4} alkylamino or (C _1-4 alkyl) ₂ amino substituted 3-8 membered cycloalkyl or 3-8 membered heterocyclyl; or (iv) amino-carbonyl, cyano-carbonyl, C _{1- 4} alkyl-carbonyl, C _1-4 alkylamino-carbonyl, (C _1-4 alkyl) ₂ amino-carbonyl, C _1-4 alkoxy-carbonyl, 3-8 membered cycloalkyl-carbonyl or 3 -8-membered heterocyclyl-carbonyl; R _{3 is} selected from hydrogen or C _1-4 alkyl; R _{4 is} selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen, carboxyl, amido, aminocarbonyl, amino sulfo acyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkylsulfonyl, C _1-4 alkylcarbonylamino, (C _1-4 alkyl) ₂ carbonyl Amino, C _1-4 alkylaminocarbonyl, (C ₁₄ alkyl) ₂ aminocarbonyl, C _1-4 alkylaminosulfonyl, (C _1-4 alkyl) ₂ aminosulfonyl or C _1-4 Alkoxy C _1-4 alkoxy; L ₃ is a bond, -N(R _c )-, -O-, -S- or C _1-4 alkyl, respectively, R _{c is} selected from hydrogen or C _1-4 Alkyl; q is 0; m is an integer from 0 to 5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by the general formula (I) according to claim 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein warhead ₂ is

R ₁₂ and R ₁₃ are independently selected from hydrogen or C _1-4 alkyl; X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single bond; R _{1 is} selected from hydrogen or C _1-4 alkyl; Cy ₃ is a divalent group of the following structure: _{substituted with one to more R b} , or unsubstituted

or

, warhead _{2 is} connected to any ring-forming N heteroatom in _{Cy 3 ; q is 0; R b is} selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl; R _{3 is} selected from hydrogen or C _1-4 Alkyl; R _{4 is} selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; m is an integer of 0-5, when m

2, R ₄ can be selected from the same or different groups. The irreversible inhibitor compound of fibroblast growth factor receptor (FGFR) represented by general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein , the aforementioned fibroblast growth factor receptor irreversible inhibitor compound is selected from the compounds of the following structures,

A pharmaceutical preparation, comprising the fibroblast growth factor receptor (FGFR) irreversible inhibitor compound represented by the general formula (I) described in any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer thereof Construct. The pharmaceutical preparation according to claim 16, wherein the aforementioned pharmaceutical preparation comprises one or more pharmaceutically acceptable carriers. The pharmaceutical preparation according to claim 16 or 17, wherein the aforementioned drug The formulation contains one or more second therapeutically active agents, the aforementioned second therapeutically active agents are antimetabolites, growth factor inhibitors, filamentous classification inhibitors, antineoplastic hormones, alkylating agents, metals, topoisomerases Inhibitors, hormone drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints or antibodies and small molecule drugs related to tumor immunotherapy. A fibroblast growth factor receptor (FGFR) irreversible inhibitor compound represented by general formula (I) described in any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof in preparation The use of medicines for the treatment of diseases mediated by abnormal FGF/FGFR. An application of the pharmaceutical preparation described in claim 16 in the preparation of a medicament for treating a disease mediated by abnormal FGF/FGFR. The application according to claim 19 or 20, wherein the disease mediated by abnormal FGF/FGFR is cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, Breast duct cancer, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, primary cancer, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma tumor, colorectal villous adenoma, melanoma, cell tumor and sarcoma and/or myelodysplastic syndrome.