CN115433190A

CN115433190A - Preparation method and application of irreversible heterocyclic compound FGFR inhibitor

Info

Publication number: CN115433190A
Application number: CN202110615730.2A
Authority: CN
Inventors: 梁永宏; 许志勇; 严文广
Original assignee: Yaoya Technology Shanghai Co ltd
Current assignee: Yaoya Technology Shanghai Co ltd
Priority date: 2021-06-02
Filing date: 2021-06-02
Publication date: 2022-12-06

Abstract

The invention discloses a preparation method and application of an irreversible heterocyclic compound FGFR inhibitor, and particularly relates to a compound shown in a general formula (I) and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound and/or the pharmaceutically acceptable salt thereofAnd the application of the compound or the pharmaceutically acceptable salt in the preparation of medicines for treating or preventing FGFR kinase related diseases, in particular tumors, wherein each substituent in the general formula (I) is defined as the specification.

Description

Preparation method and application of irreversible heterocyclic compound FGFR inhibitor

The technical field is as follows:

the present invention relates to irreversible heterocyclic compound FGFR inhibitors or pharmaceutically acceptable salts thereof; a pharmaceutical composition containing the irreversible heterocyclic compound or a pharmaceutically acceptable salt thereof; a process for producing the irreversible heterocyclic compound or a pharmaceutically acceptable salt thereof; the application of the irreversible heterocyclic compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the irreversible heterocyclic compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing FGFR related symptoms, particularly tumors.

Background art:

fibroblast Growth Factor Receptors (FGFR) are a class of Receptor Tyrosine Kinases (RTK), and the FGFR family mainly comprises four subtypes of FGFR1-, FGFR2, FGFR3 and FGFR 4. FGFR1 is a transmembrane protein belonging to the receptor tyrosine kinase, consisting of three major components: namely an extracellular domain, a transmembrane domain and a cell domain, the extracellular domain is a binding domain of the ligand Fibroblast Growth Factors (FGFs). FGFs are also a polygene family, and there are 19 members, namely FGF1, also known as acidic fibroblast growth factor (aFGF), and FGF2, also known as basic fibroblast growth-related document factor (basic FGF, bFGF), which have biological activities of stimulating the growth of fibroblasts, vascular endothelial cells, smooth muscle cells and nerve cells.

However, when FGFR is mutated or overexpressed, it causes excessive activation of FGFR signaling pathway and further induces canceration of normal cells. Wherein, over-activation of RAS-RAF-MAPK stimulates cell proliferation and differentiation; over-activation of PI3K-AKT results in inhibition of apoptosis; SATA is closely related to promoting tumor invasion and metastasis and enhancing tumor immune escape capability; the PLC gamma signal channel is an important way for regulating and controlling the metastasis of tumor cells. Next Generation Sequencing (NGS) on 4853 solid tumor-type according to a study published in Clinical cancer 2015 showed that FGFR aberrations (abortions) and abnormal activation were found in approximately 7.1% of cancers, with most of this being gene amplification (66%), followed by mutations (26%) and rearrangements (8%). FGFR distortion exists in almost all detected malignant tumors, and the abnormal activation of FGFR is also found in the tumors with high incidence rate, such as urinary non-small cell lung cancer, esophageal cancer, melanoma, gastric cancer, multiple myeloma, liver cancer, cholangiocarcinoma, prostatic cancer, skin cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, breast cancer, colon cancer, glioma, rhabdomyosarcoma and the like.

There are several non-FGFR specific drugs on the market today, such as Sunitinib from pfizer, lentitini from Eisai, and nintedanib from Boehringer Ingelheimr. Whereas the only FGFR inhibitors approved by the FDA to be marketed are Balversa (Erdafitinib) and Pemazyre (pemigatinib). Small molecule inhibitors of FGFR1/2/3 entering clinic are: infigrtinib (BGJ 398) and AZD4547, fisogatinib (BLU-554), roblitiniib (FGF 401), H3B6527, lucitanib (E-3810), futibatinib (TAS-120), RPN1371, ICP-192, derazatinib, 3D185, BPI-17509, HMPL-453.

Although the development of FGFR inhibitors has attracted the deployment of numerous companies both at home and abroad, and although 2 FGFR inhibitors are already on the market, there is still a need to develop new compounds due to the prospects they show in the treatment of various malignancies. Through continuous efforts, the invention designs an irreversible inhibitor which has proprietary intellectual property rights and shows excellent activity on FGFR-1-4 protein kinase.

Disclosure of Invention

In order to solve the above problems, the present invention provides a novel FGFR tyrosine kinase inhibitor compound represented by formula (I) or a stereoisomer, stable isotope derivative, hydrate, solvate, or pharmaceutically acceptable salt thereof:

wherein:

ring Ar is a 5-10 membered heteroaromatic ring wherein the 5-10 membered heteroaromatic ring is optionally substituted with one or more G ¹ Substituted;

R ¹ independently selected from 5-14 membered heteroaromatic rings and 5-14 membered aromatic rings containing 1-3 heteroatoms selected from S, O, N and Se, said 5-14 membered heteroaromatic rings and 5-14 membered aromatic rings being interrupted by one or more G ² Substituted;

u is independently selected from-C _0-4 Alkyl radicals-, -CR ⁷ R ⁸ -、-C _1-2 Alkyl (R) ⁷ )(OH)-、-C(O)-、-CR ⁷ R ⁸ O-、-OCR ⁷ R ⁸ -、-SCR ⁷ R ⁸ -、-CR ⁷ R ⁸ S-、-NR ⁷ -、-NR ⁷ C(O)-、-C(O)NR ⁷ -、-NR ⁷ C(O)NR ⁸ -、-CF ₂ -、-O-、-S-、-S(O) _m -、-NR ⁷ S(O) ₂ -、-S(O) ₂ NR ⁷ -；

Y is absent or C is selected _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiro cyclic, aromatic or heteroaromatic, wherein said cycloalkyl, heterocycloalkyl, spiro cyclic, fused heterocyclyl, spiro heterocyclic, aromatic or heteroaromatic is optionally substituted with one or more G ³ Substituted;

z is independently selected from cyano, -NR ⁹ CN、

Bond a is a double or triple bond;

when a is a double bond, R ^a 、R ^b And R ^c Each independently selected from H, D, cyano, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl. Wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1 or more G ⁴ Substituted;

R ^a and R ^b Or R ^b And R ^c Optionally taken together with the carbon atom to which they are attached to form a 3-6 membered ring optionally containing heteroatoms; when the bond a is a triple bond, R ^a And R ^c Is absent, R ^b Independently selected from H, D, cyano, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl by one or more G ⁵ Substituted;

R ⁹ independently selected from H, D, C _1-6 Alkyl radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1 or more G ⁶ Substituted;

G ¹ 、G ² 、G ³ 、G ⁴ 、G ⁵ and G ⁶ Each independently selected from D, cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹⁰ 、-OC(O)NR ¹⁰ R ¹¹ 、-C(O)OR ¹⁰ 、-C(O)NR ¹⁰ R ¹¹ 、-C(O)R ¹⁰ 、-NR ¹⁰ R ¹¹ 、-NR ¹⁰ C(O)R ¹¹ 、-NR ¹⁰ C(O)NR ¹¹ R ¹² 、-S(O) _m R ¹⁰ or-NR ¹⁰ S(O) _m R ¹¹ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by 1 or more cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹³ 、-OC(O)NR ¹³ R ¹⁴ 、-C(O)OR ¹³ 、-C(O)NR ¹³ R ¹⁴ 、-C(O)R ¹³ 、-NR ¹³ R ¹⁴ 、-NR ¹³ C(O)R ¹⁴ 、-NR ¹³ C(O)NR ¹⁴ R ¹⁵ 、-S(O) _m R ¹³ or-NR ¹³ S(O) _m R ¹⁴ Substituted with the substituent(s);

R ⁷ 、R ⁸ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ and R ¹⁵ Each independently selected from hydrogen, D, cyano, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl;

and m is 1 or 2.

In some embodiments, the compound of (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof described above, wherein each Ar is ₁ Is independently selected at each occurrence from

Each Ar ₁ At each occurrence independently optionally by one or more G ¹ Substituted;

G ¹ each independently selected from D, cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹⁰ 、-OC(O)NR ¹⁰ R ¹¹ 、-C(O)OR ¹⁰ 、-C(O)NR ¹⁰ R ¹¹ 、-C(O)R ¹⁰ 、-NR ¹⁰ R ¹¹ 、-NR ¹⁰ C(O)R ¹¹ 、-NR ¹⁰ C(O)NR ¹¹ R ¹² 、-S(O) _m R ¹⁰ or-NR ¹⁰ S(O) _m R ¹¹ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by 1 or more cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹³ 、-OC(O)NR ¹³ R ¹⁴ 、-C(O)OR ¹³ 、-C(O)NR ¹³ R ¹⁴ 、-C(O)R ¹³ 、-NR ¹³ R ¹⁴ 、-NR ¹³ C(O)R ¹⁴ 、-NR ¹³ C(O)NR ¹⁴ R ¹⁵ 、-S(O) _m R ¹³ or-NR ¹³ S(O) _m R ¹⁴ Substituted with the substituent(s);

R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ and R ¹⁵ Each independently selected from hydrogen, D, cyano, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl;

and m is 1 or 2.

In some embodiments, the compound of the general structural formula (I) described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein one of the following compounds, but not limited to the following compounds, is included:

the present invention provides methods for the above novel FGFR inhibitors or isomers, hydrates, solvates, polymorphs, pharmaceutically acceptable salts thereof.

The compounds of the invention are useful for the treatment or prevention of FGFR-associated tumors, such as non-small cell lung cancer, esophageal cancer, melanoma rhabdomyosarcoma, cellular carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer, and liver cancer (e.g., hepatocellular carcinoma), more particularly liver cancer, gastric cancer, and bladder cancer. Thus, in a further aspect, the present invention provides a method of treating or preventing FGFR-mediated diseases (e.g., of a tumor), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a prodrug, stable isotope derivative, polymorph, solvate, pharmaceutically acceptable salt, isomer and mixtures thereof, or a pharmaceutical composition comprising the compound.

Another aspect of the present invention relates to a compound of formula (I) or a prodrug, stable isotope derivative, polymorph, solvate, pharmaceutically acceptable salt, isomer, and mixture thereof for pharmaceutical or medicinal use for treating or preventing FGFR mediated diseases, such as tumors or inflammatory diseases, including but not limited to non-small cell lung cancer, esophageal cancer, melanin, rhabdomyosarcoma, wild cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrial cancer, uterine cancer, gastric cancer, diaphragm cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer.

The invention further relates to a pharmaceutical composition which comprises the compound or the prodrug, the stable isotope derivative, the pharmaceutically acceptable salt isomer and the mixture thereof, and pharmaceutically acceptable carriers, diluents and excipients.

Another aspect of the invention relates to the use of a compound of formula (I) or a prodrug stable isotope derivative thereof, a pharmaceutically acceptable salt, isomer and mixture thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of FGFR mediated diseases such as tumors and inflammatory diseases.

According to the present invention, the drug can be in any pharmaceutical dosage form including, but not limited to, tablets, sachets, solutions, lyophilized formulations, injections.

Certain chemical terms

Unless stated to the contrary, the following terms are used in the specification and claims.

Has the following meanings and is used herein in the manner of _x-y "denotes the range of the number of carbon atoms, wherein x and y are each an integer, e.g. C _3-8 Cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3,4, 5, 6, 7 or 8 carbon atoms. It is also understood that "C" is _3-8 "also includes any subrange therein, e.g. C _3-7 、C _3-6 、C _4-7 、C _4-6 、C _5-6 And the like.

"alkyl" refers to a straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

"alkenyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl, and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.

"alkynyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing from 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decahydronaphthyl, which may be substituted or unsubstituted.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, spiro, or bridged ring systems, to which the nitrogen, carbon, or sulfur atoms are optionally oxidized, to which the nitrogen atoms are optionally quaternized, and which may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. The heterocyclic group containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms on the non-aromatic ring are attached to the rest of the molecule. For purposes of this application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

"spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) whose m is an integer from 0 to 2, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated electronic system, preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro group. Non-limiting examples of spirocycloalkyl groups include:

"fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

"aryl" or "aryl" refers to an aromatic ring or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, most preferably the aryl ring of the phenyl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the rings attached to the parent structure are aryl rings, non-limiting examples of which include:

"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom, on which nitrogen, carbon, and sulfur atoms may be selectively oxidized, and which may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, heteroaryl is preferably a 5-8 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridinyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

"halogen" means fluorine, chlorine, bromine or iodine.

"hydroxy" means-OH, and "amino" means-NH ₂ ，“Amido "means-NHCO-," cyano "means-CN, and" nitro "means-NO ₂ "isocyano" means-NC and "trifluoromethyl" means-CF ₃ 。

The term "heteroatom" or "hetero", as used herein alone or as part of another ingredient, refers to atoms other than carbon and hydrogen, and are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, and in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.

The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a ring structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes where the event or circumstance occurs or does not occur-for example, "heterocyclic group optionally substituted with alkyl" means that alkyl may, but need not, be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3 atoms, in a group are independently substituted with a corresponding number of substituents. It goes without saying that the skilled person in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort, when the substituents are in their possible chemical positions. For example, having a free amine or hydroxyl group may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond. Such substituents include, but are not limited to, hydroxy, amine, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl groups, and the like.

"pharmaceutical composition" refers to a composition containing one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to the organism, facilitate absorption of the active ingredient and further exert biological activity.

"isomers" refer to compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or in the arrangement of their atoms in space, referred to as "isomers") isomers differing in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are either in the "R" or "S" configuration. Optical isomers, including enantiomers and diastereomers, and methods of preparing and separating optical isomers are known in the art.

Geometric isomers may also exist for the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as either the Z or E configuration, substituents around cycloalkyl or heterocyclic rings are designated as either the cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, e.g., keto-enol tautomerism.

It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not to be limited solely to any one tautomeric or stereoisomeric form employed in the nomenclature or chemical structure of the compounds.

"isotopes" are all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to favorably alter biological, pharmacological or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the present invention can be administered in the form of a prodrug. Prodrugs refer to derivatives that are converted to the biologically active compounds of the present invention under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, and the like, each of which utilizes or proceeds without the participation of an enzyme. Examples of prodrugs are the following compounds: compounds in which the amine group in the compounds of the invention is acylated, alkylated or phosphorylated, for example eicosanoylamino, propylaminoylamino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, for example acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, propylaminoyloxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, for example a peptide, which selectively delivers a drug to the target and/or to the cytosol of the cell, can be prepared from the compounds of the invention according to well-known methods.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable" means made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups can be present in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, caffeine, and the like, with particularly preferred organic bases being isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups can be present in the form of salts and can be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes inner salts or betaine salts in addition to the salt forms mentioned. The salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

Thus, when reference is made in this application to "a compound", "a compound of the invention" or "a compound of the invention", all said compound forms are included, such as prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, isomers, meso-forms, racemates, enantiomers, diastereomers and mixtures thereof.

In this context, the term "tumor" includes both benign tumors and malignant tumors (e.g., cancers).

As used herein, the term "cancer" includes various malignancies in which FGFR kinase is involved in its development, including, but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, striated muscle garnet, cellular carcinoma, multiple myeloma, breast ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer (e.g., hepatocellular cancer), more specifically liver cancer, gastric cancer, and bladder cancer.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent upon administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The term "polymorph" or "polymorph (phenomenon)" as used herein means that the compounds of the present invention have multiple crystal lattice forms, some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Crystallization often results in a solvate of a compound of the invention, and the term "solvate" as used herein refers to an association of one or more molecules of a compound of the invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may also be present only occasionally as water or as a mixture of water with some other solvent the compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not interfere with the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an undesirable biological response or interacting in an undesirable manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonizing agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

As used herein, the term "subject," "patient," "subject" or "individual" refers to an individual having a disease, disorder or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) Inhibiting the disease or disorder, i.e., controlling its development;

(iii) Relieving the disease or condition, i.e., slowing the regression of the disease or condition;

(iv) Relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

The terms "administering," "administration," "administering," and the like as used herein refer to methods that are capable of delivering a compound or composition to a desired site for a biological action. Including, but not limited to, oral, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Synthesis method

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the invention may also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein may be used. The product of each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (reaxys).

Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as Chemblocks Inc, astatech Inc or mclin, and these reagents were used directly without further purification unless otherwise stated.

Unless otherwise stated, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using a drying tube; glassware was dried and/or heat dried.

Unless otherwise stated, column chromatography purification used 200-300 mesh silica gel from Qingdao oceanic plant; preparation of thin-layer chromatography silica gel precast slab (HSGF 254) produced by Nicoti chemical industry research institute was used; MS was measured using a Therno LCD flash model (ESI) liquid chromatography-mass spectrometer.

Nuclear magnetic data ( ¹ H NMR) Using a Bruker Avance-400MHz or Varian Oxford-400Hz Nuclear magnetic Analyzer, the Nuclear magnetic data were obtained using CDCl as the solvent ₃ 、CD ₃ OD、D ₂ O、DMSO-d ₆ Etc. based on tetramethylsilane (0.000 ppm) or based on residual solvent (CDCl) _3: 7.26ppm；CD ₃ OD:3.31ppm；D ₂ O:4.79ppm；DMSO-d ₆ 2.50 ppm) when indicating the diversity of the peak shapes, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is in Hertz (Hz).

Detailed Description

The invention is further illustrated by the following specific examples.

Example 1: preparation of (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d ] pyridazin-7-one (Compound 1)

The compound, ethyl 4-cyano-1H-pyrazole-5-carboxylate (20g, 8.0mmol) and 250mL of N, N-dimethylformamide were charged into a reaction flask, and NBS (2.14g, 12.0mmol) was added in portions, and the mixture was reacted at 50 ℃ for 4 hours with stirring. After cooling to room temperature, the reaction mixture was poured into 100mL of water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound ethyl 3-bromo-4-cyano-1H-pyrazole-5-carboxylate (1.26 g, yield 69%) as a white solid. LC/MS (ESI): m/z =245.0[M+H] ⁺ .

The compound ethyl 3-bromo-4-cyano-1H-pyrazole-5-carboxylate (0.82g, 5.0 mmol), 3mL of hydrazine hydrate and 30mL of ethanol were added to a reaction flask, and the mixture was heated to reflux with stirring overnight. Cooled to room temperature and the solvent evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain compound 3-bromo-4-amino-1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (0.64 g, 56% yield) was a white solid. LC/MS (ESI) m/z =230.0[ m + H ]] ⁺ 。

Adding the compound 3-bromo-4-amino-1, 6-dihydro-7H-pyrazolo [3,4-d ] into a reaction flask]Pyridazin-7-one (0.46g, 2.0mmol), 7-methoxy-5-methylbenzo [ b ]]Thiophene-2-boronic acid (0.48g, 3.0 mmol), bis-triphenylphosphine palladium dichloride (140mg, 0.2mmol), cuprous iodide (38mg, 0.2mmol), triethylamine (1.01g, 10.0 mmol) and 15mL of N, N-dimethylformamide. The mixture was purged with nitrogen 3 times, and reacted at 90 ℃ overnight with stirring. Cooled to room temperature, the reaction solution was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain 4-amino-3- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (0.46 g, 74% yield) was a yellow solid. LC/MS (ESI) m/z =328.1[ 2[ M ] +H] ⁺ .

To a reaction flask were added (R) -1-tert-butoxycarbonyl-3-hydroxypyrrolidine (241mg, 1.2mmol), triphenylphosphine (315mg, 1.2mmol) and THF 10mL, followed by DIAD (243mg, 1.2mmol). The yellow solution is stirred for 5-10 minutes, then the intermediate 4-amino-3- (7-methoxy-5-methylbenzo [ b ] is added]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (310mg, 1.0 mmol), and the reaction was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure to give a brown oil, and the residue was purified by column chromatography to give the compound (S) -1- (N-boc-pyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b)]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (345 mg, yield 70%) was a yellow solid. LC/MS (ESI) m/z =497.2[ M + H ]] ⁺ .

Adding the intermediate (S) -1- (N-boc-pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thiophene-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (296mg, 0.6mmol), ethyl acetate (1mL), and 4N HCl (1 mL) in 1, 4-dioxane. After stirring at room temperature for 2 hours, the reaction solution was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. To obtain the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (227 mg, 96% yield) was used directly in the next step, LC/MS (ESI) m/z =397.1[ M ] +H] ⁺ .

Adding the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (197mg, 0.5mmol), triethylamine (76mg, 0.75mmol), and 2mL of methylene chloride were cooled in an ice-water bath, and then a solution of acryloyl chloride (78mg, 0.75mmol) in 0.5mL of methylene chloride was slowly added dropwise. After the addition, stirring was continued for 4 hours, and the reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 1 (97 mg, yield 43%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.52(s,1H),7.64(s,1H),7.25(s,1H),6.79(s,1H),6.42-6.33(m,1H),6.13-6.04(m,1H),5.73-5.62(m,1H),5.27-5.19(m,1H),4.06-3.97(m,2H),3.91(s,3H),3.65-3.53(m,2H),2.45-2.32(m,5H)；LC/MS(ESI):m/z＝451.2[M+H] ⁺ .

Example 2: preparation of (S) -1- (1-but-2-ynoylpyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d ] pyridazin-7-one (Compound 2)

Adding the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (197mg, 0.5mmol), triethylamine (76mg, 0.75mmol), and 2mL of methylene chloride were cooled in an ice-water bath, and a solution of but-2-ynoyl chloride (77mg, 0.75mmol) in 0.5mL of methylene chloride was slowly added dropwise. After finishing addingStirring was continued for 4 hours, and the reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 2 (86 mg, yield 37%) as a yellow solid. LC/MS (ESI) m/z =463.2[ M + H ]] ⁺ .

Example 3: preparation of (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d ] pyridazin-7-one (Compound 3)

The compound ethyl 3-cyano-1H-pyrrole-2-carboxylate (1.64g, 10.0 mmol), 5mL of hydrazine hydrate and 50mL of ethanol were added to a reaction flask, and the mixture was heated to reflux with stirring overnight. Cooled to room temperature and the solvent evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain 4-amino-1, 6-dihydro-7H-pyrrole [3,4-d]Pyridazin-7-one (0.64 g, 43% yield) was a white solid. LC/MS (ESI) m/z =151.1[ 2[ M ] +H] ⁺ 。

Adding the compound 4-amino-1, 6-dihydro-7H-pyrrole [3,4-d ] into a reaction bottle]Pyridazin-7-one (0.60g, 4.0 mmol) and N, N-dimethylformamide (10 mL) were added portionwise NBS (1.07g, 6.0 mmol), and reacted at 50 ℃ for 4 hours with stirring. After cooling to room temperature, the reaction mixture was poured into 50mL of water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain 3-bromo-4-amino-1, 6-dihydro-7H-pyrrole [3,4-d]Pyridazin-7-one (0.59 g, 65% yield) was a white solid. LC/MS (ESI) m/z =229.0[ m + H ]] ⁺ .

Adding the compound 3-bromo-4-amino-1, 6-dihydro-7H-pyrrole [3,4-d ] into a reaction bottle]Pyridazin-7-one (0.46g, 2.0 mmol), 7-methoxy-5-methylbenzo [ b ]]Thiophene-2-boronic acid (0.48g, 3.0 mmol), bis-triphenylphosphine palladium dichloride (140mg, 0.2mmol), cuprous iodide (38mg, 0.2mmol), triethylamine (1.01g, 10.0 mmol) and 15mL of N, N-dimethylformamide. The mixture was purged with nitrogen 3 times, and reacted at 90 ℃ overnight with stirring. Cooled to room temperature, the reaction solution was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic phase obtainedThen, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain 4-amino-3- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (0.44 g, 71% yield) was a yellow solid. LC/MS (ESI) m/z =327.1[ 2 ] M + H] ⁺ .

To a reaction flask were added (R) -1-tert-butoxycarbonyl-3-hydroxypyrrolidine (241mg, 1.2mmol), triphenylphosphine (315mg, 1.2mmol) and THF 10mL, followed by DIAD (243mg, 1.2mmol). The yellow solution is stirred for 5-10 minutes, then the intermediate 4-amino-3- (7-methoxy-5-methylbenzo [ b ] is added]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (310mg, 1.0 mmol), and the reaction was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure to give a brown oil, and the residue was purified by column chromatography to give the compound (S) -1- (N-boc-pyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b)]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (320 mg, yield 65%) was a yellow solid. LC/MS (ESI) that m/z =496.2[ m ] +H] ⁺ .

Adding the intermediate (S) -1- (N-boc-pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (296mg, 0.6mmol), ethyl acetate (1mL), and 4N HCl (1 mL) in 1, 4-dioxane. After stirring at room temperature for 2 hours, the reaction solution was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. To obtain the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (220 mg, 93% yield) was used directly in the next step, LC/MS (ESI) m/z =396.1[ M ] +H ]] ⁺ .

Adding the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (197mg, 0.5mmol), triethylamine (76mg, 0.75mmol), and 2mL of methylene chloride were cooled in an ice-water bath, and then a solution of acryloyl chloride (78mg, 0.75mmol) in 0.5mL of methylene chloride was slowly added dropwise. After the addition was complete, stirring was continued for 4 hours. Reaction ofThe solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 3 (92 mg, yield 41%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.52(s,1H),7.67(s,1H),7.51(s,1H),7.23(s,1H),6.81(s,1H),6.42-6.33(m,1H),6.13-6.05(m,1H),5.73-5.62(m,1H),5.22-5.14(m,1H),4.06-3.97(m,2H),3.90(s,3H),3.67-3.53(m,2H),2.45-2.30(m,5H)；LC/MS(ESI):m/z＝450.2[M+H] ⁺ .

Example 4: preparation of ((S) -1- (1-but-2-ynoylpyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d ] pyridazin-7-one (Compound 4)

Adding the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (197mg, 0.5 mmol), triethylamine (76mg, 0.75mmol), and 2mL of dichloromethane were cooled in an ice-water bath, and then a solution of but-2-ynoyl chloride (77mg, 0.75mmol) in 0.5mL of dichloromethane was slowly added dropwise. After the addition was complete, stirring was continued for 4 hours. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 4 (81 mg, yield 35%) as a yellow solid. LC/MS (ESI) m/z =462.2[ 2 ], [ M + H ]] ⁺ .

Example 5: preparation of (S) -1- (3- (8-amino-1- (N-methylindol-2-yl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 5)

In a manner similar to example 1 (intermediate exchanged for 3-bromo-4-amino-1, 6-dihydro-7H-pyrrolo [3, 4-d)]Pyridazin-7-one and 1-methylindole-2-boronic acid) to give compound 5 (86 mg, yield 43%) as a yellow solid. LC/MS (ESI) m/z =403.2[ m + H ]] ⁺ .

Example 6: preparation of (S) -1- (3- (8-amino-1- (benzofuran-2-yl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 6)

In a manner similar to example 1 (intermediate exchanged for 3-bromo-4-amino-1, 6-dihydro-7H-pyrrolo [3, 4-d)]Pyridazin-7-one and benzofuran-2-boronic acid) to give compound 6 (76 mg, yield 39%) as a yellow solid. LC/MS (ESI) m/z =390.2[ m + H ]] ⁺ .

Example 7: preparation of (S) -1- (3- (8-amino-1- (N-methylindol-3-yl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 7)

In a manner similar to example 1 (intermediate exchanged for 3-bromo-4-amino-1, 6-dihydro-7H-pyrrolo [3, 4-d)]Pyridazin-7-one and 1-methylindole-3-boronic acid) to give compound 7 (93 mg, yield 46%) as a yellow solid. LC/MS (ESI) m/z =403.2[ m + H ]] ⁺ .

Example 8: preparation of (S) -1- (3- (8-amino-1- (naphthalen-2-yl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 9)

In a manner similar to example 1 (intermediate exchanged for 3-bromo-4-amino-1, 6-dihydro-7H-pyrrolo [3, 4-d)]Pyridazin-7-one and 2-naphthaleneboronic acid) to give compound 8 (80 mg, yield 40%) as a yellow solid. LC/MS (ESI) m/z =400.2[ m + H ]] ⁺ .

Example 9: preparation of (S) -1- (3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 9)

3-chloropyrazine-2-methylamine dihydrochloride (2.16g, 10mmol) and dichloromethane 50mL are added into a reaction bottle, 10mL of a dichloromethane solution of N-Cbz-pyrrolidine-3-formyl chloride (3.211g, 12mmol) is dropwise added at 0 ℃, then the temperature is raised to room temperature, and the mixture is stirred for half an hour. The mixture was quenched with 30mL of saturated aqueous sodium bicarbonate, the organic phase was separated, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure to give a crude product which was purified by flash column to give (S) -benzyl 3- (((3-chloropyrazin-2-yl) methyl) carbamoyl) pyrrolidine-1-carboxylate (2.74 g, yield 73%), LC/MS (ESI): m/z =375.1[ M ] +H] ⁺ .

The (S) -benzyl 3- (((3-chloropyrazin-2-yl) methyl) carbamoyl) pyrrolidine-1-carboxylic ester (1.87g, 5 mmol) and acetonitrile 25mL are added in a reaction flask, phosphorus oxychloride 4mL and a few drops of N, N-dimethylformamide are added dropwise at room temperature, and the temperature is raised to 80 ℃ under the protection of nitrogen and the reaction is stirred for 2 hours. Cooled to room temperature and the solvent evaporated to dryness under reduced pressure. The residue was poured into ice water, extracted with dichloromethane, and the resulting organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (S) -benzyl 3- (8-chloroimidazo [1,5-a ]]Pyrazin-3-yl) pyrrolidine-1-carboxylate (0.73 g, yield 41%), LC/MS (ESI) m/z =357.1[ M ] +H ]] ⁺ .

Adding the compound (S) -benzyl 3- (8-chloroimidazole [1,5-a ] into a reaction bottle]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester (0.71g, 2.0 mmol) and 6mL of N, N-dimethylformamide were added in portions of NBS (0.54g, 4.0 mmol), and the mixture was reacted at room temperature for 3 hours with stirring. The reaction solution was poured into 50mL of water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (S) -benzyl 3- (1-bromo-8-chloroimidazole [1,5-a ]]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester (0.65 g, 75% yield) was a white solid. LC/MS (ESI) m/z =435.0[ M + H ]] ⁺ .

In a reaction flaskAdding the compound (S) -benzyl 3- (1-bromo-8-chloroimidazole [1,5-a ]]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester (0.65g, 1.5 mmol), isopropanol 10mL, and aqueous ammonia (30%, 2 mL) were refluxed with stirring for 5 hours. Cooled to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (S) -benzyl 3- (8-amino-1-bromoimidazole [1,5-a ]]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester (0.54 g, 87% yield) was a white solid. LC/MS (ESI) m/z =416.3[ 2 ] M + H] ⁺ .

Adding the compound (S) -benzyl 3- (8-amino-1-bromoimidazole [1,5-a ] into a reaction bottle]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester (0.50g, 1.2mmol), 7-methoxy-5-methylbenzo [ b]Thiophene-2-boronic acid (0.29g, 1.8mmol), bis-triphenylphosphine palladium dichloride (140mg, 0.2mmol), cuprous iodide (38mg, 0.2mmol), triethylamine (0.5g, 5.0mmol), and 10mL of N, N-dimethylformamide. The mixture was purged with nitrogen 3 times, and reacted at 90 ℃ overnight with stirring. The reaction solution was cooled to room temperature, diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (S) -benzyl 3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) [1,5-a]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester (0.52 g, 85% yield) was a yellow solid. LC/MS (ESI) m/z =514.2[ m + H ]] ⁺ .

The compound (S) -benzyl 3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (0.52g, 1.0 mmol) and 4mL of concentrated hydrochloric acid were added to a reaction flask and reacted at room temperature for 24 hours. Pouring the reaction solution into ice water, adjusting the pH value to be alkalescent by using a 1N sodium hydroxide solution, extracting by using dichloromethane, washing the obtained organic phase by using a saturated sodium bicarbonate solution, drying by using anhydrous sodium sulfate, and evaporating the organic phase to dryness under reduced pressure. To give the compound (S) -1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -3- (pyrrolidin-3-yl) imidazo [1,5-a ] pyrazin-8-amine (0.38 g, 85% yield), LC/MS (ESI): m/z

＝451.2[M+H] ⁺ .

The compound (S) was added to the reaction flask) -1- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) -3- (pyrrolidin-3-yl) imidazole [1,5-a]Pyrazine-8-amine (225mg, 0.5mmol), triethylamine (76mg, 0.75mmol), and 2mL of methylene chloride were cooled in an ice-water bath, and then a solution of acryloyl chloride (78mg, 0.75mmol) in 0.5mL of methylene chloride was slowly added dropwise. After the addition was complete, stirring was continued for 4 hours. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 9 (70 mg, yield 32%) as a yellow solid. ¹ HNMR(400MHz,DMSO-d ₆ )δ:7.64(s,1H),7.26-7.14(m,3H),6.79(s,1H),6.42-6.33(m,1H),6.13-6.04(m,1H),5.91-5.78(br s,2H),5.73-5.62(m,1H),4.18-3.95(m,3H),3.91(s,3H),3.64-3.53(m,2H),2.49-2.30(m,5H)；LC/MS(ESI):m/z＝434.2[M+H] ⁺ .

Example 10: preparation of (S) -1- (3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 10)

Adding the compound (S) -8-amino 1- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -3- (pyrrolidin-3-yl) imidazo [1,5-a]Pyrazine (190mg, 0.5 mmol), triethylamine (76mg, 0.75mmol), and 2mL of dichloromethane were cooled in an ice-water bath and then a solution of but-2-alkynylchloride (78mg, 0.75mmol) in 0.5mL of dichloromethane was slowly added dropwise. After the addition was complete, stirring was continued for 4 hours. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 10 (82 mg, yield 37%) as a yellow solid. LC/MS (ESI) m/z =446.2[ m + H ]] ⁺ .

Example 11: preparation of (S) -1- (3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) imidazo [5,1-f ] [1,2,4] triazin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 11)

By a method similar to the first three steps of example 9 (raw material changed to 3-Amino-6- (aminomethyl) -1,2, 4-triazin-5 (4H) -one dihydrochloride to give the intermediate (S) -benzyl 3- (2-amino-5-bromo-4-hydroxyimidazole [5,1-f ]][1,2,4]Triazine-7-yl) pyrrolidine-1-carboxylic acid ester (2.25 g, 67% yield). LC/MS (ESI) m/z =433.1[ 2[ M ] +H] ⁺ .

The compound tert-butyl nitrite (0.77g, 7.5 mmol), tetrahydrofuran (10 mL) and a few drops of N, N-dimethylformamide were added to a reaction flask, and (S) -benzyl 3- (2-amino-5-bromo-4-hydroxyimidazole [5,1-f ] was added dropwise][1,2,4]5mL of a tetrahydrofuran solution of triazine-7-yl) pyrrolidine-1-carboxylic acid ester (2.17g, 5 mmol) was stirred at room temperature for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure. Purifying the residue by column chromatography to obtain intermediate (S) -benzyl 3- (5-bromo-4-hydroxyimidazole [5,1-f ]][1,2,4]Triazine-7-yl) pyrrolidine-1-carboxylic acid ester (1.30 g, 62% yield) was a yellow solid. LC/MS (ESI) m/z =418.0[ m + H ]] ⁺ .

The compound (S) -benzyl 3- (5-bromo-4-hydroxyimidazole [5,1-f ]][1,2,4]Triazine-7-yl) pyrrolidine-1-carboxylic acid ester (1.25g, 3 mmol) was dissolved in 15mL of toluene, and phosphorus oxychloride (3.1mL, 33mmol) was added and the reaction was stirred at reflux for 24 hours. The mixture was cooled to room temperature, the residue was poured into ice water, extracted with dichloromethane, and the resulting organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound (S) -benzyl 3- (5-bromo-4-chloroimidazole [5,1-f ]][1,2,4]Triazine-7-yl) pyrrolidine-1-carboxylic acid ester (1.02 g, 78% yield). LC/MS (ESI) m/z =436.0[ m + H ]] ⁺ .

Subsequent procedures in a similar manner to the last four steps of example 9 gave compound 11 (80 mg, yield 37%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:8.73(s,1H),7.26-7.14(m,2H),6.81(s,1H),6.42-6.33(m,1H),6.15-6.05(m,1H),5.96-5.82(br s,2H),5.71-5.63(m,1H),4.18-3.95(m,3H),3.91(s,3H),3.64-3.53(m,2H),2.49-2.30(m,5H)；LC/MS(ESI):m/z＝435.2[M+H] ⁺ .

Example 12: preparation of (S) -1- (3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) imidazo [5,1-f ] [1,2,4] triazin-7-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 12)

Adding the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) imidazoles [5,1-f][1,2,4]Triazine (190mg, 0.5 mmol), triethylamine (76mg, 0.75mmol), and 2mL of dichloromethane were cooled in an ice-water bath, and then a solution of but-2-alkynylchloride (78mg, 0.75mmol) in 0.5mL of dichloromethane was slowly added dropwise. After the addition was complete, stirring was continued for 4 hours. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 12 (100 mg, yield 45%) as a yellow solid. LC/MS (ESI) m/z =447.2[ 2 ], [ M + H ]] ⁺ .

Example 13: preparation of 1- (1-acryloylazetidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d ] pyridazin-7-one (Compound 13)

To a reaction flask were added (R) -1-tert-butoxycarbonyl-3-hydroxypyrrolidine (241mg, 1.2mmol), triphenylphosphine (315mg, 1.2mmol) and THF 10mL, followed by DIAD (243mg, 1.2mmol). The yellow solution is stirred for 5-10 minutes, then the intermediate 4-amino-3- (7-methoxy-5-methylbenzo [ b ] is added]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (310mg, 1.0 mmol), and the reaction was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure to give a brown oil, and the residue was purified by column chromatography to give the compound (S) -1- (N-boc-pyrrolidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b)]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (338 mg, yield 70%) was a yellow solid. LC/MS (ESI) m/z =483.2[ M + H ]] ⁺ .

Adding the intermediate (S) -1- (N-boc-pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (296mg, 0.6mmol), ethyl acetate (1mL), and 4N HCl (1 mL) in 1, 4-dioxane. Stirring at room temperature for 2 hours, dissolving the reaction solution with 1N sodium hydroxideLiquid neutralization and ethyl acetate extraction. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. To obtain the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ]]Thien-2-yl) -1, 6-dihydro-7H-pyrazolo [3,4-d]Pyridazin-7-one (220 mg, 96% yield) was used directly in the next step, LC/MS (ESI) m/z =383.1[ m ] +H] ⁺ .

Adding the compound (S) -1- (pyrrolidine-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] into a reaction bottle]Thien-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d]Pyridazin-7-one (191mg, 0.5 mmol), triethylamine (76mg, 0.75mmol) and 2mL of dichloromethane were cooled in an ice-water bath, and then a solution of acryloyl chloride (78mg, 0.75mmol) in 0.5mL of dichloromethane was slowly added dropwise. After the addition was complete, stirring was continued for 4 hours. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 13 (94 mg, yield 43%) as a yellow solid. LC/MS (ESI) m/z =437.1[ m + H ]] ⁺ .

Example 14: preparation of 1- (1-acryloylazetidin-3-yl) -4-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1, 6-dihydro-7H-pyrrolo [3,4-d ] pyridazin-7-one (Compound 14)

In a manner similar to example 13 (intermediate exchanged for 3-bromo-4-amino-1, 6-dihydro-7H-pyrrolo [3, 4-d)]Pyridazin-7-one and 2-naphthaleneboronic acid) to give compound 14 (92 mg, yield 42%) as a yellow solid. LC/MS (ESI) m/z =436.1[ 2 ] M + H] ⁺ .

Example 15: preparation of 1- (3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) imidazo [1,5-a ] pyrazin-3-yl) azetidin-1-yl) prop-2-en-1-one (Compound 15)

Using a method analogous to example 9 (intermediate exchanged for 1- ((benzyloxycarbonyl) azacyclic)Butane-3-carboxylic acid) to give compound 15 (67 mg, yield 32%) as a yellow solid. LC/MS (ESI) m/z =420.1[ 2 ] M + H] ⁺ .

Example 16: preparation of 1- (3- (8-amino-1- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) imidazo [5,1-f ] [1,2,4] triazin-7-yl) azetidin-1-yl) prop-2-en-1-one (Compound 16)

Using a method similar to example 11 (intermediate is changed to 1- ((benzyloxycarbonyl) azetidine-3-carboxylic acid) gives compound 16 (74 mg, yield 35%) as a yellow solid LC/MS (ESI): m/z =421.1[ M + H ] +] ⁺ .

Example 17: preparation of 2- (1-acryloylazetidin-3-yl) -4-amino-6- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1H-pyrimidine-6-carboxamide (Compound 17)

A reaction flask was charged with tert-butyl 3-guanidinoiminoazetidine-1-carboxylic acid ester hydrochloride (2.35g, 10mmol), sodium methoxide (2.16g, 40mmol) and 40mL of methanol, and after cooling in an ice-water bath, a solution of malonic acid ester (1.92g, 12mmol) in 5mL of methanol was slowly added dropwise. After the addition, the reaction mixture was naturally returned to room temperature and stirred for 12 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound tert-butyl 3- (4, 6-hydroxypyrimidin-2-yl) azetidine-1-carboxylate (2.22 g, yield 83%) as a white solid. LC/MS (ESI) m/z =268.1[ 2 ] M + H] ⁺ .

Adding 2mL of N, N-dimethylformamide and 6mL of phosphorus oxychloride into a reaction flask, stirring for 1 hour in an ice-water bath, adding a compound tert-butyl 3- (4, 6-hydroxypyrimidin-2-yl) azetidine-1-carboxylic ester (2.14g, 8mmol), heating to reflux, and stirring for reacting for 4 hours. Cooled to room temperature, the residue was poured into ice water,extracting with dichloromethane, washing the obtained organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution, drying with anhydrous sodium sulfate, and evaporating the organic phase under reduced pressure. The residue was purified by column chromatography to give the compound tert-butyl 3- (4, 6-dichloro-5-formylpyrimidin-2-yl) azetidine-1-carboxylate (2.31 g, 87% yield) as a yellow solid. LC/MS (ESI) m/z =332.1[ 2 ] M + H] ⁺ .

To a reaction flask was added tert-butyl 3- (4, 6-dichloro-5-formylpyrimidin-2-yl) azetidine-1-carboxylate (1.66g, 5 mmol), tetrachloromethane 20mL, sulfonyl chloride (1.01g, 7.5 mmol), azobisisobutyronitrile (41mg, 0.25mmol). The temperature is increased to 80 ℃ and the reaction is stirred for 4 hours, the mixture is cooled to room temperature and filtered, the filtrate is decompressed and evaporated to dryness, and the compound tert-butyl 3- (4, 6-dichloro-5- (chloroformyl) pyrimidin-2-yl) azetidine-1-carboxylate (1.83 g, the yield is 100%) is obtained as yellow solid.

Tert-butyl 3- (4, 6-dichloro-5- (chloroformyl) pyrimidin-2-yl) azetidine-1-carboxylate (1.83g, 5mmol) and tetrahydrofuran (20 mL) were added to a reaction flask and placed under an ammonia atmosphere. The reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was evaporated to dryness under reduced pressure, the residue was diluted with ethyl acetate and water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The compound tert-butyl 3- (4-amino-5-carbamoyl-6-chloropyrimidin-2-yl) azetidine-1-carboxylate (1.33 g, yield 81%) was obtained as a yellow solid. LC/MS (ESI) m/z =328.1[ 2 ] M + H] ⁺ .

Subsequent procedures in a similar manner to example 1 gave compound 17 (61 mg, yield 29%) as a yellow solid. LC/MS (ESI) m/z =424.1[ 2[ M + H ]] ⁺ .

Example 18: preparation of 1- (1-acryloyl azetidin-3-yl) -5-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1H-pyrazole-4-carboxamide (Compound 18)

The compound 3- (5-amino-4-cyano-3- (7-methoxy-5-methyl) was obtained in a similar manner to that in example 1Phenylpropylthiophene-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylic acid ester. LC/MS (ESI) m/z =424.1[ 2 ] M + H] ⁺ .

The intermediate 3- (5-amino-4-cyano-3- (7-methoxy-5-methyl phenylpropylthiophene-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylic acid ester (0.85g, 2.0 mmol) in the previous step, 4ml of ethyl acetate, and 4ml of a solution of 4NHCl in 1, 4-dioxane were added to a reaction flask. After stirring at room temperature for 2 hours, the reaction solution was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 5-amino-1- (azetidin-3-yl) -3- (7-methoxy-5-methylphenylthiophen-2-yl) -1H-pyrazole-4-carboxamide (0.61 g, 85% yield). LC/MS (ESI) m/z =358.1[ 2 ] M + H] ⁺ 。

The compound 5-amino-1- (azetidin-3-yl) -3- (7-methoxy-5-methyl phenythrophenyl-2-yl) -1H-pyrazole-4-carboxamide (179mg, 0.5 mmol), triethylamine (76mg, 0.75mmol) and 2mL of dichloromethane were added to a reaction flask, and after cooling in an ice-water bath, a solution of acryloyl chloride (78mg, 0.75mmol) in 0.5mL of dichloromethane was slowly added dropwise. After the addition was completed, stirring was continued for 4 hours, and the reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 18 (68 mg, yield 33%) as a yellow solid. LC/MS (ESI) m/z =412.1[ 2[ M ] +H] ⁺ .

Example 19: preparation of (S) -2- (1-acryloylpyrrolidin-3-yl) -4-amino-6- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1H-pyrimidine-6-carboxamide (Compound 19)

In a similar manner to example 17 (starting material was changed to (S) -tert-butyl 3-guanidinoiminopyrrolidine-1-carboxylic acid ester hydrochloride), compound 19 (83 mg, yield 38%) was obtained as a yellow solid. ¹ H NMR(400MHz,CD ₃ OD)δ:7.69(s,1H),7.21(s,1H),6.73(s,1H),6.32(dd,1H),5.76(dd,1H),5.02(dd,1H),4.11-3.73(m,7H),3.61-3.45(m,1H),2.41-1.95(m,5H)；LC/MS(ESI):m/z＝438.2[M+H] ⁺ .

Example 20: preparation of (S) -1- (1-acryloylpyrrolidin-3-yl) -5-amino-3- (7-methoxy-5-methylbenzo [ b ] thiophen-2-yl) -1H-pyrazole-4-carboxamide (Compound 20)

Compound 20 (87 mg, yield 41%) was obtained as a yellow solid in a similar manner to that in example 1. ¹ H NMR(400MHz,CD ₃ OD)δ:7.72(s,1H),7.16(s,1H),6.75(s,1H),6.34(dd,1H),5.75(dd,1H),5.04(dd,1H),4.11-4.03(m,1H),3.97-3.71(m,6H),3.59-3.45(m,1H),2.39-1.93(m,5H)；LC/MS(ESI):m/z＝426.2[M+H] ⁺ .

Example 21: in vitro activity inhibition assay for kinases FGFR1, FGFR2, FGFR3 and FGFR4

The activity of FGFR1, FGFR2, FGFR3 and FGFR4 protein kinases is determined by using a Caliper mobility shift assay technology (Caliper mobility shift assay). The compounds were dissolved in DMSO, diluted with kinase buffer, and 5. Mu.L of the compound (10% DMS0) at 5-fold reaction final concentration was added to a 384-well plate. After adding 10. Mu.L of a 2.5-fold enzyme solution (FGFR 1, FGFR2, FGFR3 and FGFR4, respectively), the mixture was incubated at room temperature for 10 minutes, and then 10. Mu.L of a 2.5-fold substrate (FAM-labeledpeptide and dATP) solution was added. After incubation at 28 ℃ for 30-60 minutes, 25. Mu.L of stop buffer (pH 7.5100mM HEPES,0.015% Brij-35,0.2% conversion reagent #3,50mM EDTA) was added to stop the reaction. Conversion data were read on a Caliper EZ Reader II (Caliper Life Sciences). The conversion was converted to inhibition data (% inhibition = (max-sample conversion)/(max-min) × 100). Wherein max refers to the conversion rate of a DMSO control, and min refers to the conversion rate of an enzyme-free control. The concentration and the inhibition rate of the compound are used as horizontal and vertical coordinates to draw a curve, XLFit excel add-in version4.3.1 software is used for fitting the curve and calculating IC ₅₀ . The results of the assay are shown in the following table showing the activity data of compounds 1-20 on the kinases FGFR1, FGFR2, FGFR3 and FGFR 4. Active utilization of IC ₅₀ Characterization, wherein "A" represents IC ₅₀ Less than or equal to 10nM; "B" means 10<IC ₅₀ Less than or equal to 100nM; "C" means 100<IC ₅₀ Less than or equal to 500nM; "D" means 500<IC ₅₀ ≤2000nM。

TABLE 1 inhibitory Activity on FGFR1, FGFR2, FGFR3 and FGFR4

Example 21: human hepatoma cell Hep3B survival assay

The human liver cancer Hep3B cell strain is derived from ATCC. The cells were cultured in DMEM liquid medium, and fetal bovine serum (10% FBS) and penicillin-streptomycin (100,000U/L) were additionally added. The cells were maintained in culture at 37 ℃, 95% humidity and 5% carbon dioxide. For the experiments Hep3B cells were plated at a density of 3000 cells per well in 96-well plates at a cell suspension volume of 100PL per well and cultured overnight to allow cell attachment. The following day, each compound was diluted in DMSO in a three-fold gradient, and a 1PL compound DMSO solution was added to the cell culture medium, with IM DMSO as a control, with three parallel side wells for each compound concentration. The cells were then placed in a 37 ℃ incubator and after 72 consecutive hours of compound treatment, 50 μ L CellTiter-Glo (Promega, madisonWI) was added to the cell culture medium and the Relative Luminescence Units (RLU) of each well were determined and the cell viability and compound activity (IC) were calculated (IC) ₅₀ ) Wherein "A" represents IC ₅₀ Less than or equal to 10nM; "B" means 10<IC ₅₀ Less than or equal to 100nM; "C" means 100<IC ₅₀ Less than or equal to 500nM; "D" means 500<IC ₅₀ Less than or equal to 2000nM. The results of the inhibitory activity of the example compounds on Hep3B cells are shown in table 2 below:

TABLE 2 inhibitory Activity on Hep3B cells

Sample numbering	IC ₅₀ (nM)
		1	A
3	A
		9	A
11	A
		19	A
20	A

Claims

1. A compound having the general formula (I) or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof,

wherein:

u is independently selected from-C _0-4 Alkyl-, -CR ⁷ R ⁸ -、-C _1-2 Alkyl (R) ⁷ )(OH)-、-C(O)-、-CR ⁷ R ⁸ O-、-OCR ⁷ R ⁸ -、-SCR ⁷ R ⁸ -、-CR ⁷ R ⁸ S-、-NR ⁷ -、-NR ⁷ C(O)-、-C(O)NR ⁷ -、-NR ⁷ C(O)NR ⁸ -、-CF ₂ -、-O-、-S-、-S(O) _m -、-NR ⁷ S(O) ₂ -、-S(O) ₂ NR ⁷ -；

Y is absent or C is selected _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiro cyclic group, 5-12 membered spiro heterocyclic group, aromatic group or heteroaromatic group, wherein said cycloalkyl, heterocycloalkyl, spiro cyclic group, fused heterocyclic group, spiro heterocyclic group, aromatic group or heteroaromatic group is optionally substituted with one or more G ³ Substituted;

z is independently selected from cyano, -NR ⁹ CN、

Bond a is a double or triple bond;

R ^a and R ^b Or R ^b And R ^c Optionally taken together with the carbon atom to which they are attached to form a 3-6 membered ring optionally containing heteroatoms;

when the bond a is a triple bond, R ^a And R ^c Is absent, R ^b Independently selected from H, D, cyano, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl interrupted by one or more G ⁵ Substituted;

G ¹ 、G ² 、G ³ 、G ⁴ 、G ⁵ and G ⁶ Each independently selected from D, cyanogenRadical, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-to 8-membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹⁰ 、-OC(O)NR ¹⁰ R ¹¹ 、-C(O)OR ¹⁰ 、-C(O)NR ¹⁰ R ¹¹ 、-C(O)R ¹⁰ 、-NR ¹⁰ R ¹¹ 、-NR ¹⁰ C(O)R ¹¹ 、-NR ¹⁰ C(O)NR ¹¹ R ¹² 、-S(O) _m R ¹⁰ or-NR ¹⁰ S(O) _m R ¹¹ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by 1 or more cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-to 8-membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹³ 、-OC(O)NR ¹³ R ¹⁴ 、-C(O)OR ¹³ 、-C(O)NR ¹³ R ¹⁴ 、-C(O)R ¹³ 、-NR ¹³ R ¹⁴ 、-NR ¹³ C(O)R ¹⁴ 、-NR ¹³ C(O)NR ¹⁴ R ¹⁵ 、-S(O) _m R ¹³ or-NR ¹³ S(O) _m R ¹⁴ Substituted with the substituent(s);

and m is 1 or 2.

2. A compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein each Ar is ₁ Is independently selected at each occurrence from

Each Ar ₁ Optionally at each occurrence independently by one or more G ¹ Substituted;

and m is 1 or 2.

3. A compound according to claim 1 or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof and a mixture form thereof; it is selected from the following compounds:

or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, isomer, and mixtures and forms thereof.

4. A pharmaceutical composition comprising a compound of claims 1-3 or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

5. Use of a compound according to any one of the claims or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, polymorph or isomer thereof in the manufacture of a medicament for the treatment of an FGFR-mediated disease.

6. The use of claim 5, wherein the FGFR-mediated disease is one or more of non-small cell lung cancer, esophageal cancer, melanoma, gastric cancer, multiple myeloma, liver cancer, cholangiocarcinoma, prostate cancer, skin cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, breast cancer, colon cancer, glioma, and rhabdomyosarcoma.

7. A compound according to any one of claims 5 or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier for use as a medicament.