CN115141176A

CN115141176A - Alkyne-indole FGFR inhibitor and preparation method and application thereof

Info

Publication number: CN115141176A
Application number: CN202110355019.8A
Authority: CN
Inventors: 梁永宏; 曾兆森; 严文广; 凌苑; 熊方均
Original assignee: Yaoya Technology Shanghai Co ltd
Current assignee: Yaoya Technology Shanghai Co ltd
Priority date: 2021-03-31
Filing date: 2021-03-31
Publication date: 2022-10-04
Anticipated expiration: 2041-03-31
Also published as: CN115141176B

Abstract

The invention discloses an alkynopyrazine compound serving as an FGFR inhibitor, a preparation method and medical application thereof. In particular, the present invention relates toThe invention relates to a compound shown in general formulas (I) and (II) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and/or the pharmaceutically acceptable salt thereof, and application of the compound or the pharmaceutically acceptable salt thereof in medicaments for treating or preventing FGFR kinase related diseases, particularly tumors, and discloses a preparation method of the pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof. Wherein each substituent group in the general formula (I) is defined as the specification.

Description

Alkyne-indole FGFR inhibitor and preparation method and application thereof

The technical field is as follows:

the invention relates to an acetylenic heterocyclic compound or a pharmaceutically acceptable salt thereof as an FGFR inhibitor; a pharmaceutical composition containing the alkynylated heterocyclic compound or a pharmaceutically acceptable salt thereof; a process for producing the alkyno-heterocyclic compound or a pharmaceutically acceptable salt thereof; the application of the alkynylated heterocyclic compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the alkynylated heterocyclic compound or pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing FGFR related diseases, particularly tumors.

The background art comprises the following steps:

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 polygenic 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 the FGFR signaling pathway and further induces normal cell carcinogenesis. 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 capacity; 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 lines showed, according to a study published in Clinical Cancer Research in 2015, that FGFR aberrations (abortions) and abnormal activation were found in approximately 7.1% of cancers, with a majority of 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 currently some non-FGFR specific drugs on the market, such as Sunitinib from pfizer, lentitini from Eisai, and nintedanib from Boehringer ingelheimer. 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 clinical use 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 the formulae (I) and (II) or a stereoisomer, stable isotope derivative, hydrate, solvate, or pharmaceutically acceptable salt thereof:

wherein:

x1, X2, X3 may be independently selected from N, CR ¹ ；

X ₄ May be independently selected from absent, N, CR ¹ ；

The bonds a and b are single bonds or double bonds;

ring B is a phenyl ring or a 5-6 membered heteroaromatic ring wherein the above phenyl and heteroaromatic rings are optionally substituted by one or more G ¹ Substituted;

R ¹ independently selected from H, cyano, halogen, C _1-6 Alkyl, OR ² or-NHR ² ；

R ² Independently selected from H, cyano, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OR ³ 、-NR ³ R ⁴ 、-C(O)NR ³ R ⁴ Wherein said alkyl, cycloalkyl OR heterocycloalkyl is optionally substituted by cyano, halogen, -OR ⁵ 、-NR ⁵ R ⁶ 、C _1-6 Alkyl radical, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

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 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 ² Substituted;

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

Bond c is a double or triple bond;

when c is a double bond, R ^a 、R ^b And R ^c Each independently selected from H, 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 ³ 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 c is a triple bond, R ^a And R ^c Is absent, R ^b Independently selected from H, cyano, halogen, C _1-6 Alkyl radical, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl by one or more G ⁴ Substituted;

R ⁹ independently selected from H, 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 ⁵ Substituted;

G ¹ 、G ² 、G ³ 、G ⁴ and G ⁵ Each independently selected from 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 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-to 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 ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ and R ¹⁵ Each independently selected from hydrogen, cyano, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and is provided with

m is 1 or 2.

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 neoplasm), 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, stable isotope derivative, pharmaceutically acceptable salt isomer and mixture thereof, and pharmaceutically acceptable carriers, diluents and excipients.

Another aspect of the invention relates to the use of compounds of formula (I) or their prodrug stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof, or pharmaceutical compositions for the manufacture of a medicament for the treatment or prophylaxis of FGFR mediated diseases such as tumors and inflammatory diseases.

According to the present invention, the drug may 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 "represents a carbon atomA range of numbers, wherein x and y are both integers, 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 Etc. of in that respect.

"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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-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, e.g., 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" means a stable 3-to 18-membered monovalent non-aromatic ring comprising 2 to 12 carbon atoms, 1 to 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, a heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and 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, 1,1-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 a heteroatom of S (0) whose m is an integer of 0 to 2, the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings has 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 monocyclic 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, heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, 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, which may be selectively oxidized at nitrogen, carbon and sulfur atoms, and which may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-to 11-membered monocyclic aromatic rings containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferred are stable 5-8 membered mono 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 5-8 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, 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, "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 is 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 each other, 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 cyclic 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 instances 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 their bonding of atoms or the spatial arrangement of their atoms, referred to as "isomers", and isomers differing in the spatial arrangement of their atoms, 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. These optical isomers are either "R" or "S" configurations depending on the configuration of the substituents around the chiral carbon atom. 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 appropriate isotopically-labeled reagents in place of non-isotopically-labeled reagents. 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" refers to those 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, purine, piperazine, piperidine, choline, caffeine, and the like, with isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine being particularly preferred organic bases. 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 respective salts are obtained by customary 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 cancer 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 carcinoma), 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 that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after 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 disorder-relieving effect. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The term "polymorph" or "polymorph" 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 present invention, and the term "solvate" as used herein refers to an association of one or more molecules of a compound of the present 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 the 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 suffering from 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 unknown) and therefore are not to be considered as diseases but only as unwanted conditions or syndromes, some more or less specific symptoms of which have been 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 biological action. Including, but not limited to, oral routes, 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 taken in any way as a limitation of the scope of the invention. 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).

Example 1: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-alkynylaminopiperidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 1)

Preparation of key intermediate 4-bromo-5-fluoroindole-7-carbonitrile

In N ₂ The solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (15.0 g,56.8 mmol) in dry THF (200 mL) was cooled to-50 deg.C under protection, a solution of vinylmagnesium bromide in THF (1M, 341 mL,341 mmol) was added dropwise, the reaction mixture stirred at the same temperature and warmed to-40 deg.C in 1.5h, the reaction mixture was quenched with saturated aqueous NH4Cl solution and then warmed to room temperature, after 1 hour, the reaction mixture was acidified with 1M hydrochloric acid, diluted with EtOAc, washed with brine and Na ₂ SO ₄ Drying and removing the solvent under reduced pressure to give crude 4-bromo-5-fluoro-1H-indole-7-carboxylic acid (6.15g, 42%), LC/MS (ESI): m/z =259[ M +H ])] ⁺ .

4-bromo-5-fluoro-indole-7-carboxylic acid (4) is reacted at room temperature46 g,17.3 mmol), EDC (4.97 g,25.9 mmol) and HOBT (3.44 g,22.5 mmol in a mixed solvent of tetrahydrofuran (276 mL) and dichloromethanic agent (69 mL) were stirred for 1h and then treated with 28% aqueous ammonium hydroxide (5.38 mL,138 mmol). The resulting suspension was stirred at room temperature for 4 days. The mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. This combined organic layer was washed with brine, dried sodium sulfate anhydrous, and concentrated to provide 4-bromo-1H-indole-7-carboxamide (4.18g, 94%), LC/MS (ESI): m/z =258[ M ] +H ] as a yellow solid] ⁺ 。

4-bromo-5-fluoro-1H-indole-7-carboxamide (4.04g, 14.2mmol) was dissolved in dichloromethane (81 ml), pyridine (5 g) was added, then phosphorus trichloride (1.98mL, 21.3mmol) was added dropwise over 2min at room temperature, and the mixture was stirred for reaction for 20 min. Then the solvent was removed by reduced evaporation, water was further added to the residue, and the mixture was stirred for 30 minutes, filtered and dried to give 4-bromo-5-fluoro-1H-indole-7-carbonitrile (3.61g, 91%), LC/MS (ESI): m/z =239[ M ] +H ] as a tan solid] ⁺ 。

Step 1: synthesis of Compound 1b

(R) -3-Boc-aminopiperidine (3.39g, 16.9mmol), 4-bromo-5-fluoro-1H-indole-7-carbonitrile (3.4g, 15.4mmol), cesium carbonate (10g, 30.8mmol) and BINAP (0.96g, 1.54mmol) were dissolved in 1.4-dioxane (138 mL), and the mixture was degassed by bubbling nitrogen gas for 5min. Adding Pd to the reaction mixture ₂ (dba) ₃ (0.71g, 0.77mmol), the reaction mixture was stirred at reflux for 24 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (750 mL), washed with water (100 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude product as a brown solid which was passed through silica gel containing ethyl acetate (900 mL) to remove any minerals. Then recrystallizing with acetonitrile to obtain intermediate 1b (4.5g, 83%), LC/MS (ESI) m/z =359.2[ M ] +H ]] ⁺ .

Step 2: synthesis of Compound 1c

Intermediate 1b (2.65g, 7.4 mmol) and NBS (1.58g, 8.88mmol) obtained in the previous step were put in a 25ml eggplant-shaped bottle, and then addedDissolving in DMF (10 ml) in an oil bath at 80 deg.C, heating and refluxing for 5 hr to change the solution from yellow turbid solution to red transparent solution. The reaction was essentially complete by TLC. Naturally cooling the reaction solution to room temperature, pouring into ice water (50 ml), stirring, precipitating a large amount of yellow solid, filtering, washing a filter cake with water, and drying to obtain an intermediate 1c, wherein the yellow solid is 2.84g, the yield is 88%, and LC/MS (ESI) is m/z =438.1[ M ] +H ]] ⁺ .

And step 3: synthesis of Compound 1d

To a reaction flask were added compound 1c (2.19g, 5.0mmol), 3,5-dimethoxyphenylacetylene (1.22g, 7.5mmol), bis (triphenylphosphine) palladium dichloride (702mg, 1.0mmol), cuprous iodide (190mg, 1.0mmol), triethylamine (5.06g, 50.0mmol) and 50ml 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. The residue was purified by column chromatography to give compound 1b (1.55 g, 74% yield). LC/MS (ESI) m/z =419.1[ m + H ]] ⁺ .

And 4, step 4: synthesis of Compound 1e

A reaction flask was charged with intermediate 1d (0.84g, 2.0 mmol) from the previous step, 4mL of ethyl acetate, 4mL of 4N HCl 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. Compound 1e (0.74 g, 85% yield) is obtained and used directly in the next step, LC/MS (ESI) m/z =437.2[ M ] +H] ⁺ 。

And 5: synthesis of Compound 1

A reaction flask was charged with compound 1e (437mg, 1.0mmol), triethylamine (152mg, 1.5mmol) and 4ml of tetrahydrofuran, and after cooling in an ice-water bath, a solution of but-2-alkynylchloride (136mg, 1.5mmol) in 0.5ml of tetrahydrofuran 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 1 (205 mg, yield 41%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.68(s,1H),8.46(br s,1H),7.91(br s,1H),7.65-6.75(m,6H),3.99-3.82(m,1H),3.78(s,6H),3.19-3.08(m,1H),3.06-2.89(m,1H),3.06-2.90(m,1H),2.81(br s,1H),1.95(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.34(s,1H)；LC/MS(ESI):m/z＝503.2[M+H] ⁺ .

Example 2: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-alkynylaminopiperidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 2)

In a similar manner to example 1 (intermediate was changed to (S) -3-Boc-aminopiperidine), compound 2 (158 mg, yield 31%, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ: ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.68(s,1H),8.47(br s,1H),7.91(br s,1H),7.65-6.75(m,6H),3.99-3.82(m,1H),3.78(s,6H),3.19-3.08(m,1H),3.06-2.89(m,1H),3.06-2.90(m,1H),2.81(br s,1H),1.95(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.34(s,1H)；LC/MS(ESI):m/z＝503.2[M+H] ⁺ .

Example 3: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopiperidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 3)

In a similar manner to example 1 (intermediate was changed to acryloyl chloride), compound 3 (167 mg, yield 34%, this is the final step yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.76(s,1H),8.13(br s,1H),7.90(br s,1H),7.65-6.75(m,6H),6.28-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.02(br s,1H),3.77(s,6H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.67(m,3H),1.36(s,1H)；LC/MS(ESI):m/z＝491.2[M+H] ⁺ .

Example 4: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopiperidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 4)

In a similar manner to example 1 (intermediate was changed to acryloyl chloride), compound 3 (157 mg, yield 32%, which was the final step yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.76(s,1H),8.13(br s,1H),7.90(br s,1H),7.65-6.75(m,6H),6.28-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.02(br s,1H),3.77(s,6H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.67(m,3H),1.36(s,1H)；LC/MS(ESI):m/z＝491.2[M+H] ⁺ .

Example 5: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-alkynylaminopiperidin-1-yl) indole-7-carboxamide (Compound 5)

Preparation of key intermediate 4-bromoindole-7-carbonitrile

4-bromo-5-fluoro-1H-indole-7-carboxamide may be prepared as 4-bromo-1H-indole-7-carboxamide.

A suspension of 4-bromo-1H-indole-7-carboxamide (5.06g, 21.2mmol) in tetrahydrofuran (151 mL) was slowly treated with phosphorus oxychloride (13.8mL, 148mmol). The resulting mixture was stirred at room temperature for 23 hours, and then concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the precipitate was collected by filtration, and then the solid was washed with water, a saturated aqueous sodium bicarbonate solution and water in this order. The organic filtrate was concentrated and the residue was suspended in water. The resulting precipitate was collected by filtration, washed successively with water, saturated aqueous sodium bicarbonate solution and water. Drying the mixed precipitateTo give 4-bromo-1H-indole-7-carbonitrile (3.89g, 83%), LC/MS (ESI) as a yellow solid, m/z =222[ M +H ]] ⁺ 。

In a similar manner to example 1 (intermediate was changed to 4-bromo-1H-indole-7-carbonitrile), compound 5 (140 mg, yield 29%, which is the final yield, same below) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.66(s,1H),8.43(s,1H),7.83(br s,1H),7.46-6.53(m,7H),3.99-3.83(m,1H),3.77(s,6H),3.19-3.08(m,1H),3.06-2.89(m,1H),3.06-2.90(m,1H),2.81(br s,1H),1.97(s,3H),1.91-1.81(m,1H),1.73(s,2H),and 1.36(s,1H)；LC/MS(ESI):m/z＝485.2[M+H] ⁺ .

Example 6: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-ynylamidopiperidin-1-yl) indole-7-carboxamide (Compound 6)

Using a method similar to example 5 (intermediate was changed to (S) -3-tert-butoxycarbonylaminopiperidine), compound 6 (155 mg, yield 32%, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.66(s,1H),8.43(s,1H),7.83(br s,1H),7.46-6.53(m,7H),3.99-3.83(m,1H),3.77(s,6H),3.19-3.08(m,1H),3.06-2.89(m,1H),3.06-2.90(m,1H),2.81(br s,1H),1.97(s,3H),1.91-1.81(m,1H),1.73(s,2H),and 1.36(s,1H)；LC/MS(ESI):m/z＝485.2[M+H]+.

Example 7: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopiperidin-1-yl) indole-7-carboxamide (Compound 7)

In a similar manner to example 5 (intermediate was changed to acryloyl chloride), compound 7 (174 mg, yield 37%, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.64(s,1H),8.12(br s,1H),7.90(br s,1H),7.46-6.54(m,7H),6.28-6.16(m,1H),6.13-6.03(m,1H),5.60(dd,1H),4.04(br s,1H),3.78(s,6H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.68(m,3H),1.38(s,1H)；LC/MS(ESI):m/z＝473.2[M+H] ⁺ .

Example 8: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopiperidin-1-yl) indole-7-carboxamide (Compound 8)

In a similar manner to example 6 (intermediate was changed to acryloyl chloride), compound 8 (165 mg, yield 35%, this is the last step yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.64(s,1H),8.12(br s,1H),7.90(br s,1H),7.46-6.54(m,7H),6.28-6.16(m,1H),6.13-6.03(m,1H),5.60(dd,1H),4.04(br s,1H),3.78(s,6H),3.39(br s,1H),3.17(br s,1H),2.64(br s,1H),2.43(br s,1H),1.99-1.68(m,3H),1.38(s,1H)；LC/MS(ESI):m/z＝473.2[M+H] ⁺ .

Example 9: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-alkynylaminopyrrolidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 9)

Using a method similar to example 1 (intermediate was changed to (R) -3-tert-butoxycarbonylaminopyrrolidine), the compound 9 (137 mg, yield 28%, this is the last step yield, the same applies hereinafter) was obtained as a pale yellow solid ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.79(s,1H),8.38(br s,1H),8.30(br s,1H),7.78-6.64(m,6H),4.45-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.38-2.20(m,1H),1.97(s,3H),1.84-1.78(m,1H)；LC/MS(ESI):m/z＝489.2[M+H] ⁺ .

Example 10: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-alkynylaminopyrrolidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 10)

Using a method similar to example 9 (intermediate was changed to (S) -3-tert-butoxycarbonylaminopyrrolidine), compound 10 (151 mg, yield 31%, which is the last step yield, same below) was obtained as a pale yellow solid ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.79(s,1H),8.38(br s,1H),8.30(br s,1H),7.78-6.64(m,6H),4.45-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.38-2.20(m,1H),1.97(s,3H),1.84-1.78(m,；LC/MS(ESI):m/z＝489.2[M+H] ⁺ .

Example 11: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopyrrolidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 11)

In a similar manner to example 9 (intermediate was changed to acryloyl chloride), compound 11 (133 mg, yield 28%, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.34(s,1H),8.39(br s,1H),8.30(br s,1H),77.78-6.65(m,6H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,1H),4.45-4.30(m,1H),3.77(s,6H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.38-2.22(m,1H),1.85-1.76(m,1H)；LC/MS(ESI):m/z＝477.2[M+H] ⁺ .

Example 12: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopyrrolidin-1-yl) -5-fluoroindole-7-carboxamide (Compound 12)

In a similar manner to example 10 (intermediate was changed to acryloyl chloride), compound 12 (148 mg, yield 31%, which is the final step yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.34(s,1H),8.39(br s,1H),8.30(br s,1H),77.78-6.65(m,6H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,1H),4.45-4.30(m,1H),3.77(s,6H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.38-2.22(m,1H),1.85-1.76(m,1H)；LC/MS(ESI):m/z＝477.2[M+H] ⁺ .

Example 13: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-ynylamidopyrrolidin-1-yl) indole-7-carboxamide (Compound 13)

In a similar manner to example 9 (intermediate was changed to (4-bromo-1H-indole-7-carbonitrile) to give compound 13 (179 mg, yield 38%, which is the final yield, the same applies hereinafter) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.77(s,1H),8.38(br s,1H),8.30(br s,1H),7.78-6.64(m,6H),6.48(d,1H)4.32(m,1H),3.78(s,6H),3.26-3.13(m,2H),3.12-2.98(m,2H),2.38-2.20(m,1H),1.97(s,3H),1.84(m,1H)；LC/MS(ESI):m/z＝471.2[M+H] ⁺ .

Example 14: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-alkynylaminopyrrolidin-1-yl) indole-7-carboxamide (Compound 14)

Using a method similar to example 13 (intermediate was changed to (S) -3-tert-butoxycarbonylaminopyrrolidine), compound 14 (136 mg, yield 29%, which is the final yield, same below) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.77(s,1H),8.38(br s,1H),8.30(br s,1H),7.78-6.64(m,6H),6.48(d,1H)4.32(m,1H),3.78(s,6H),3.26-3.13(m,2H),3.12-2.98(m,2H),2.38-2.20(m,1H),1.97(s,3H),1.84(m,1H)；LC/MS(ESI):m/z＝471.2[M+H] ⁺ .

Example 15: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopyrrolidin-1-yl) indole-7-carboxamide (Compound 15)

In a similar manner to example 13 (intermediate was changed to acryloyl chloride), compound 15 (123 mg, yield 27%, this is the final step yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.75(s,1H),8.39(d,1H),8.31(s,1H),7.78-6.65(m,6H),6.48(d,1H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,2.0Hz,1H),4.44-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.36-2.23(m,1H),and 1.84-1.77(m,1H)；LC/MS(ESI):m/z＝459.2[M+H] ⁺ .

Example 16: preparation of (S) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopyrrolidin-1-yl) indole-7-carboxamide (Compound 16)

In a similar manner to example 14 (intermediate was changed to acryloyl chloride), compound 16 (141 mg, yield 31%, this is the last step yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:11.75(s,1H),8.39(d,1H),8.31(s,1H),7.78-6.65(m,6H),6.48(d,1H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,2.0Hz,1H),4.44-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.36-2.23(m,1H),and 1.84-1.77(m,1H)；LC/MS(ESI):m/z＝459.2[M+H] ⁺ .

Example 17: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-but-2-ynylamidopyrrolidin-1-yl) indazole-7-carboxamide (Compound 17)

Preparation of key intermediate 4-bromoindazole-7-carbonitrile

DMF (10 mL) was added in the order specified under nitrogen,4-bromo-7-iodoindazole (2.11g, 6.54mmol), zinc cyanide (0.21g, 3.93mmol), and tetrakis (triphenylphosphine) palladium (0.378g, 0.32mmol)). Heating the mixture to 100 ℃, and reacting for 1.5h; TLC followed the reaction to completion. After completion of the reaction, the mixture was cooled, celite was filtered, and the solvent was evaporated to dryness. Then 20mL of water was added and extracted three times with 20mL of ethyl acetate. The organic layer was washed three times with water, dried over sodium sulfate and the solvent was distilled off. The product obtained is purified by column chromatography, eluting with hexane: ethyl acetate (9:1) gave 4-bromoindazole-7-carbonitrile (1.28g, 88%) as a brown solid. LC/MS (ESI) m/z =223[ M + H ]] ⁺ .

In a similar manner to example 9 (intermediate was changed to 4-bromoindazole-7-carbonitrile), compound 17 (150 mg, yield 32%, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. LC/MS (ESI) m/z =472.2[ m + H ]] ⁺ .

Example 18: preparation of (R) -3- (3,5-dimethoxyphenylethynyl) -4- (3-acrylamidopyrrolidin-1-yl) indazole-7-carboxamide (Compound 18)

In a similar manner to example 17 (intermediate was changed to acryloyl chloride), compound 18 (174 mg, yield 37%, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. LC/MS (ESI) m/z =472.2[ m + H ]] ⁺ .

Example 19: preparation of 6- (3,5-dimethoxyphenylethynyl) -4- (1-acryloylpyrrolidin-1-ylamino) imidazo [3,4-c ] pyridine-7-carboxamide (Compound 19)

Step 1: synthesis of Compound 19b

Raw materials 2,6-dichloro-3-nitro-4-aminopyridine 1a (20.8g, 0.1mol), N-Boc-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole (29.5g, 0.1mol), cesium carbonate (33g, 0.3mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane (3.65g, 5 mmol), cesium carbonate, 1,4-dioxane (500 mL) and water (100 mL) were mixed, heated under reflux under nitrogen, and stirred for reaction for 16 hours. The reaction was cooled to room temperatureStirring overnight, evaporating the reaction solution under reduced pressure, purifying by column chromatography to obtain beige solid 1b (11.9 g, 35%), performing the next reaction without further purification, LC/MS (ESI) with m/z =342[ M ] +H] ⁺ 。

And 2, step: synthesis of Compound 19c

To a solution of the last-step compound 1b (6.84g, 20mmol) in ethyl acetate (100 mL) and methanol (100 mL) was added 10% by volume of Pd/C (2 g), and the reaction was degassed 6 times with hydrogen, and then stirred at room temperature under a hydrogen atmosphere for 12 hours. The solution was filtered and the filtrate was evaporated to crude product 1c (6.07g, 97%) as a brown solid, which was carried out without further purification for the next reaction, LC/MS (ESI) m/z =314[ 2 ], [ M +H] ⁺ 。

And step 3: synthesis of Compound 19d

N-bromosuccinimide (3.56g, 20mmol) was added to a solution of 19c (4.71g, 15mmol) in acetic acid (80 mL). After stirring at 60 ℃ for 2 hours, acetic acid was removed under reduced pressure. The residue was suspended in water (50 mL) and saturated sodium bicarbonate solution (40 mL) was added. The solid was filtered and stirred in water (150 mL) at 80 ℃ for 30 minutes. After cooling to ambient temperature, the solid was filtered and dried under vacuum to give crude tan solid 19d (5.2g, 89%), which was used for the next reaction without further purification, LC/MS (ESI): m/z =392[ M ] +H ]] ⁺ 。

And 4, step 4: synthesis of Compound 19e

Under the protection of nitrogen, 19d (5.1g, 13mmol), zn (CN) ₂ A mixture of (940mg, 8mmol), tris (dibenzylideneacetone) dipalladium (0.61g, 0.65mmol), and 1,1' -bis (diphenylphosphino) ferrocene (0.74g, 1.35mmol) was added to DMF/H2O (99, 50 mL), stirred for 30 minutes, then heated to 120 ℃ and the reaction stirred for 24 hours. The resulting mixture was cooled to room temperature, and saturated NH ₄ Cl solutionConcentrated ammonia water H ₂ O (4. The reaction was cooled to 0 ℃ and filtered. Using saturated NH for filter cake ₄ Cl solution, concentrated ammonia water and H ₂ O (4] ⁺ 。

And 5: synthesis of Compound 19f

To a reaction flask were added compound 19e (1.68g, 5.0mmol), 3,5-dimethoxyphenylacetylene (1.62g, 5.0mmol), bis (triphenylphosphine) palladium dichloride (351mg, 0.5mmol), cuprous iodide (95mg, 0.5mmol), triethylamine (2.53g, 25.0mmol) and 20ml of N, N-dimethylformamide. The mixture was purged with nitrogen 3 times, and reacted at 100 ℃ 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 compound 19f (1.55 g, yield 67%) as a tan solid, LC/MS (ESI): m/z =464[ M ] +H] ⁺ .

Step 6: synthesis of Compound 19g

The product 19f (1.39g, 3.0 mmol) obtained in the previous step and trimethyl orthoformate (40 ml) were added dropwise slowly to concentrated hydrochloric acid (3 ml) at room temperature, and stirred at room temperature overnight. The bulk solid precipitate was filtered and the filter cake was washed with petroleum ether and dried to give 19g (1.02 g,92% yield) of a tan solid compound, LC/MS (ESI): m/z =373[ M ] +H ]] ⁺ .

And 7: synthesis of Compound 1h

1g (0.56g, 1.5 mmol) of the compound of the previous step was added in portions to 80% sulfuric acid (11 mL), and the reaction was stirred at 60 ℃ for 2.5 hours. After cooling to room temperature, the reaction mixture was added to ice and heated to room temperature with stirring. The pH was adjusted to 8 with KOH and extracted with ethyl acetate (2X 10). Drying with anhydrous sodium sulfate, concentrating and decompressing to obtain brown solid intermediate 1h (0.55g, 92%) without further purification for next reaction, LC/MS (ESI): m/z =392[ M ] +H] ⁺ 。

And 8: synthesis of Compound 19

The compound (392mg, 1.0 mmol) and triethylamine were added to the reaction flask for 1h(152mg, 1.5 mmol), 4ml of dichloromethane, and after cooling in an ice-water bath, a solution of acryloyl chloride (136mg, 1.5 mmol) in 0.5ml of dichloromethane was slowly added dropwise. After the addition was complete, stirring was continued for 3 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 19 (151 mg, yield 34%) as a pale yellow solid. ¹ H NMR(400MHz,CD ₃ OD)δ:6.74-6.58(m,4H),6.32-6.22(m,1H),5.84-5.74(m,1H),4.13-3.96(m,1H),3.94-3.77(m,8H),3.76-3.63(m,2H),2.54-2.32(m,2H)；LC/MS(ESI):m/z＝446.2[M+H] ⁺ .

Example 20: preparation of 3- (3,5-dimethoxyphenylethynyl) -4- (1-acryloylpyrrolidin-3-amino) -2-oxoimidazo [3,4-c ] pyridine-7-carboxamide (Compound 20)

In a similar manner to example 19 (ring-closing starting material was changed to urea) was used to obtain compound 20 (129 mg, yield 28%, which is the final yield, the same applies hereinafter) as a yellow solid. ¹ H NMR(400MHz,CD ₃ OD)δ:6.75-6.58(m,4H),6.31-6.23(m,1H),5.83-5.74(m,1H),4.13-3.97(m,1H),3.94-3.76(m,8H),3.76-3.63(m,2H),2.53-2.33(m,2H)；LC/MS(ESI):m/z＝462.2[M+H] ⁺ .

Example 21: preparation of 6- (3,5-dimethoxyphenylethynyl) -4- (1-acryloylpyrrolidin-1-ylamino) -2-methylimidazo [3,4-c ] pyridine-7-carboxamide (Compound 21)

In a similar manner to example 19 (ring-closing material was changed to acetic anhydride), compound 21 (160 mg, yield 35%, this is the final yield, the same applies hereinafter) was obtained as a yellow solid. ¹ H NMR(400MHz,CD ₃ OD)δ:6.74-6.57(m,4H),6.32-6.22(m,1H),5.84-5.74(m,1H),4.13-3.97(m,1H),3.94-3.76(m,8H),3.76-3.63(m,2H),2.54-2.33(m,2H),1.96(s,3H)；LC/MS(ESI):m/z＝460.2[M+H] ⁺ .

Example 22: preparation of 6- (3,5-dimethoxyphenylethynyl) -4- (1-acryloylpyrrolidin-1-ylamino) -2,3-dioxopyrido [3,4-b ] pyrazine-7-carboxamide (Compound 22)

In a similar manner to example 19 (ring-closing raw material was changed to acetic anhydride), compound 22 (151 mg, yield 31%, which is the final yield, the same applies hereinafter) was obtained as a yellow solid. ¹ H NMR(400MHz,CD3OD)δ:6.76-6.57(m,4H),6.32-6.21(m,1H),5.84-5.74(m,1H),4.13-3.96(m,1H),3.94-3.78(m,8H),3.76-3.63(m,2H),2.54-2.30(m,2H)；LC/MS(ESI):m/z＝490.1[M+H] ⁺ .

Example 23: in vitro activity inhibition assay for kinases FGFR1, FGFR2, FGFR3 and FGFR4

FGFR1, FGFR2, FGFR3 and FGFR4 protein kinase activities are determined by using a Caliper mobility shift assay (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 the Caliper EZ Reader II (Caliper life Sciences). The conversion was converted into 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. Taking the concentration and the inhibition rate of the compound as horizontal and vertical coordinates, drawing a curve, fitting the curve by using XLFit excel add-in version4.3.1 software and calculating IC ₅₀ . The results of the assay are shown in the table below for the activity data of compounds 1-28 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" tableShow 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

Claims

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

wherein:

x1, X2, X3 may be independently selected from N, CR ¹ ；

X ₄ May be independently selected from absent, N, CR ¹ ；

The bonds a and b are single bonds or double bonds;

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 -；

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

Bond c is a double or triple bond;

G ¹ 、G ² 、G ³ 、G ⁴ and G ⁵ Each is independentSelected from 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);

m is 1 or 2.

2. A compound according to claim 1 or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, polymorph or isomer thereof and a mixture form thereof.

3. 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.