CN115073469A

CN115073469A - Preparation and application of pyrrolopyrimidine compound as kinase inhibitor

Info

Publication number: CN115073469A
Application number: CN202110277575.8A
Authority: CN
Inventors: 梁永宏
Original assignee: Yaoya Technology Shanghai Co ltd
Current assignee: Yaoya Technology Shanghai Co ltd
Priority date: 2021-03-15
Filing date: 2021-03-15
Publication date: 2022-09-20
Anticipated expiration: 2041-03-15
Also published as: CN115073469B

Abstract

The invention relates to a novel Bruton's tyrosine kinase inhibitor, which is a compound containing a polyaromatic heterocyclic structure and comprises a compound shown as a formula (I) or an isomer, a hydrate, a solvate, a polymorphic substance and a pharmaceutically acceptable salt thereof, and also discloses a preparation method of the compound and treatment by using the novel compoundOr preventing Bruton's tyrosine kinase related diseases such as Acute Lymphocytic Leukemia (ALL), Chronic Myelocytic Leukemia (CML), Mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, lupus erythematosus, etc.

Description

Preparation and application of pyrrolopyrimidine compound as kinase inhibitor

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a novel Bruton's tyrosine kinase inhibitor, and a preparation method and application thereof.

Background

Bruton's tyrosine kinase is a member of the Tec family of non-receptor protein tyrosine kinases. The Tec family is the 2 nd large family of human non-receptor kinases, next to the Src family, whose major members include Bruton's tyrosine kinase, bmx (etk), ITK, Tec, and txk (plk). Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agammaglobulinemia (XLA). This protein is expressed in ALL stages of B cell development (except for terminally differentiated plasma cells), Bruton's tyrosine kinase is an essential gene for cell differentiation and proliferation during the transition from pre-B lymphocytes to post-B cells, and is expressed in B cell lymphomas, Acute Lymphoblastic Leukemia (ALL), and plasmacytomas. In addition, there is a small amount of expression in bone marrow cells and erythroid progenitor cells.

Currently, Bruton's tyrosine kinase small molecule inhibitors such as ibrutinib (ibrutinib), acarabutinib (acarabutinib), and zebritinib (zanubutinib) are approved by the FDA in the united states for marketing for the treatment of Mantle Cell Lymphoma (MCL) and CLL.

Although ibrutinib, acartinib and zertinib are effective in treatment, a significant proportion of patients with clinical B-cell lymphoma are not susceptible to treatment except some patients who develop resistance at a later stage, for example, about 1/3 patients in MCL do not respond to treatment and the response rate in DLBCL is not high. In view of the above, there remains a need in the art to develop Bruton's tyrosine kinase inhibitors that are highly active and resistant to drugs.

Disclosure of Invention

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

wherein:

x1, X2, X3, X4 may be independently selected from N, CR ¹ ；

Ar ₁ And Ar ₂ Independently selected from a phenyl ring or a 5-6 membered heteroaromatic ring wherein said phenyl and heteroaromatic rings are optionally substituted by one or more G ¹ Get itGeneration; r ¹ Independently selected from H, D, cyano, halogen, C _1-6 Alkyl, COOH, CONH2, NHCOH, CONHR2, OR ² or-NHR ² ；

R ² Independently selected from H, D, 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;

L ₁ 、L ₂ and L ₃ Independently selected from absent, -C _0-4 Alkyl-, -CR ⁷ R ⁸ -、-C _1-2 Alkyl (R) ⁷ )(OH)-、-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 selects C _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclic, 5-12 membered spiroheterocyclic, wherein said cycloalkyl, heterocycloalkyl, spirocyclic, fused cyclic, fused heterocyclyl, spiroheterocyclic is optionally substituted with one or more G ² Substituted;

G ¹ and G ² Each independently selected from H, 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 ⁹ 、-OC(O)NR ⁹ R ¹⁰ 、-C(O)OR ⁹ 、-C(O)NR ⁹ R ¹⁰ 、-C(O)R ⁹ 、-NR ⁹ R ¹⁰ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ C(O)NR ¹⁰ R ¹¹ 、-S(O) _m R ⁹ or-NR ⁹ S(O) _m R ¹⁰ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more of 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 ¹² 、-OC(O)NR ¹² R ¹³ 、-C(O)OR ¹² 、-C(O)NR ¹² R ¹³ 、-C(O)R ¹² 、-NR ¹² R ¹³ 、-NR ¹² C(O)R ¹³ 、-NR ¹² C(O)NR ¹³ R ¹⁴ 、-S(O) _m R ¹² or-NR ¹² S(O) _m R ¹³ Substituted with the substituent(s); r ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、

And R ¹⁴ Each independently selected from H, D, cyano, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and is

m is 1 or 2.

Typical compounds of the invention include, but are not limited to, the following:

the invention provides a novel Bruton's tyrosine kinase inhibitor or an isomer, a hydrate, a solvate, a polymorph, a pharmaceutically acceptable salt and application of a pharmaceutically acceptable carrier in preparing the novel Bruton's tyrosine kinase inhibitor.

The pharmaceutical composition is in the form of tablets, capsules, granules, sprays or injections.

The pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder and a lubricant. Including but not limited to any and all solvents, dispersion media, coatings, absorption delaying agents, and the like, for use in the pharmaceutical active substance application in the art.

The invention also provides application of the novel Bruton's tyrosine kinase inhibitor or isomer, hydrate, solvate, polymorph and pharmaceutically acceptable salt thereof as the Bruton's tyrosine kinase inhibitor.

Further, the protein tyrosine kinase inhibitor is Bruton's tyrosine kinase inhibitor.

Use of a novel Bruton's tyrosine kinase inhibitor or an isomer, hydrate, solvate, polymorph, pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for the treatment or prevention of Bruton's tyrosine kinase related diseases.

Further, the Bruton's tyrosine kinase related diseases are selected from the group consisting of: acute Lymphocytic Leukemia (ALL), Chronic Myelocytic Leukemia (CML), Mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, lupus erythematosus, etc.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments of embodiments. It should not be understood that the scope of the above-described subject matter of this invention is limited to the following examples. All the technologies realized based on the above contents belong to the scope of the present invention.

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 so on.

"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, 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 can alternatively be fused together in two or three rings, such as decahydronaphthyl, which can 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 may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur of the heterocyclyl group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group 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-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 with one atom (called the spiro atom) shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) The remaining ring atoms are 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 spiroheterocyclyl radicals 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 monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

"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 4-11 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 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-CN, "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 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 the 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. 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.

The compounds of the present invention may also exist as geometric isomers. 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, such as 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. The compounds of the invention which contain acidic groups can therefore be present in salt form 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, in addition to the salt forms mentioned, internal or betaine salts. 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 benign tumors and malignant tumors (e.g., cancers).

The term "cancer" as used herein includes various malignancies in which Bruton's tyrosine kinase is involved, including, but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, striated muscle garnet, cell 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 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" 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 affect 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 adverse biological response or interacting in an adverse 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 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 can also be synthesized using synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein. 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).

The alkyne heterocyclic har compound of the general formula (I) can be synthesized according to the route of the method A: 1. starting material A1 was reacted with SEMCl under base action to form A2, 2, A2 was coupled with arylboronic acids by suzuki to give A3; 3. a3 and precursor L ₂ -Y undergoes a substitution reaction under the action of a base to form A4; 4. deprotection in A4 SEM afforded compounds of formula (I).

The method A comprises the following steps:

it can also be synthesized according to the route described in method B, starting material A2 and precursor L ₂ -Y undergoes a substitution reaction under the action of a base to form B1; coupling B1 with an aryl boronic acid through suzuki to obtain A4, and then obtaining the compound shown in the general formula (I) by the method of the method A.

Method B

It can also be synthesized according to the route described in method C, B1 with precursor L ₁ -Ar ₁ -L ₂ -Ar ₂ Carrying out substitution reaction under the action of alkali to generate C1; deprotection at C1 SEM afforded compounds of formula (I).

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

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 was performed using 200-300 mesh silica gel from Qingdao oceanic chemical plants; preparation of thin-layer chromatography silica gel precast slab (HSGF254) 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 (1H NMR) Using a Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic spectrometer, the nuclear magnetic data was performed using CDCl as the solvent ₃ 、CD ₃ OD、D ₂ O, DMS-d6, based on tetramethylsilane (0.000ppm) or based on residual solvent (CDCl) _3: 7.26ppm；CD ₃ OD:3.31ppm；D ₂ 4.79ppm of O; d6-DMSO:2.50ppm) when indicating the diversity of the peak shapes, the following abbreviations represent 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 given in Hertz (Hz).

Example 1: preparation of (R) -3- (4-phenoxy) phenoxy-4- (2-hydroxymethylmorpholin-4-yl) pyrrolo [2,3-d ] ] pyrimidine (Compound 1)

Method C for procurement, first step: synthesis of 1- (2- (trimethylsilyl) ethoxymethyl) -4-chloro-3-iodopyrrolo [2,3-d ] pyrimidine 1b

4-chloro-3-iodo-7H-pyrrolo [2,3-d]Pyrimidine (7.08g, 25.3mmol) was dissolved in dry DMF (100mL) and NaH (1.11g, 27.9mmol) was added at 0 ℃ under nitrogen, the solution was stirred for 30 minutes, then 2- (chloromethoxy) ethyltrimethylsilane (6.73mL, 38.0mmol) was added, and the solution was stirred at room temperature for 16 h. The mixture was diluted with NaOH (1m, 100mL), filtered, and the resulting solid was dried under reduced pressure to give the title product (9.8g, 95%). LC/MS (ESI) 410.1[ M + H ]] ⁺ .

The second step is that: synthesis of the Compound (R) -4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -3-iodopyrrolo [2,3-d ] pyrimidine 1c

(R) -morpholine-2-methanol hydrochloride (4.31g, 28.1mmol) and N, N-diisopropylethylamine (12.3g, 100.2mmol) were added to 1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d ]]Pyrimidine (12.3g, 25.6mmol) in n-butanol (300mL) and the reaction mixture was heated at reflux for 18 h and then concentrated under reduced pressure. Aqueous hydrochloric acid (0.1M, 1000mL) was added, the resulting solid was collected by filtration, washed with water (20mL) and dried under vacuum to afford the product (R) -4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -3-iodopyrrolo [2, 3-d) as a yellow solid]Pyrimidine (7.78g, 62%). LC/MS (ESI) M/z 491.1[ M + H ]] ⁺ .

The fourth step: synthesis of the Compound (R) -3- (4-phenoxy) phenoxy-4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d ] pyrimidine 1e

Under the protection of nitrogen, adding K ₂ CO ₃ (0.71g, 5.13mmol), 4-phenoxyphenol (0.35g, 1.88mmol) was added to (R) -4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -3-iodopyrrolo [2,3-d ]]Pyrimidine (0.84g, 1.71mmol) was dissolved in a solution of anhydrous 1, 4-dioxane (25 mL). The solution was stirred at 90 ℃ for 16 h. The mixture was filtered by rinsing through celite with MeOH (150mL)The compound was concentrated under reduced pressure and the filtrate was purified by flash column chromatography to give (R) -3- (4-phenoxy) phenoxy-4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d]Pyrimidine 0.524g, 56%). LC/MS (ESI) M/z 549.2[ M + H ]] ⁺ .

The fifth step: synthesis of Compound 1

The intermediate (R) -3- (4-phenoxy) phenoxy-4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2, 3-d) obtained in the last step]Pyrimidine (0.55g, 1mmol) dissolved in CF ₃ COOH (10mL), stirred at room temperature for 2h, then concentrated under reduced pressure, the residue dissolved in 10mL of methanol, then K ₂ CO ₃ Adjusting to neutral pH>8, followed by filtration, concentration under reduced pressure and purification by flash column chromatography, gave compound 1(176mg, yield 42%, this is the last step yield, the same below) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.52(br s,1H),8.52(s,1H),7.44(t,2H),7.36(d,2H),7.18-7.04(m,6H),4.22-4.01(m,3H),3.79-3.56(m,4H),3.08-2.98(m,1H),2.88-2.84(m,1H),2.10-2.03(m,1H)；LC/MS(ESI):m/z＝419.2[M+H] ⁺ .

Example 2: preparation of (S) -3- (4-phenoxy) phenoxy-4- (2-hydroxymethylmorpholin-4-yl) pyrrolo [2,3-d ] ] pyrimidine (Compound 2)

In a similar manner to example 1 (intermediate was changed to (S) -morpholine-2-methanol hydrochloride) gave compound 2(175mg, 42% yield, which was the final yield, the same applies hereinafter) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.53(br s,1H),8.52(s,1H),7.44(t,2H),7.36(d,2H),7.18-7.04(m,6H),4.22-4.01(m,3H),3.79-3.56(m,4H),3.08-2.98(m,1H),2.88-2.84(m,1H),2.10-2.03(m,1H)；LC/MS(ESI):m/z＝419.2[M+H] ⁺ .

Example 3: preparation of (R) -3- (4-phenoxymethyl) phenyl-4- (2-hydroxymethylmorpholin-4-yl) pyrrolo [2,3-d ] pyrimidine (Compound 2)

The purchasing method A comprises the following steps: synthesis of Compound (R) -3- (4-phenoxymethyl) phenyl-1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d ] pyrimidine 3a

Under the protection of nitrogen, adding K ₂ CO ₃ (7.08g, 51.3mmol), 4-phenoxymethylphenylboronic acid (4.29g, 18.8mmol) and Pd (DPPF) Cl ₂ (1.5g, 2.1mmol) was added to 1- (2- (trimethylsilyl) ethoxymethyl) -4-chloro-3-iodopyrrolo [2,3-d ]]Pyrimidine (7g, 17.1mmol) was dissolved in a solution of anhydrous 1, 4-dioxane (150 mL). The solution was stirred at 90 ℃ for 16 h. The mixture was filtered by rinsing with MeOH (150mL) through celite, the filtrate was concentrated under reduced pressure and purified by flash column chromatography to give 3- (4- (pyridin-2-aminoyl) phenyl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d]Pyrimidine (5.66g, 71%). LC/MS (ESI) M/z 467.2[ M + H ]] ⁺ .

The second step is that: synthesis of Compound (R)3- ((4-phenoxymethyl) phenyl) -4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d ] pyrimidine 3b

(R) -piperidine-3-methanol hydrochloride (431mg, 2.81mmol) and N, N-diisopropylethylamine (1.23g, 10.2mmol) were added to 3- (4- (pyridin-2-aminoacyl) phenyl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d]Pyrimidine (1.23g, 2.56mmol) in n-butanol (30mL) and the reaction mixture was heated at reflux for 18 h and then concentrated under reduced pressure. Aqueous hydrochloric acid (0.1M, 100mL) was added, the resulting solid was collected by filtration, washed with water (20mL) and dried under vacuum to afford the product (R) -3- (4- (pyridin-2-aminoacyl) phenyl) -4- (3-3-hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2, 3-d) as a yellow solid]Pyrimidine (1.06g, 76%). LC/MS (ESI) M/z 547.2[ M + H ]] ⁺ .

The third step: synthesis of Compound 3

The intermediate (R) -3- (4-phenoxymethyl) phenyl-4- (3-3-Hydroxymethylpiperidin-1-yl) -1- (2- (trimethylsilyl) ethoxymethyl) -4-chloropyrrolo [2,3-d]Pyrimidine (0.55g, 1mmol) dissolved in CF ₃ COOH (10mL), stirred at room temperature for 2h, then concentrated under reduced pressure, the residue dissolved in 10mL of methanol, then K ₂ CO ₃ Adjusting to neutral pH>8, followed by filtration, concentration under reduced pressure and purification by flash column chromatography, gave compound 3(191mg, yield 46%, which is the final step yield, the same below) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.61(br s,1H),8.46(s,1H),7.46-7.28(m,6H),7.10-7.03(m,4H),5.12(s,2H),4.22-4.01(m,3H),3.79-3.56(m,4H),3.08-2.98(m,1H),2.88-2.83(m,1H),2.10-2.02(m,1H)；LC/MS(ESI):m/z＝417.2[M+H] ⁺ Example 4: (S) -3- (4-phenoxymethyl) phenyl-4- (2-hydroxymethylmorpholin-4-yl) pyrrolo [2,3-d]]Preparation of pyrimidine (Compound 4)

In a similar manner to example 3 (intermediate was changed to (S) -morpholine-2-methanol hydrochloride), compound 4(195mg, 47% yield, which is the final yield, the same applies hereinafter) was obtained as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.58(br s,1H),8.46(s,1H),7.46-7.28(m,6H),7.10-7.03(m,4H),5.12(s,2H),4.22-4.01(m,3H),3.79-3.56(m,4H),3.08-2.98(m,1H),2.88-2.83(m,1H),2.10-2.02(m,1H)；LC/MS(ESI):m/z＝417.2[M+H] ⁺ .

Example 5: preparation of 3- (4-phenoxy) phenoxy-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] ] pyrimidine (Compound 5)

Using a method similar to example 1 (intermediate is exchanged for (2S,5R) -5-amino-2-tetrahydropyranyl)]Methanol) to give compound 5(156mg, yield 36%, which is the final step yield, the same below) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.48(br s,1H),8.52(s,1H),7.44(t,2H),7.36(d,2H),7.18-7.04(m,6H),4.68-4.67(m,1H),4.17-4.15(m,2H),3.43-3.32(m,3H),3.14-3.11(m,1H),2.21-2.18(m,1H),1.80-1.77(m,1H),1.58-1.55(m,1H),1.41-1.38(m,1H)；LC/MS(ESI):m/z＝433.2[M+H] ⁺ .

Example 6: preparation of 3- (4-anilino) phenoxy-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] ] pyrimidine (Compound 6)

In a similar manner to example 5 (intermediate was changed to 4-anilinophenol), Compound 6(176mg, yield 41% this was the last step yield, the same applies hereinafter) was obtained as a pale yellow solid. LC/MS (ESI): M/z 432.2[ M + H%] ⁺ .

Example 7: preparation of 3- (4-phenoxy) -3-chlorophenoxy-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] pyrimidine (Compound 7)

In a similar manner to example 5 (intermediate was changed to 4-phenoxy-2-chlorophenol) was obtained compound 7(196mg, yield 42%, which is the final yield, the same applies hereinafter) as a yellow solid. LC/MS (ESI) M/z 468.2[ M + H ]] ⁺ .

Example 8: preparation of 3- (4-phenoxy) -3-fluorophenoxy-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] pyrimidine (Compound 8)

Using a method similar to example 5 (intermediate was changed to 4-phenoxy-2-fluorophenol) gave compound 8(189mg, 42% yield, which is the final yield, the same applies hereinafter) as a yellow solid. LC/MS (ESI) with M/z 451.2[ M + H ]] ⁺ .

Example 9: preparation of 3-3- (4-phenoxymethyl) phenyl-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] pyrimidine (Compound 9)

Using a method similar to example 3 (intermediate is exchanged for (2S,5R) -5-amino-2-tetrahydropyranyl)]Methanol) to give compound 9(206mg, yield 48%, which is the final yield, the same below) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.47(br s,1H),8.46(s,1H),7.46-7.28(m,6H),7.10-7.01(m,4H),5.12(s,2H),4.68-4.67(m,1H),4.17-4.15(m,2H),3.43-3.31(m,3H),3.14-3.10(m,1H),2.22-2.18(m,1H),1.80-1.78(m,1H),1.59-1.55(m,1H),1.41-1.37(m,1H)；LC/MS(ESI):m/z＝431.2[M+H] ⁺ .

Example 10: preparation of 3-3- (4-Phenylmethoxy) phenyl-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] pyrimidine (Compound 10)

In a similar manner to example 9 (intermediate was changed to 4-benzyloxyphenylboronic acid), compound 10(232mg, yield 54%, which is the final yield, the same applies hereinafter) was obtained as a yellow solid. LC/MS (ESI) M/z 431.2[ M + H ]] ⁺ .

Example 11: preparation of 3-3- (4- (pyridin-2-yloxymethyl)) phenyl-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] ] pyrimidine (Compound 11)

In a similar manner to example 9 (intermediate was changed to 4- (pyridine-2-oxymethyl) phenylboronic acid), compound 11(224mg, yield 52%, which is the final yield, the same applies hereinafter) was obtained as a yellow solid. LC/MS (ESI): M/z 432.2[ M + H%] ⁺ .

Example 12: preparation of 3-3- (4- (pyridin-2-methoxy)) phenyl-4- (((3R,6S) -6- (hydroxymethyl) tetrahydropyran-3-yl) amino) pyrrolo [2,3-d ] pyrimidine (Compound 12)

In a similar manner to example 1 (intermediate was changed to 4- (pyridine-2-methoxy) phenylboronic acid), compound 12(207mg, yield 48%, which is the final yield, the same applies hereinafter) was obtained as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ:12.53(br s,1H),8.66-8.62(m,1H),8.47(s,1H),7.52-7.44(m,3H),7.34-7.30(m,1H),7.18(d,2H),7.08-7.01(m,2H),5.27(s,2H),4.68-4.67(m,1H),4.17-4.15(m,2H),3.43-3.32(m,3H),3.14-3.11(m,1H),2.22-2.18(m,1H),1.80-1.79(m,1H),1.59-1.55(m,1H),1.41-1.38(m,1H)；LC/MS(ESI):m/z＝432.2[M+H] ⁺ .

Example 13: in vitro activity inhibition assay for kinases BTK, BTK (R28H)

1.1BTK inhibitory Activity screening

With kinase buffer (50mM HEPES, 10mM MgCl) ₂ 2mM DTT, 1mM EGTA, 0.01% Tween20) 350ng/uL of BTK stock solution was diluted, 6. mu.L of 1.67 X0.134 ng/uL working solution (final concentration of 0.08 ng/uL) was added to each well, and DMSO-dissolved different compounds 1-16 were added to the wells using a nanoliter loader so that the final concentration of the compounds was 1000nM-0.244nM, the final concentration of the positive drugs was 50nM-0.0122nM, 4-fold gradient, for a total of 7 concentrations, while blank (no enzyme) and negative (enzyme-containing, vehicle DMSO) control wells were set, and 2 replicate wells were set. After the enzyme reacts with the compound or the solvent for 30min, 5 X250. mu. MATP (final concentration of 50uM) prepared by using a kinase buffer solution and 5 X0.5. mu.M substrate (final concentration of 0.1. mu.M, ULight-poly GT) are mixed according to a ratio of 1:1, and 4. mu.L of the substrate per well is added into the well; after the plate was covered with a membrane, after 2 hours of reaction at room temperature, 5. mu.L of 4X 8nM detection reagent (final concentration: 2nM, Ab) was added to each well and incubated at room temperature for 1 hour; the plate was read with a PE instrument (excitation 620nm, emission 665 nm). Calculating the inhibition ratio, and calculating IC ₅₀ The value is obtained. The results of the measurements are shown in the following table,wherein "A" represents IC ₅₀ Less than or equal to 10 nM; "B" means 10nM<IC ₅₀ Less than or equal to 100 nM; "C" means 100<IC ₅₀ ≤2000nM。

Claims

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

wherein:

x1, X2, X3, X4 may be independently selected from N, CR ¹ ；

Ar ₁ And Ar ₂ Independently selected from a phenyl ring or a 5-6 membered heteroaromatic ring wherein said phenyl and heteroaromatic rings are optionally substituted by one or more G ¹ Substituted;

R ¹ independently selected from H, D, cyano, halogen, C _1-6 Alkyl, COOH, CONH2, NHCOH, CONHR2, OR ² or-NHR ² ；

L ₁ ，L ₂ and L ₃ Independently selected from absent, -C _0-4 Alkyl-, -CR ⁷ R ⁸ -、-C _1-2 Alkyl (R) ⁷ )(OH)-、-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 -；

G ¹ and G ² Each independently selected from H, 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 ⁹ 、-OC(O)NR ⁹ R ¹⁰ 、-C(O)OR ⁹ 、-C(O)NR ⁹ R ¹⁰ 、-C(O)R ⁹ 、-NR ⁹ R ¹⁰ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ C(O)NR ¹⁰ R ¹¹ 、-S(O) _m R ⁹ or-NR ⁹ S(O) _m R ¹⁰ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more of 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 ¹² 、-OC(O)NR ¹² R ¹³ 、-C(O)OR ¹² 、-C(O)NR ¹² R ¹³ 、-C(O)R ¹² 、-NR ¹² R ¹³ 、-NR ¹² C(O)R ¹³ 、-NR ¹² C(O)NR ¹³ R ¹⁴ 、-S(O) _m R ¹² or-NR ¹² S(O) _m R ¹³ Substituted with a substituent of (a);

R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ and R ¹⁴ Each independently selected from H, D, cyano, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and is

m is 1 or 2.

2. A compound, pharmaceutically acceptable salt, polymorph or isomer of claim 1, and mixtures thereof.

3. Selected from the following compounds

Or pharmaceutically acceptable salts, isomers and mixtures and forms thereof.

4. A pharmaceutical composition comprising a novel Bruton's tyrosine kinase inhibitor of claim 1 or 3, or an isomer, hydrate, stable isotope derivative, solvate, polymorph, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.

6. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder, and a lubricant.

7. Use of a novel Bruton's tyrosine kinase inhibitor according to claims 1 and 3, or isomers, hydrates, solvates, polymorphs, pharmaceutically acceptable salts thereof, as protein tyrosine kinase inhibitors.

8. Use according to claim 7, characterized in that: the protein tyrosine kinase inhibitor is Bruton's tyrosine kinase inhibitor.

9. Use of a novel Bruton's tyrosine kinase inhibitor of claims 1 and 3 or an isomer, hydrate, solvate, polymorph, pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 4 to 6 for the treatment or prevention of Bruton's tyrosine kinase related diseases.

10. Use according to claim 9, characterized in that: the Bruton's tyrosine kinase related diseases are selected from the group consisting of: acute Lymphocytic Leukemia (ALL), Chronic Myelocytic Leukemia (CML), Mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplantation rejection, psoriasis, lupus erythematosus, etc.