CN114957242B - Preparation and application of pyrido heterocyclic compounds as kinase inhibitors - Google Patents

Abstract

The invention relates to a novel Bruton's tyrosine kinase inhibitor, which is a compound containing a polyaromatic heterocyclic structure, comprising compounds shown in formulas (I) and (II) or isomers, stable isotope derivatives, hydrates, solvates, polymorphs and pharmaceutically acceptable salts thereof, and also discloses a preparation method of the compound and a method for using the novel compound to treat or prevent Bruton's tyrosine kinase related diseases such as Acute Lymphoblastic Leukemia (ALL), chronic Myeloblastic Leukemia (CML), mantle Cell Lymphoma (MCL), colorectal cancer, rheumatoid arthritis, organ transplantation rejection resistance, psoriasis resistance, lupus erythematosus and the like.

Description

Preparation and application of pyrido heterocyclic compounds as kinase inhibitors

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 largest family of human non-receptor kinases next to the Src family, the major members of which 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 agaropectinemia (X-linked agammaglobulinemia, XLA). This protein is expressed at various stages of B cell development (except for terminally differentiated plasma cells), and 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 also a small expression in bone marrow cells and erythroid progenitors.

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

Although ibrutinib, acartinib and zebutinib are therapeutically effective, a significant proportion of clinical B-cell lymphoma patients are not susceptible to their treatment, except for a proportion of patients who develop resistance later, such as approximately 1/3 of the patients in MCL do not respond to their treatment, nor do the response rates in DLBCL. In view of the above, there remains a need in the art to develop highly active, specific inhibitors of Bruton's tyrosine kinase.

Disclosure of Invention

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

X ₁ ，X ₂ ，X ₄ can be independently selected from N, CR ¹ ；

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

X ₃ can be independently selected from the group consisting of absence, N, CR ¹

Ar ₁ And Ar is a group ₂ Independently selected from benzene rings or 5-6 membered heteroaromatic rings, wherein said benzene rings and heteroaromatic rings are optionally substituted with one or more G ¹ Substituted;

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

R ² Independently selected from H, cyano, halogen, C _1-6 Alkyl, 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 with cyano, halogen, -OR ⁵ 、-NR ⁵ R ⁶ 、C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

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

Y is absent or C is selected _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiroheterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, spiroheterocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is optionally substituted with one or more G ¹ Substituted;

z is independently selected from cyano, -NR ¹² CN、Bond c is a double bond or a triple bond;

when c is a double bond, R ^a 、R ^b And R is ^c Each independently selected from H, cyano, halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl. Wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G ² Substituted;

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

When bond c is a triple bond, R ^a And R is ^c Absent, R ^b Independently selected from H, cyano, halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl groups substituted by one or more G ³ Substituted;

R ¹² independently selected from H, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G ⁴ Substituted;

G ¹ 、G ² 、G ³ and G ⁴ Each independently selected from cyano, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, 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 Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more cyano, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ¹⁶ 、-OC(O)NR ¹⁶ R ¹⁷ 、-C(O)OR ¹⁶ 、-C(O)NR ¹⁶ R ¹⁷ 、-C(O)R ¹⁶ 、-NR ¹⁶ R ¹⁷ 、-NR ¹⁶ C(O)R ¹⁷ 、-NR ¹⁶ C(O)NR ¹⁷ R ¹⁸ 、-S(O) _m R ¹⁶ or-NR ¹⁶ S(O) _i R ¹⁷ Is substituted by a substituent of (2);

R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ and R is ¹⁸ Each independently selected from hydrogen, cyano, halogen, C _1-6 Alkyl, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and m is 1 or 2.

Typical compounds of the present 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 and a pharmaceutically acceptable salt thereof, and application of a pharmaceutically acceptable carrier in preparing the novel Bruton's tyrosine kinase inhibitor.

The pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.

The pharmaceutically acceptable carrier is selected from one or more of filler, disintegrant, binder and lubricant. Including but not limited to any and all solvents, dispersion media, coatings, absorption retarders, and the like, such media and agents being used in the art for pharmaceutically active substances.

The invention also provides application of the novel Bruton's tyrosine kinase inhibitor or isomers, hydrates, solvates, polymorphs and pharmaceutically acceptable salts thereof as the Bruton's tyrosine kinase inhibitor.

Further, the protein tyrosine kinase inhibitor is a 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 prophylaxis of Bruton's tyrosine kinase associated disorders.

Further, the Bruton's tyrosine kinase related disease is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, lupus erythematosus, etc.

It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments. It should not be understood that the scope of the above subject matter of the present invention is only the following examples. All techniques based on the above are within the scope of the present invention.

Certain chemical terms

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

The expression "C" as used herein has the following meaning _x-y "means a range of carbon number wherein x and y are integers, e.g. C _3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C _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.

"alkyl" refers to a straight or branched hydrocarbon 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 hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 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 hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 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 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 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 decalin, which cycloalkyl groups may be substituted or unsubstituted.

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

"spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl 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 the other rings in the system, one or more of which may contain one or more double bonds, but none of which 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 from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Condensed heterocyclic radicals Non-limiting embodiments 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, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, 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, the heteroaryl group is preferably a 5-8 membered heteroaryl group 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, "amino" means-NH ₂ "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," Isocyano "means-NC," trifluoromethyl "means-CF ₃ 。

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

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

The term "spiro" or "spiro" 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, e.g., an "optionally alkyl-substituted heterocyclic group" 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, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, the substituents being in their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl groups, and the like.

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

"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". 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 in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.

The compounds of the 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 Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as 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 limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.

"isotopes" are all isotopes of atoms that are present in compounds of the 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, respectively, for example but not limited toNot limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the invention according to well known methods.

"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared 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 encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the invention containing acidic groups may be present in salt form and may 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 salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups may be present in salt form and may 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 includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual 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, in the present application, when referring to "a compound", "a compound of the application" or "a compound of the application" all such compound forms, e.g. prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof are included.

Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).

As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, 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 cancer), more particularly liver cancer, gastric cancer and bladder cancer.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers 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 of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.

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

Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds 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 is also possible. 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 simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a material (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 material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.

The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, 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, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related 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, including

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

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

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

(iv) Relieving symptoms caused by diseases or symptoms.

The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.

The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, 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, however, should not be regarded as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.

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

Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.

Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Therno LCD Fleet type (ESI) liquid chromatograph-mass spectrometer.

Nuclear magnetic data (1H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments, the solvent used for the nuclear magnetic data was CDCl ₃ 、CD ₃ OD、D ₂ O, DMS-d6, etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) _3: 7.26ppm；CD ₃ OD:3.31ppm；D ₂ O4.79 ppm; d6-DMSO:2.50 ppm) when peak shape diversity is indicated, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).

Example 1: preparation of (S) -7- (4-phenoxyphenyl) -5- (3-but-2-ynylamidopiperidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] bipyrazine-8-carboxamide (Compound 1)

Step 1: synthesis of Compound 1b

Raw material 2, 6-dichloro-3-nitro-4-aminopyridine 1a (20.8 g,0.1 mol), (S) -3-Boc-aminopiperidine (22 g,0.11 mol), potassium carbonate (22 g,0.2 mmol) catalytic amount of potassium iodide and DMF (2000 mL) were mixed, heated to 120℃and stirred for 4 hours. Cooled to room temperature and evaporated under reduced pressure to give 1c (20.8 g, 56%) as a yellow solid, LC/MS (ESI): m/z=373 [ M+H ]] ⁺ 。

Step 2: synthesis of Compound 1c

After mixing the product 1b (18.59 g,0.05 mol), 4-phenoxyphenylboronic acid (10.7 g,0.05 mol), tris (dibenzylideneacetone) dipalladium (4 g,4.4 mmol), cesium carbonate, 1, 4-dioxane (500 mL) and water (100 mL) obtained in the previous step, the mixture was then The mixture was heated to 120℃under reflux and reacted with stirring for 16 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (10 mL) and the solids were collected by filtration. The crude product was slurried with methanol (50 mL) and then a beige solid 1b (12.9 g, 51%) was obtained, which was used in the next reaction without further purification, LC/MS (ESI): m/z=506 [ M+H ]] ⁺ 。

Step 3: synthesis of Compound 1d

N-bromosuccinimide (5.2 g,29.6 mmol) was added to a solution of 1c (12.1 g,24 mmol) in acetic acid (100 mL). After stirring at 60℃for 2 hours, acetic acid was removed under reduced pressure. The residue was suspended in water (60 mL) and saturated sodium bicarbonate solution (40 mL) was added. The solid was filtered and stirred in 80 ℃ water (200 mL) for 30 minutes. After cooling to ambient temperature, the solid was filtered and dried under vacuum to give crude tan solid 1d (12.2 g, 87%) which was used in the next reaction without further purification, LC/MS (ESI): m/z=585 [ m+h ]] ⁺ 。

Step 4: synthesis of Compound 1e

Under nitrogen, 1d (7.8 g,13.35 mmol), zn (CN) ₂ A mixture of (940 mg,8 mmol), tris (dibenzylideneacetone) dipalladium (0.61 g,0.65 mmol) and 1,1' -bis (diphenylphosphino) ferrocene (0.74 g,1.35 mmol) was added to DMF/H2O (99:1, 50 mL), stirred for 30 min, then heated to 120℃and stirred for 24H. The resulting mixture was cooled to room temperature, and saturated NH ₄ Cl solution, concentrated ammonia water, H ₂ O (4:1:4, 10 mL) was precipitated. The reaction was cooled to 0 ℃ and filtered. Saturated NH for filter cake ₄ Cl solution, concentrated ammonia water, H ₂ O (4:1:4, 2 mL) and drying under vacuum afforded a dark brown solid (5.38 g, 76%) which was used in the next reaction without further purification, LC/MS (ESI): m/z=531 [ M+H ]] ⁺ 。

Step 5: synthesis of Compound 1f

1e (5.31 g,10 mmol) was dissolved in 50mL of ethanol and hydrogenated over Raney nickel catalyst (2.0 g) at room temperature under 1.0atm H2 atmosphere for 4h. After the reaction was completed, 1.6g of celite was added to the solution, the mixture was vigorously stirred and filtered over a pad of celite. Purifying the filtrate by silica gel column chromatography to obtain dark brownSolid 1f (4.70 g, 94%) was used in the next reaction without further purification, LC/MS (ESI): m/z=501 [ M+H ]] ⁺ 。

Step 6: synthesis of Compound 1g

To a solution of 1f (2.5 g,5 mmol) and 20ml methanol was added sodium methoxide (0.63 g) and the mixture was stirred at room temperature for 30 minutes. A solution of diethyl oxalate (0.76 g,5.1 mmol) in 8ml of methanol was added dropwise to the mixture for 30 minutes, and the resulting mixture was heated to reflux for 7h. The mixture was concentrated under reduced pressure, diluted with 30mL of water, and then cooled in an ice bath. The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to give 1g (2.6 g, 94%) of compound as a yellow solid, which was used in the next reaction without further purification, LC/MS (ESI): m/z=555 [ m+h ] ] ⁺ 。

Step 7: synthesis of Compound 1h

1g (1.66 g,3 mmol) of the compound from 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). Drying over anhydrous sodium sulfate, concentration and depressurization afforded brown solid intermediate 1h (1.40 g, 97%) for the next reaction without further purification, LC/MS (ESI) m/z=473 [ M+H ]] ⁺ 。

Step 8: synthesis of Compound 1

To a 25mL three-necked flask was added intermediate 1h (237 mg,0.5 mmol) in N, N-dimethylformamide (8 mL) and-2-butynoic acid (46.2 mg,0.55 mmol), HATU (379 mg, 164 mmol) and N-ethyldiisopropylamine (275. Mu.L) (temperature raised to 35 ℃). The final solution was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (10 ml) and washed with water (5 ml). The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2X 10 ml). The combined organic extracts were washed with wash water (containing small amounts of sodium chloride) (4×10 ml), rinsed with brine (10 ml) and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give compound 1 (140 mg, yield 52%) as a yellow solid. ¹ HNMR(400MHz,CD3OD)δ:7.41-7.04(m,11H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝539.2[M+H] ⁺ .

Example 2: preparation of (R) -7- (4-phenoxyphenyl) -5- (3-but-2-ynylamidopiperidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] bipyrazine-8-carboxamide (Compound 2)

Using a method similar to example 1 (intermediate changed to (R) -3-Boc-aminopiperidine), compound 2 (129 mg, yield 48%, which was the final step yield, the same applies hereinafter) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.41-7.04(m,9H),3.98-3.84(m,1H),3.19-3.06(m,1H),3.06-2.89(m,1H),3.08-2.90(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＝539.2[M+H] ⁺ .

example 3: preparation of (S) -7- (4-phenoxyphenyl) -5- (3-acrylamidopiperidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] and pyrazine-8-carboxamide Compound 3)

Using a method similar to example 1 (intermediate was changed to acrylic acid), compound 3 (100 mg, yield 38%, which was the final yield, the same as that described below) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.43-7.04(m,9H),6.27-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.01(br s,1H),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),1.35(s,1H)；LC/MS(ESI):m/z＝527.2[M+H] ⁺ .

example 4: preparation of (R) -7- (4-phenoxyphenyl) -5- (3-acrylamidopiperidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] and pyrazine-8-carboxamide Compound 4)

Using a method similar to example 1 (intermediate was changed to acrylic acid), compound 4 (84 mg, yield 32%, which was the final yield, the same as that described below) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.43-7.04(m,9H),6.27-6.17(m,1H),6.13-6.03(m,1H),5.59(dd,1H),4.01(br s,1H),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),1.35(s,1H)；LC/MS(ESI):m/z＝511.2[M+H] ⁺ .

example 5: preparation of (S) -7- (4-phenoxyphenyl) -5- (3-but-2-ynylamidopyrrolidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] bipyrazine-8-carboxamide (Compound 5)

Using a method similar to example 1 (intermediate changed to (S) -3-Boc-aminopyrrolidine), compound 5 (147 mg, 56% yield, the last step yield, the same below) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),4.34(m,1H),3.26-3.13(m,2H),3.11-2.97(m,2H),2.24(m,1H),1.94(s,3H),1.85(m,1H)；LC/MS(ESI):m/z＝525.2[M+H] ⁺ .

example 6: preparation of (R) -7- (4-phenoxyphenyl) -5- (3-but-2-ynylamidopyrrolidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] bipyrazine-8-carboxamide (Compound 6)

Using a method similar to example 2 (intermediate changed to (R) -3-Boc-aminopyrrolidine), compound 6 (160 mg, 61% yield, which was the final step yield, the same applies hereinafter) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),4.34(m,1H),3.26-3.13(m,2H),3.11-2.97(m,2H),2.24(m,1H),1.94(s,3H),1.85(m,1H)；LC/MS(ESI):m/z＝525.2[M+H] ⁺ .

example 7: preparation of (S) -7- (4-phenoxyphenyl) -5- (3-acrylamidopyrrolidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] naphthyridine-8-carboxamide (Compound 7)

Using a method similar to example 2 (intermediate changed to (S) -3-Boc-aminopyrrolidine), compound 7 (97 mg, 38% yield, the last step yield, the same below) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),6.71-6.55(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝513.2[M+H] ⁺ .

example 8: preparation of (R) -7- (4-phenoxyphenyl) -5- (3-acrylamidopyrrolidin-1-yl) -2, 3-dioxo-pyridine [3,4-b ] ] naphthyridine-8-carboxamide (Compound 8)

Using a method similar to example 1 (intermediate changed to (R) -3-Boc-aminopyrrolidine), compound 8 (92 mg, 36% yield, which was the final step yield, the same applies hereinafter) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.42-7.06(m,9H),6.71-6.55(d,1H),6.32-6.22(m,1H),5.74(m,1H),4.40-4.23(m,2H),3.91(dd,1H),3.86-3.58(m,3H),2.24-2.02(s,2H)；LC/MS(ESI):m/z＝513.2[M+H] ⁺ .

Example 9: preparation of (S) -6- (4-phenoxyphenyl) -4- (3-but-2-ynylamidopiperidin-1-yl) -imidazo [4,5-c ] pyridine-7-carboxamide (Compound 9)

Using a method similar to example 1 (intermediate was changed to triethyl orthoformate) compound 9 (123 mg, yield 52%, which was the final yield, the same below) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:8.13(s,1H),7.41-7.06(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝495.2[M+H] ⁺ .

example 10: preparation of (S) -6- (4-phenoxyphenyl) -4- (3-but-2-ynylamidopiperidin-1-yl) -2-methylimidazole [4,5-c ] naphthyridine-7-carboxamide (Compound 10)

Using a method similar to example 1 (intermediate was changed to acetic anhydride), compound 9 (124 mg, yield 49%, which was the final yield, the same as below) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.43-7.08(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝509.2[M+H] ⁺ .

example 11: preparation of 6- (4-phenoxyphenyl) -5- (1-acrylamidopiperidin-4-yl) -2-oxo-imidazo [4,5-c ] pyridine-8-carboxamide (Compound 11)

Preparation of key intermediate 4, 6-dichloro-2-oxo-imidazo [4,5-c ] ] pyridine-7-carboxamide 11a

N-bromosuccinimide (5.2 g,29.6 mmol) was added to 4, 6-dichloro-2-oxo-imidazo [4,5-c]]And pyridine (5.6 g,27 mmol) in acetic acid (100 mL). After stirring at 60℃for 2 hours, acetic acid was removed under reduced pressure. The residue was suspended in water (60 mL) and saturated sodium bicarbonate solution (40 mL) was added. The solid was filtered and stirred in 80℃water (200 mL) for 30 And (3) minutes. After cooling to ambient temperature, the solid was filtered and dried under vacuum to give crude 4, 6-dichloro-6-bromo-2-oxo-imidazo [4,5-c]]7.11g of naphthyridine and 93 percent of yield. LC/MS (ESI) m/z=283 [ M+H ]] ⁺ .

N, N' -tetramethyl ethylenediamine (9 g,50.1 mmol) was added to the product of the last step 4, 6-dichloro-6-bromo-2-oxo-imidazo [4,5-c]]And pyridine (5.64 g,20 mmol) in anhydrous tetrahydrofuran (100 mL) and the solution was stirred under nitrogen at-60℃for 1 min. N-butyllithium (20.4 mL,50.1mmol, 2.5M in hexanes) was slowly added and the mixture was stirred for 2 hours. Dry carbon dioxide gas was bubbled into the solution, and the mixture was stirred at-60℃for 1 hour. After heating to ambient temperature, water (100 mL) was added. Tetrahydrofuran was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous layer was acidified with 1M hydrochloric acid to ph=1 and the solid was filtered to give crude 4, 6-dichloro-2-oxo-imidazo [4,5-c]]3.77g of naphthyridine-7-carboxylic acid, yield 76%. LC/MS (ESI) m/z=249 [ M+H ]] ⁺ .

4, 6-dichloro-2-oxo-imidazo [4,5-c]]And pyridine-7-carboxylic acid (2.49 g,10 mmol) was dissolved in thionyl chloride (40 ml), and the mixture was stirred at 75℃for 2 hours. Excess thionyl chloride was removed under vacuum and the residue was dissolved in anhydrous tetrahydrofuran (40 mL). Aqueous ammonia (6.0 mL) was added at 0 ℃ and the mixture stirred at ambient temperature for 10 hours. The solid was filtered and recrystallized from ethanol (20 mL) to give 4, 6-dichloro-2-oxo-imidazo|4, 5-c ]Pyridine-7-carboxamide 2.08g, 84% yield. LC/MS (ESI) m/z=248 [ M+H ]] ⁺ .

Step 1: synthesis of Compound 6- (4-phenoxyphenyl-2-oxo-imidazo [4,5-c ] pyridine-8-carboxamide 11b

The raw material 4, 6-dichloro-2-oxo-imidazole [4,5-c]]And pyridine-7-carboxamide 11a (3.7 g,15 mmol), 4-phenoxyphenylboronic acid (6.42 g,30 mmol) and tripotassium phosphate monohydrate (10.35 g,45 mmol) were dissolved in dioxane (200 mL) and water (20 mL). After multiple nitrogen charges, tetrakis (triphenylphosphine) palladium (2.31 g,2 mmol) was added. The mixture was sprayed with nitrogen for another 5 minutes and then heated at reflux for 24 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow colorAnd (3) precipitate. The reaction mixture was diluted with water (10 mL) and the solids were collected by filtration. The crude product was slurried with methanol (150 mL) and then a beige solid 1b (2.91 g, 52%) was obtained, which was used in the next reaction without further purification, LC/MS (ESI): m/z=382 [ M+H ]] ⁺ 。

Step 2: synthesis of Compound 11c

The intermediate 6- (4-phenoxyphenyl-2-oxo-imidazole [4, 5-c) of the previous step]And pyridine-8-carboxamide 11b (1.9 g,5 mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (2.31 g,7.5 mmol), potassium carbonate (2.07 g,15 mmol), tetrakis (triphenylphosphine) palladium, 1, 4-dioxane (100 mL) and water (25 mL) were mixed, and then heated under reflux under nitrogen atmosphere, followed by stirring for 16 hours. The reaction was cooled to room temperature and stirred overnight, the reaction mixture was evaporated under reduced pressure and purified by column chromatography to give off-white solid 1b (1.0 g, 38%) which was used in the next reaction without further purification, LC/MS (ESI): m/z=528 [ m+h ] ] ⁺ 。

Step 3: synthesis of Compound 11d

To a solution of the compound 11C (528 mg,1 mmol) of the previous step in ethyl acetate (10 mL) and methanol (10 mL) was added 10% Pd/C (0.1 g), and the reaction was degassed 6 times with hydrogen, then stirred at room temperature under a hydrogen atmosphere for 12h. The solution was filtered and the filtrate was evaporated to a brown solid, crude product 11d (507 mg, 96%) which was subjected to the next reaction without further purification, LC/MS (ESI): m/z=530 [ M+H ]] ⁺ 。

Step 4: synthesis of Compound 11e

To the reaction flask was added the last intermediate 11d (0.265 g,0.5 mmol), 2ml ethyl acetate, 4ml 1N HCl in 1, 4-dioxane. The mixture was stirred at room temperature for 2 hours, the reaction mixture 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 evaporated to dryness under reduced pressure. Compound 11e (0.170 g, 79% yield) was obtained and used directly in the next step, LC/MS (ESI): m/z=430.2 [ M+H ]] ⁺ 。

Step 5: synthesis of Compound 11

In a reaction flask was charged compound 11e (129 mg,0.3 mmol), triethylamine (51 mg,0.5 mmol), 4ml tetrahydrofuran, iceAfter cooling in a water bath, a solution of but-2-ynyl chloride (45 mg,0.5 mmol) in 0.5ml of tetrahydrofuran was slowly added dropwise. Stirring was continued for 4 hours after the addition was completed. The reaction mixture was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 11 (52 mg, yield 36%) as a yellow solid. ¹ H NMR(400MHz,CD ₃ OD)δ:7.43-7.08(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝484.2[M+H] ⁺ .

Examples 12 and 13: preparation of (S) -6- (4-phenoxyphenyl) -5- (3-acrylamidopiperidin-4-yl) -2-oxo-imidazo [4,5-c ] pyridine-8-carboxamide (Compound 12) and (R) -6- (4-phenoxyphenyl) -5- (3-acrylamidopiperidin-4-yl) -imidazo [4,5-c ] pyridine-8-carboxamide (Compound 13)

Using a method similar to example 11 (intermediate was changed to 1-tert-butoxycarbonyl-3, 6-dihydro-2H-pyridine-5-boronic acid pinacol ester), compound 9 (124 mg, yield 49%, final step yield, the same follows) was obtained as a pale yellow solid, ¹ H NMR(400MHz,CD3OD)δ:7.43-7.08(m,9H),3.98-3.83(m,1H),3.19-3.07(m,1H),3.06-2.89(m,1H),3.06-2.91(m,1H),2.80(br s,1H),2.54(s,3H),1.96(s,3H),1.91-1.80(m,1H),1.73(s,2H),and 1.35(s,1H)；LC/MS(ESI):m/z＝509.2[M+H] ⁺ .

example 14: preparation of (S) -6- (4-phenoxyphenyl) -4- (3-but-2-ynylamidopiperidin-1-yl) -pyrrole [3,2-c ] ] bipyridinyl-7-carboxamide (Compound 14)

Preparation of key intermediate 4, 6-dichloro-pyrrolo [3,2-c ] ] pyridine-7-carboxamide 14a

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N-butyllithium (27.8 mL, 2.5M in hexanes, 69.6 mmol) was added to a solution of diisopropylamine (7.5 g,74.3 mmol) in tetrahydrofuran (50 mL) at-78deg.C, the mixture was stirred at-78deg.C for 30 min, and a solution of 2, 6-dibromo-nitropyridine (19.0 g,67.6 mmol) in tetrahydrofuran (50 mL) was added over 40 min. The mixture was stirred at-78 ℃ for 3 hours. The dried carbon dioxide was bubbled into the reaction mixture, and the mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate (50 mL) and 10% aqueous sodium hydroxide solution (100 mL). The aqueous phase was made acidic with concentrated hydrochloric acid and extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give intermediate 2, 6-dibromo-4-nitronicotinic acid (), without further purification. LC/MS (ESI) m/z=326 [ M+H ] ] ⁺ 。

2, 6-dibromo-4-nitronicotinic acid (49 g,154mmol in dry THF (1000 mL), cooled to-40deg.C and-50deg.C and stirred for about 5mm, then vinylmagnesium bromide (692 mL,692mmol in THF) was added dropwise, the mixture stirred for about 4h at about-40deg.C and-50deg.C, saturated NH was used ₄ Aqueous C1 (20 mL) quenched the reaction. The solvent was removed under reduced pressure to give a residue which was purified by preparative HPLC to give 4, 6-dibromo-1H-pyrrolo [3,2-c]Pyridine-7-carboxylic acid (5.4 g), yield 11%. LC/MS (ESI) m/z=321 [ M+H ]] ⁺ 。

To 4, 6-dibromo-1H-pyrrolo [3,2-c]To a solution of pyridine-7-carboxylic acid (3.2 g,1. Mmol) in DMF (50 mL) was added HOBt (2.29 g,15 mmol) and EDCl (2.88 g,15 mmol). After stirring the reaction mixture at room temperature for about 1 hour, NH was added ₃ THF (200 mL) and the resulting mixture was stirred at room temperature overnight. The suspension was then filtered and the filtrate concentrated under reduced pressure. Water was added thereto, and extraction was performed with ethyl acetate. The combined organic phases were washed with brine, taken up in Na ₂ SO ₄ Drying above, filtering and concentrating under reduced pressure to give 4, 6-dibromo-1H-pyrrolo [3,2-c ]]Pyridine-7-carboxamide (1.53 g, 48%). LC/MS (ESI) m/z=320 [ M+H ]] ⁺ 。

Step 1: synthesis of Compound 6- (4-phenoxyphenyl) -4-bromo-pyrrole [3,2-c ] ] naphthyridine-7-carboxamide 14b

The raw material 4, 6-dibromo-1H-pyrrolo [3,2-c]Pyridine-7-carboxamide 11a (0.64 g,2 mmol), 4-phenoxyphenylboronic acid (0.86 g,4 mmol) and tripotassium phosphate monohydrate (1.38 g,6 mmol) were dissolved in dioxane (15 mL) and water (8 mL). After multiple nitrogen fills, tetrakis (triphenylphosphine) palladium (0.35 g,0.3 mmol) was added. The mixture was sprayed with nitrogen for another 5 minutes and then heated at reflux for 24 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (10 mL) and the solids were collected by filtration. The crude product was slurried with methanol (50 mL) and then a beige solid 14b (0.457 g, 56%) was obtained, which was used in the next reaction without further purification, LC/MS (ESI): m/z=409 [ M+H ]] ⁺ 。

Step 2: synthesis of Compound 14c

Starting material 6- (4-phenoxyphenyl) -4-bromo-pyrrole [3,2-c]]And pyridine-7-carboxamide 14b (0.409 g,1 mmol), (S) -3-Boc-aminopiperidine (0.22 g,1.1 mmol), potassium carbonate (0.22 g,2 mmol) catalytic amount of potassium iodide and DMF (20 mL) were mixed, heated to 120℃and reacted with stirring for 4 hours. Cooled to room temperature and evaporated under reduced pressure to give 14c (0.27 g, 51%) as a yellow solid, LC/MS (ESI): m/z 529[ M+H ]] ⁺ 。

Step 3: synthesis of Compound 14d

To the reaction flask was added intermediate 14c (0.27 g,0.5 mmol), 2ml ethyl acetate, and 4ml 1N HCl in 1, 4-dioxane. The mixture was stirred at room temperature for 2 hours, the reaction mixture 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 evaporated to dryness under reduced pressure. Compound 14d (0.187 g, 87% yield) was obtained and used directly in the next step, LC/MS (ESI): m/z=428.2 [ M+H ] ] ⁺ 。

Step 4: synthesis of Compound 14

To the reaction flask was added compound 14d (128 mg,0.3 mmol), triethylamine (51 mg,0.5 mmol), 4ml tetrahydrofuran, and after cooling in an ice-water bath, a solution of but-2-ynyl chloride (45 mg,0.5 mmol) in 0.5ml tetrahydrofuran was slowly added dropwise. After the addition is finishedStirring was continued for 4 hours. The reaction mixture was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 11 (53 mg, yield 36%) as a yellow solid. LC/MS (ESI) m/z=494.2 [ M+H ]] ⁺ 。

Example 15: preparation of (R) -6- (4-phenoxyphenyl) -4- (3-but-2-ynylamidopiperidin-1-yl) -pyrrole [3,2-c ] ] bipyridinyl-7-carboxamide (Compound 15)

Using a method similar to example 14 (intermediate substituted with acetic anhydride), compound 15 (68 mg, 46% yield, final yield, supra) was obtained as a pale yellow solid, LC/MS (ESI): m/z=494.2 [ M+H ]] ⁺ .

Example 16: preparation of 6- (4-phenoxyphenyl) -4- (1-propenylpiperidin-4-yl) -pyrrole [3,2-c ] ] bipyridinyl-7-carboxamide (Compound 16)

Using a method similar to example 11 (intermediate substituted with acetic anhydride), compound 16 (59 mg, 42% yield, the final step yield, the same applies hereinafter) was obtained as a pale yellow solid, LC/MS (ESI): m/z=467.2 [ M+H ] ⁺ .

Examples 17 and 18: preparation of (S) -6- (4-phenoxyphenyl) -4- (1-propenylpiperidin-3-yl) -pyrrole [3,2-c ] ] bipyridinyl-7-carboxamide (Compound 17) and (R) -6- (4-phenoxyphenyl) -4- (1-propenylpiperidin-3-yl) -pyrrole [3,2-c ] ] bipyridinyl-7-carboxamide (Compound 18)

By a method similar to example 16 (intermediate was changed to 1-t-butoxycarbonyl-3, 6-dihydro-2H-pyridine-5-boronic acid pinacol ester), the racemic compound (R, S) -6- (4-phenoxyphenyl) -4- (1-propenoylpiperazine was obtainedPyridin-3-yl) -pyrrole [3,2-c]]And pyridine-7-carboxamide 18 (67 mg, 49% yield, this is the last step yield, the same applies below) as a pale yellow solid, LC/MS (ESI): m/z=467.2 [ M+H)] ⁺ .

Example 19: inhibition test of in vitro Activity of kinases BTK, BTK (R28H)

1.1 BTK inhibition activity screening

With kinase buffer (50 mM HEPES, 10mM MgCl) ₂ 2mM DTT, 1mM EGTA, 0.01% Tween 20) was diluted with 350ng/uL of BTK stock, 6. Mu.L of 1.67 X0.134 ng/. Mu.L of working solution (final concentration 0.08 ng/. Mu.L) was added to each well, and different DMSO-dissolved compounds 101-128 were added to the wells using a nanoliter-type applicator to give final concentrations of 1000nM-0.244nM, and positive drug concentrations of 50nM-0.0122nM, a 4-fold gradient, 7 total, and blank wells (without enzyme) and negative control wells (with enzyme, with vehicle DMSO) were set. After 30min of reaction of the enzyme with the compound or vehicle, 5X 250. Mu. MATP (final concentration of 50. Mu.M) prepared with kinase buffer was mixed with 5X 0.5. Mu.M substrate (final concentration of 0.1. Mu.M, ULIght-poly GT) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate, the reaction was carried out at room temperature for 2 hours, and then 5. Mu.L of a 4X 8nM detection reagent (final concentration: 2nM, ab) was added to each well and incubated at room temperature for 1 hour; PE instrument read plate (excitation 620nm, emission 665 nm). Calculate the inhibition rate and calculate IC ₅₀ Values. The results of the measurements are shown in the following Table

1.2 BTK (R28H) inhibitory activity screening

200ng/uL of BTK (R28H) stock was diluted with kinase buffer (50 mM HEPES, 10mM MgCl2, 2mM DTT, 1mM EGTA, 0.01% Tween 20), 6. Mu.L of 1.67 X1.67 ng/. Mu.L of working solution (final concentration of 1 ng/. Mu.L) was added to each well, and DMSO-dissolved different compounds 101-128 were added to the wells using a nanoliter-type-applicator to give final concentrations of 2000nM-0.488nM, positive drug concentration was 200nM-0.0488nM, 4-fold gradient for 7 total concentrations, and blank wells (containing no enzyme) and negative control wells (containing enzyme, plus vehicle DMSO) were set for 2 multiplex wells. After 30min of reaction of the enzyme with the compound or vehicle, 5X 500. Mu. MATP (final concentration 100. Mu.M) and 5X 0.5. Mu.M substrate (final concentration 0.1. Mu.M, ULIG) were prepared with kinase bufferht-poly GT), mixing at 1:1, adding 4 μl per well into the well; after sealing the plates, the plates were allowed to react at room temperature for 2 hours, 5. Mu.L of 4X 40mM EDTA (final concentration: 10 mM) was added to each well, and incubated at room temperature for 5 minutes, followed by 5. Mu.L of 4X 8nM detection reagent (final concentration: 2nM, ab) to each well; PE instrument read plate (excitation 620nm, emission 665 nm). Calculate the inhibition rate and calculate IC ₅₀ Values. The results of the assay are shown in the following table, showing the activity data of compounds 1-28 for wild-type BTK, mutant BTK (R28H). Active utilization IC ₅₀ Characterization, wherein "A" represents IC ₅₀ Less than or equal to 10nM; "B" means 10<IC ₅₀ Less than or equal to 100nM; "C" means 100<IC ₅₀ Less than or equal to 500nM; "D" means 500<IC ₅₀ ≤2000nM。

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Claims (6)

1. A compound selected from any one of the following:

2. a pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, wherein the dosage form of the pharmaceutical composition is selected from any one of the following: tablets, capsules, granules, sprays and injections.

4. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder, and a lubricant.

5. Use of a compound according to claim 1 in the preparation of a protein tyrosine kinase inhibitor.

6. The use according to claim 5, wherein the protein tyrosine kinase inhibitor is a Bruton's tyrosine kinase inhibitor.