Bruton's tyrosine kinase inhibitor and preparation method thereof

Abstract

A class of Bruton's tyrosine kinase inhibitors and preparation methods and applications in the medical field, wherein the Bruton's tyrosine kinase inhibitors can be used to prevent and / or treat diseases related to Bruton's tyrosine kinase, such as autoimmune diseases, cancer or inflammatory diseases. The provided compounds have been experimentally studied to have high selectivity for Bruton's tyrosine kinase targets and can exhibit excellent pharmacodynamic effects in in vivo animal experiments.

Description

[0001] This application claims the priority of the Chinese patent application filed with the China Patent Office on June 18, 2020, with application number 202010558345.4 and invention name “Bruton’s tyrosine kinase inhibitor and preparation method thereof”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of medicine and relates to a class of compounds used as Bruton's tyrosine kinase inhibitors and a preparation method thereof and application in the field of medicine. The compounds provided by the present invention can be used to prevent and / or treat autoimmune diseases, cancer or inflammatory diseases, etc. Background Art

[0003] Bruton's tyrosine kinase (BTK) is a member of the Tec family kinases (TFK). There are five members in this family, namely BTK, ITK, TEC, BMX and TXK. BTK is mainly expressed in B cells and myeloid cells, distributed in the lymphatic system, hematopoietic and blood systems, but lower levels of BTK expression have also been found in T cells and plasma cells.

[0004] In B cells, BTK is mainly responsible for the conduction and amplification of intracellular and extracellular signals, and is necessary for B cell maturation. Its upstream signal receptors include growth factor and cytokine receptors, G protein-coupled receptors such as chemokine receptors, antigen receptors (especially B cell receptor (BCR) and integrins, etc. The downstream signaling pathways activated by BTK include phosphoinositide-3 kinase (PI3K)-AKT pathway, phospholipase-C (PLC), protein kinase C and nuclear factor κB (NF-κB), etc. Therefore, BTK is a key kinase in the B cell antigen receptor (BCR) signaling pathway, which can regulate the proliferation, differentiation and apoptosis of normal B cells. After BTK overexpression causes abnormal activation of the BCR signaling pathway, B cells can be dysfunctional, the immune tolerance state can be changed, and they can be transformed into autoreactive B cells, secreting a large amount of autoantibodies to induce autoimmune diseases. Of course, it will also affect the proliferation, differentiation and apoptosis of B cells, thereby causing various malignant lymphomas.

[0005] Currently, most BTK inhibitor studies on autoimmune diseases are still in Phase I and II clinical trials. Their main indications include rheumatoid arthritis (RA), systemic lupus erythematosus, psoriasis, urticaria, rhinitis and asthma.

[0006] The binding modes of BTK inhibitors to protein kinases are divided into covalent binding and non-covalent binding. Among them, Ibrutinib, which was launched in 2013, is a representative of covalent binding and is mainly used for the treatment of various lymphomas; the BTK inhibitor (GDC-0853) (WO2013 / 067274, WO2013 / 067260) developed by Genentech Inc., which is a representative of non-covalent binding, is mainly used to treat various immune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus, etc., and is currently in Phase II clinical trials. Since the selectivity of known BTK inhibitors is not ideal, such as BTK inhibitor (GDC-0853), it still has inhibitory effects on multiple kinases (Src, Bmx, Fgr, etc.) in terms of selectivity (J.Med.Chem.2018,61,2227-2245), more BTK inhibitors need to be developed clinically for the treatment of various immune diseases, while overcoming the various side effects caused by poor selectivity.

[0007] The present invention newly designs and synthesizes a class of BTK inhibitors. Experimental studies have shown that the compounds have high selectivity for BTK targets and can exhibit excellent pharmacodynamic effects in in vivo animal experiments. Summary of the invention

[0008] The object of the present invention is to provide a compound represented by general formula (I), or its tautomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives thereof,

[0009]

[0010] Where X is CR a or N;

[0011] R a is hydrogen or cyano;

[0012] R0 is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, cyano or C 1-6 Alkoxy;

[0013] When X is N, R0 is hydrogen; when X is CR a , R a When it is cyano, R0 is hydrogen;

[0014] R1 is hydrogen, deuterium, halogen, cyano, trifluoromethyl, C 0-6 Substituted amino, C 1-6 Alkyl; C 1-6 Alkoxy;

[0015] R2 and R3 are independently C 1-3 alkyl;

[0016] R is hydroxy or halogen, preferably hydroxy;

[0017] A is

[0018] R4 is a straight chain C 1-6 Alkyl or branched C 3-6 alkyl;

[0019] R5 is hydrogen or C 1-3 alkyl;

[0020] X1 is CH or N;

[0021] T and T0 are independently a nitrogen-containing 5-6-membered heterocycloalkyl or a nitrogen-containing 9-11-membered spirocycloalkyl, wherein the 5-6-membered heterocycloalkyl is unsubstituted, or substituted by one T1 or T2, or substituted by both T1 and T2;

[0022] wherein the spirocycloalkyl is unsubstituted, or is substituted by one T3 or T4, or is substituted by both T3 and T4;

[0023] T1 is C 1-6 alkyl;

[0024] T2 is C 1-6 Alkyl or 3-6 membered heterocycloalkyl;

[0025] T3 is hydroxyl or C 1-6 alkyl;

[0026] T4 is C 1-6 Alkyl or 3-6 membered heterocycloalkyl.

[0027] T and T0 may further preferably be

[0028] T and T0 can be specifically

[0029] The synthesis process of the compound provided by the present invention is:

[0030] The compounds represented by the general formula of the present invention can be synthesized according to a variety of reaction schemes, and those skilled in the art can easily design reaction schemes for other compounds through some preparation methods provided in the examples herein.

[0031] The present invention relates to a method for preparing a compound represented by general formula (1) or a pharmaceutically acceptable salt thereof. The compound represented by general formula (I) is prepared by the following scheme:

[0032] Scenario 1:

[0033] When A is R is hydroxyl, R1 is halogen or C 1-6 When the alkyl group is present, the synthetic route of the compound represented by the general formula (I) is as follows:

[0034]

[0035] Scenario 2:

[0036] When A is When R is hydroxyl and R1 is hydrogen, the synthetic route of the compound represented by general formula (I) is as follows:

[0037]

[0038] Scenario 3:

[0039] When A is When R is hydroxyl and R1 is hydrogen, the synthetic route of the compound represented by general formula (I) is as follows:

[0040]

[0041] The catalyst described in Scheme 1 includes tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, palladium acetate, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 1,10-phenanthroline, and cuprous iodide; the reducing agent 1 is lithium aluminum tetrahydride, borane tetrahydrofuran, borane dimethyl sulfide, and reduced iron powder; the reducing agent 2 is sodium borohydride, potassium borohydride, sodium triacetylborohydride, and sodium cyanoborohydride.

[0042] The catalysts described in Schemes 2 and 3 include tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, palladium acetate, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 1,10-phenanthroline, and cuprous iodide; the reducing agent 1 is lithium aluminum tetrahydride, borane tetrahydrofuran, borane dimethyl sulfide, and reduced iron powder; the reagents for the alkaline conditions can be selected from potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, or cesium fluoride.

[0043] According to the compound represented by general formula (I) of the present invention and its pharmaceutically acceptable salt, the compound is specifically:

[0044] (S)-9-fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0045] (S)-9-chloro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0046] (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7,9-trimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0047] (S)-2-(3'-(hydroxymethyl)-1-isopropyl-5-((5-(2-methyl-4-(oxa-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0048] (S)-3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(hydroxymethyl)-5-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile;

[0049] (S)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)-4-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile;

[0050] (S)-4-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)-2-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile;

[0051] 2-(3-(Hydroxymethyl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)furo[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H);

[0052] 2-(3-(Hydroxymethyl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)furo[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H);

[0053] 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0054] 2-(5-((5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-fluoro-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0055] 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0056] 9-Fluoro-2-(5-((5-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0057] 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0058] 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0059] 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0060] (S)-9-bromo-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0061] (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-1-carbonyl-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-9-carbonitrile;

[0062] (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-1-carbonyl-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-9-carbonitrile;

[0063] (S)-9-ethoxy-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0064] (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-methoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0065] (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-9-propoxy-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0066] (S)-9-cyclopropyloxy-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0067] (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-isopropoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0068] (S)-9-amino-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one;

[0069] (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-isopropoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one.

[0070] The pharmaceutically acceptable salts described in the present invention refer to inorganic base salts, such as sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, ammonium salts, quaternary ammonium salts or aluminum salts; organic base salts, such as lysine salts, arginine salts, diethylamine salts, triethylamine salts, ethanolamine salts, trimethylamine salts, dicyclohexylamine salts, choline salts, dibenzylamine salts, piperidine salts and other pharmaceutically acceptable organic amine salts.

[0071] When the compound molecule of the present invention contains at least one nitrogen atom that can form a salt, it can be converted into a corresponding salt by reacting with a corresponding organic acid or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran. Typical organic acids include oxalic acid, tartaric acid, maleic acid, succinic acid, methanesulfonic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, aminosulfonic acid, citric acid, glutamic acid, pyroglutamic acid, aspartic acid, glucuronic acid, naphthalenesulfonic acid, glutaric acid, acetic acid, trifluoroacetic acid, malic acid, fumaric acid, salicylic acid, 4-aminosalicylic acid, lactic acid, palmitate, stearic acid, lauric acid, cinnamic acid, alginic acid, and ascorbic acid, and typical inorganic acids include nitric acid, hydrochloric acid, sulfuric acid, and phosphoric acid.

[0072] When the compounds of the present invention have one or more asymmetric carbon atoms, they can exist in the following forms: optically pure enantiomers, pure diastereomers, enantiomeric mixtures, diastereomeric mixtures, enantiomeric racemic mixtures, racemates or racemate mixtures. All possible isomers, stereoisomers and mixtures thereof of the compounds of formula (II) are also within the scope of the present invention.

[0073] The present invention also provides a pharmaceutical composition comprising at least one compound as described above and optionally one or more pharmaceutically acceptable carriers and / or diluents.

[0074] The pharmaceutical composition provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained-release preparations of active ingredients, wherein examples of capsules include hard or soft gelatin capsules, and granules and powders can be non-effervescent or effervescent forms.

[0075] The pharmaceutical composition of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, which are suitably formulated for administration. For example, the pharmaceutically or physiologically acceptable carrier may be saline, hot pressed water, Ringer's solution, buffered saline, glucose, maltodextrin, glycerol, ethanol, and mixtures thereof. The pharmaceutical composition of the present invention may also include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, adhesives, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, solvents, coating agents, foaming agents, or aromatics.

[0076] Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate; examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid; examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth gum, glucose solution, acacia gum, gelatin solution, sucrose, and starch paste; examples of glidants include, but are not limited to, colloidal silicon dioxide; examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, maltose, and cellulose acetate. potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose; examples of sweeteners include, but are not limited to, sucrose, lactose, mannitol and artificial sweeteners such as sodium cyclamate and saccharin, and any number of spray-dried flavoring agents; examples of flavoring agents include, but are not limited to, natural flavoring agents extracted from plants, such as fruits, and tastier compounds such as, but not limited to, mint and methyl salicylate; examples of wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

[0077] The pharmaceutical composition of the present invention can be administered by various routes according to conventional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous administration.

[0078] The pharmaceutically acceptable carrier optionally added to the pharmaceutical composition of the present invention is: one or more of water, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate, talc, kaolin, glycerol, Tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starches and its derivatives, silicon derivatives, celluloses and its derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalates, acrylic acid copolymers, and trimellitic acid esters.

[0079] The present invention also provides use of the above compound or pharmaceutical composition in preparing a drug for preventing and / or treating related diseases mediated by Bruton's tyrosine kinase.

[0080] The Bruton's tyrosine kinase-mediated diseases mentioned above include, but are not limited to, autoimmune disorders, cancers or inflammatory diseases.

[0081] The cancers mentioned above include, but are not limited to, esophageal cancer, lung cancer, colorectal cancer, pancreatic cancer, thyroid cancer, lymphoma or leukemia. The autoimmune diseases or inflammatory diseases mentioned above may be arthritis, systemic lupus erythematosus, inflammatory bowel inflammation, Crohn's disease, multiple sclerosis, asthma, thrombocytopenic purpura, chronic obstructive pulmonary disease, psoriasis, organ transplant rejection, allergy or rhinitis. DETAILED DESCRIPTION

[0082] In order to make the purpose, technical scheme, and advantages of the present invention more clearly understood, the present invention is further described in detail with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0083] The abbreviations used in the present invention are summarized in Table 1.

[0084] Table 1

[0085] Serial number abbreviation Chinese name 1 XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 2 Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene 3 BINAP 1,1'-Binaphthyl-2,2'-bis(diphenylphosphine) 4 DME dimethyl ether 5 DMF N,N-Dimethylformamide 6 DIPEA N,N-Diisopropylethylamine 7 NMP N-Methylpyrrolidone 8 NBS N-Bromosuccinimide 9 DCM Dichloromethane 10 TEA Triethanolamine 11 LDA Lithium diisopropylamide 12 TFA Trifluoroacetic acid 13 TBAF Tetrabutylammonium fluoride

[0086] Example 1 (S)-9-fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0087]

[0088]

[0089] The first step is tert-butyl (S)-3-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 1-2b

[0090] Compound 1-2a (20 g, 100 mmol), Int-1 (24 g, 150 mmol) and potassium carbonate (50 g, 235 mmol) were dissolved in toluene (250 mL), and palladium acetate (0.68 g, 3 mmol) and BINAP (2.0 g, 3 mmol) were added after sufficient stirring, and then the mixture was ventilated three times under nitrogen conditions, and the reaction temperature was raised to 90 ° C and stirred for 3 hours. Water was added to quench, and dichloromethane was extracted. The organic phase was washed with water (100 mL) and saturated brine (100 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain the title compound 1-2b (19.5 g, 58.7 mmol) with a yield of 58.7%.

[0091] MS m / z(ESI):323.2[M+H] + .

[0092] Step 2 (S)-5-(2-methylpiperazin-1-yl)pyridin-2-amine 1-2c

[0093] Compound 1-2b (10.0 g, 32.2 mmol) was dissolved in a hydrochloric acid methanol solution (100 mL), and then 20 mL of concentrated hydrochloric acid was added and stirred for 24 hours, a large amount of golden yellow solid precipitated, and the solid was filtered, dissolved in dichloromethane, and then freed with a saturated potassium carbonate solution. It was then extracted with dichloromethane, and the organic phase was washed with water (100 mL) and saturated brine (100 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 1-2c (7.0 g, 31.5 mmol), with a yield of 98.0%.

[0094] MS m / z(ESI):223.1[M+H] + .

[0095] Step 3 (S)-2-methyl-1-(6-nitropyridin-3-yl)-4-(oxyethane-3-yl)piperazine 1-2d

[0096] Compound 1-2c (7.0 g, 31.5 mmol) was dissolved in THF (50 mL), 2 mL of acetic acid was added, and then Int 2 (3.0 g, 41 mmol) was added. After stirring at room temperature for 15 min, sodium acetate borohydride (10.0 g, 47.3 mmol) was added in batches. After stirring at room temperature for 3 hours, water was added to quench, and dichloromethane was extracted. The organic phase was washed with water (150 mL) and saturated brine (150 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (pure ethyl acetate) to obtain the title compound 1-2d (3.5 g, 12.5 mmol) with a yield of 40.0%.

[0097] MS m / z(ESI):279.1[M+H] + .

[0098] Step 4 (S)-5-(2-methyl-4-(oxyethane-3-yl)piperazine-1-yl)pyridin-2-amine 1-2e

[0099] Compound 1-2d (3.5 g, 12.5 mmol) was dissolved in methanol and stirred evenly, then palladium carbon (1.7 g, 16.0 mmol) was added and ventilated with a hydrogen balloon for 3 times, and stirred at room temperature for about 12 hours. Filtered by suction, the filtrate was dried by rotary evacuation to obtain crude product 1-2e (2.8 g, 11.3 mmol), with a yield of 70.5%. MS m / z (ESI): 249.1 [M+H] + .

[0100] Step 5 (S)-5-bromo-1-methyl-3-((5-(2-methyl-4-(oxyethane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridin-2(1H)-one 1-2f

[0101] Compound 1-2e (2.8 g, 11.3 mmol) and compound Int 3 (3.2 g, 12.0 mmol) were dissolved in toluene (25 mL), palladium acetate (0.27 g, 1.1 mmol), Xantphos (1.4 g, 2.2 mmol) and potassium carbonate (4.8 g, 34 mmol) were added under stirring, and the mixture was ventilated three times under nitrogen conditions and refluxed at 105 ° C for 3.0 hours. After cooling, saturated ammonium chloride solution was added to quench. The mixture was extracted with dichloromethane, and the organic phase was washed with water (100 mL) and saturated brine (100 mL) several times, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM: MeOH = 97: 3) was used to obtain the title compound 1-2f (2.8 g, 6.5 mmol), with a yield of 57.1%.

[0102] MS m / z(ESI):434.2[M+H] + .

[0103] Step 6 (S)-1-methyl-3-((5-(2-methyl-4-(oxyethane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxanol-2-yl)pyridin-2(1H)-one 1f

[0104] Compound 1-2f (2.8 g, 6.5 mmol) was dissolved in THF (25 mL), 2.5 g of pinacol borate (B2pin2) was added and stirred evenly, and then Pd2(dba)3 (0.19 g, 0.33 mmol), XPhos (0.62 g, 1.3 mmol) and potassium carbonate (4.8 g, 34 mmol) were added. The mixture was evacuated three times under nitrogen conditions, and saturated ammonium chloride solution was added after reaction at 65 ° C for 6.0 hours to quench. The organic phase was extracted with dichloromethane, and the organic phase was washed with water (100 mL) and saturated brine (100 mL) for many times, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM: MeOH = 98: 2) was used to obtain the title compound 1f (1.4 g, 3.2 mmol), with a yield of 50%.

[0105] MS m / z(ESI):560.4[M+H] + .

[0106] Step 7: 2-Chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde 1-2

[0107] In a 1L reaction bottle, compound 1-1 (20g, 0.177mmol) was dissolved in dichloromethane (350ml), and DMF (32.5g, 0.44mol) was added under ice bath conditions, and then POCl3 (57.0g, 0.375mol, 2.1eq) was slowly added dropwise to the above reaction system. After the addition, the reaction solution was slowly heated to 30°C and kept stirring at room temperature for 30 minutes, and then 3,3-dimethyl-cyclopentanone (20g, 0.178mol) was slowly added dropwise to the above reaction solution, and the reaction solution was gradually heated to reflux state and reacted for 5 hours. After the reaction solution was cooled to room temperature, K3PO4 (10% w aq, 300ml) was added dropwise to the reaction solution under ice bath conditions to quench the reaction, stir and stand, the aqueous phase was stripped once with dichloromethane (200ml), the organic phases were combined, dried and spin-dried to obtain 30g of crude product, which was directly used in the next step reaction.

[0108] Step 8: 2-Chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde 1a

[0109] The crude product 1-2 obtained in the previous step and 2-piperazinone (18.5 g, 0.19 mol), NMP (300 ml) and DIPEA (46 g, 0.36 mol) were added to the reaction flask in sequence, and the temperature was raised to 120 ° C for 5 hours under nitrogen protection. LCMS detected that the reaction was complete. After cooling, water (1000 ml) was added to the reaction solution, and a large amount of solid precipitated. The solid was filtered and then slurried with petroleum ether: ethyl acetate (5:1, 200 ml), filtered and dried to obtain product 1-3

[0110] 1H NMR (400MHz, CDCl3) δ6.73–6.67(m,1H),5.97(s,1H),4.01–3.88(m,2H),3.70–3.60(m,2H),2.51–2.49(m,2H),2.47(q,J=0.7Hz,2H),1.23(s,6H).

[0111] MS m / z(ESI):205(M+1) +

[0112] Step 9: 9-Bromo-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one 1b

[0113] Compound 1a (1 g, 4.9 mmol) was dissolved in dichloromethane (30 mL), cooled to -20 ° C, NBS (1.05 g, 5.88 mmol) was added to the solution, and the reaction solution was heated to room temperature and stirred overnight. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 mL) and washed with a saturated Na2S2O3 aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 1b (960 mg) with a yield of 69%.

[0114] Step 10: 9-Fluoro-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one 1c

[0115] Compound 1b (560 mg, 2.0 mmol) was dissolved in tetrahydrofuran (15 mL), and then n-butyl lithium (30 mL, 7.0 mmol) was added dropwise while stirring at -78 ° C. The resulting solution was stirred at -40 ° C for 3 hours, then cooled to -78 ° C, and a solution of N-fluorobenzenesulfonimide (1.26 g, 4.0 mmol) in tetrahydrofuran (10 mL) was added dropwise to the solution. The resulting solution was stirred at room temperature for 3 hours, and the reaction was quenched by adding water (15 mL), and extracted with ethyl acetate (50 × 2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product, and purified by silica gel column chromatography to obtain compound 1c (310 mg) with a yield of 70%.

[0116] Step 11: 4-Chloro-2-(9-fluoro-7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde 1e

[0117] Compound 1c (250 mg, 1.12 mmol), compound 1d (246.4 mg, 1.12 mmol), Pd2(dba)3 (211 mg, 0.23 mmol), XantPhos (266 mg, 0.46 mmol) and potassium carbonate (309 mg, 2.24 mmol) were suspended in tetrahydrofuran (15 mL). After two nitrogen replacements, the reaction solution was heated to 65 ° C and stirred for 2 hours. After the reaction was complete, the reaction solution was dried and the residue was purified by silica gel column chromatography to obtain compound 1e (170 mg) with a yield of 42%.

[0118] Step 12 (S)-2'-(9-fluoro-7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carbaldehyde 1g

[0119] Compound 1e (130 mg, 0.36 mmol), compound 1f (173 mg, 0.36 mmol), Pd(dppf)Cl2 (26.3 mg, 0.036 mmol) and potassium phosphate (114.5 mg, 0.54 mmol) were dissolved in a mixed solution of tetrahydrofuran (16 mL) and water (4 mL). After two nitrogen replacements, the reaction solution was heated to 65 ° C and stirred for 3 hours. After the reaction was complete, the solution was dried, diluted with water (30 mL), and extracted with dichloromethane (30×2 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. Compound 1g (40 mg) was purified by silica gel column chromatography with a yield of 16%.

[0120] Step 13 (S)-9-fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0121] Compound 1g (40 mg, 0.06 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (3 mL), and K2HPO4 (10.4 mg, 0.06 mmol) and NaOH (2.4 mg, 0.06 mmol) were added, and then sodium borohydride (6.7 mg, 0.18 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, diluted with water (20 mL), and extracted with dichloromethane (30×2 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, and purified by silica gel column chromatography. Compound 1 (5 mg).

[0122] 1H NMR (400MHz, DMSO-d6) δ8.61 (d, J = 2.3Hz, 1H), 8.48 (d, J = 5.0 Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H), 4.94(t,J=5.1Hz,1H),4.55(td,J=6.5,2.9Hz,2H),4.49-4.39(m,4H),4.25-4.12(m,3H),3.82(d,J=11.1Hz, 1H),3.67(d,J=5.5Hz,1H),3.60(s,3H),3.40(q,J=6.2Hz,1H),3.13–3.06(m,1H),2.94(t,J=8.9Hz,1H),2.5 8-2.53(m,3H),2.45(s,2H),2.36-2.28(m,2H),2.19(t,J=9.1Hz,1H),1.22(s,6H),0.93(d,J=6.3Hz,3H).MS m / z(ESI):683[M+H] + .

[0123] Example 2 (S)-9-chloro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0124]

[0125] A synthetic method similar to that of Example 1 was used to replace N-bromosuccinimide with N-chlorosuccinimide to obtain 9-chloro-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one intermediate, which was directly subjected to reactions similar to those after the third step of Example 1 to obtain the title product 2 in a yield of 13%.

[0126] 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz, 1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J=5.1Hz,1H),4.55(td,J=6.5,2.9Hz,2H),4.49-4.39(m,4H),4.25-4 .12(m,3H),3.82(d,J=11.1Hz,1H),3.67(d,J=5.5Hz,1H),3.60(s,3H),3.40(q,J=6.2Hz,1H),3.13–3.06(m,1H),2.94(t,J= 8.9Hz,1H),2.58-2.53(m,3H),2.42(s,2H),2.38-2.29(m,2H),2.19(t,J=9.1Hz,1H),1.21(s,6H),0.93(d,J=6.3Hz,3H).MS m / z(ESI):699(M+1) + .

[0127] Example 3 (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridinyl-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7,9-trimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0128]

[0129] Step 1: 7,7,9-trimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0130] Compound 1a (0.5 g, 2.45 mmol) was dissolved in acetic acid (10 mL), and hydroiodic acid (10 mL) and paraformaldehyde (0.5 g) were added. The reaction solution was stirred at 25 ° C for 3 hours under nitrogen protection, and hypophosphorous acid (50%, 0.8 mL) was added dropwise until the reaction solution was colorless. Saturated ammonium chloride was added under ice bath, and then extracted with ethyl acetate (50×2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 3b (280 mg) with a yield of 52.4%.

[0131] MS m / z(ESI):215(M+1) +

[0132] The subsequent steps were similar to the reactions after step 5 in Example 1 to obtain the title product 3 in a yield of 19%.

[0133] 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=2.4Hz,1H),8.46–8.42(m,2H),7.81(d,J=2.8Hz,1H),7.46(d,J= 2.4Hz,1H),7.36–7.30(m,2H),7.23–7.21(m,1H),4.95(t,J=5.2Hz,1H),4.55–4.38(m,6H),4.18–4. 10(m,3H),3.78–3.75(m,1H),3.65(s,1H),3.58(s,3H),3.40–3.35(m,2H),3.09–3.06(m,1H),2.95– 2.90(m,1H),2.57–2.51(m,2H),2.34–2.30(m,4H),2.17(s,4H),1.19(s,6H),0.91(d,J=6.4Hz,3H).

[0134] Example 4 (S)-2-(3'-(Hydroxymethyl)-1-isopropyl-5-((5-(2-methyl-4-(oxa-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one 4

[0135]

[0136] Step 1 3,5-Dibromo-1-isopropylpyridin-2(1H)-one 4b

[0137] Compound 4a (2.52 g, 10 mmol) was dissolved in DME (30 mL), and 2-iodopropane (2.04 g, 1.2 mmol) and cesium carbonate (3.9 g, 1.2 mmol) were added. The reaction solution was refluxed at 80 ° C for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate (60 mL) and washed with NaHCO3 aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered and dried to give a crude product, which was purified by silica gel column chromatography to give compound 4b (1.7 g) with a yield of 58%.

[0138] Step 2 (S)-5-Bromo-1-isopropyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyridin-2(1H)-one 4d

[0139] Compound 4b (1 g, 3.4 mmol), compound 4c (843 mg, 3.4 mmol), palladium acetate (152 mg, 0.68 mmol), Xantphos (786 mg, 1.36 mmol) and potassium carbonate (1.41 g, 10.2 mmol) were suspended in toluene (30 mL). After two nitrogen replacements, the reaction solution was heated to 100 ° C. and stirred for 2 hours. After the reaction was complete, the reaction solution was dried by rotation, and the obtained residue was dissolved in dichloromethane (60 mL), washed with saturated brine (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 4d (670 mg) with a yield of 43%.

[0140] Step 3 (S)-1-isopropyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)boryl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 4e

[0141] Compound 1d (560 mg, 1.2 mmol), bipyralidone (309 mg, 1.2 mmol), Pd2(dba)3 (220 mg, 0.24 mmol), XPhos (228 mg, 0.48 mmol) and potassium acetate (235 mg, 2.4 mmol) were suspended in tetrahydrofuran (20 mL). After two nitrogen replacements, the reaction solution was heated to 70 ° C and stirred for 2 hours. After the reaction was complete, the reaction solution was dried and the residue was purified by silica gel column chromatography to obtain compound 4e (500 mg) with a yield of 81%.

[0142] Step 4 (S)-2'-((7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1-isopropyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino-6-oxo-1,6-dihydro-[3,4'-bipyridine]-3'-carbaldehyde 4f

[0143] Compound 4e (506 mg, 1 mmol), compound 8a (343 mg, 1 mmol), Pd(dppf)Cl2 (73.1 mg, 0.1 mmol) and potassium phosphate (424 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 mL). After two nitrogen replacements, the reaction solution was heated to 50 ° C and stirred for 3 hours. After the reaction was complete, the solution was dried, diluted with water (30 mL), and extracted with dichloromethane (50×2 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. Compound 4g (350 mg) was purified by silica gel column chromatography with a yield of 51%.

[0144] Step 5 (S)-2-(3'-(hydroxymethyl)-1-isopropyl-5-((5-(2-methyl-4-(oxa-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one 4

[0145] Compound 4g (250 mg, 0.36 mmol) was dissolved in a mixed solution of tetrahydrofuran (15 mL) and water (3 mL), and K2HPO4 (62.6 mg, 0.36 mmol) and NaOH (14.4 mg, 0.36 mmol) were added, and then sodium borohydride (38 mg, 1 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, diluted with water (30 mL), and extracted with dichloromethane (30×2 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. Compound 4 (80 mg) was purified by silica gel column chromatography with a yield of 32%.

[0146] 1H NMR(400MHz, DMSO-d6)δ8.59(d,J=2.2Hz,1H),8.52–8.40(m,2H),7.81(d,J=3.0Hz,1H),7.61(d,J=2.3Hz,1H), 7.40–7.29(m,2H),7.21(d,J=9.0Hz,1H),6.53(s,1H),5.21(p,J=6.8Hz,1H),5.07(s,1H),4.52(td,J=6.4,2.9 Hz,2H),4.40(dt,J=21.9,5.9Hz,4H),4.18(t,J=8.7Hz,3H),3.87–3.73(m,1H),3.65(s,1H),3.36(q,J=6.3Hz, 1H),3.14–3.00(m,1H),2.91(t,J=10.3Hz,1H),2.61–2.48(m,2H),2.39(s,2H),2.28(d,J=3.9Hz,2H),2.14(t, J=9.2Hz,1H),1.34(d,J=6.8Hz,6H),1.27–1.12(m,7H),0.89(d,J=6.3Hz,3H).

[0147] MS m / z(ESI):693[M+H] + .

[0148] Example 5 (S)-3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(hydroxymethyl)-5-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile

[0149]

[0150] Step 1 3,5-Dibromo-4-methylbenzoyl chloride 5b

[0151] 3,5-Dibromo-4-methylbenzoic acid (5.0 g, 17.0 mmol, 1.0 eq) was dissolved in DCM (50 ml), and oxalyl chloride (7.2 ml, 85.0 mmol, 5.0 eq) and DMF (2 drops) were added dropwise under ice-water cooling. The mixture was reacted at room temperature overnight and evaporated to dryness under reduced pressure to obtain crude product 5b, which was used directly in the next step.

[0152] Step 2 3,5-Dibromo-4-methylbenzamide 5c

[0153] Compound 5b (5.3 g, 17.0 mmol, 1.0 eq) was dissolved in anhydrous THF (5 ml), added to 25% aqueous ammonia, reacted at room temperature for 30 min, extracted with ethyl acetate (50 ml), the organic layer was washed with brine and dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a white solid (4.9 g) 5c.

[0154] MS m / z(ESI):293[M+1] +

[0155] Step 3 3,5-Dibromo-4-methylbenzonitrile 5d

[0156] Compound 5c (4.6 g, 15.7 mmol), triphenylphosphine (45 mg, 0.16 mmol) and TEA (6.5 ml, 47.1 mmol) were added to DCM (100 ml), cooled in an ice-water bath, oxalyl chloride (2.7 ml, 31.4 mmol) was added, warmed to room temperature, reacted for 30 min, concentrated, and flash column purified to obtain a white solid (HHT0130-180-1A, 3.0 g).

[0157] MS m / z(ESI):275[M+1]+

[0158] Step 4: 3,5-Dibromo-4-(bromomethyl)benzonitrile 5e

[0159] Compound 5d (1.0 g, 3.6 mmol, 1.0 eq) was dissolved in DCM (30 ml) and water (6 ml), and NBS (0.64 g, 3.6 mmol) and hydrogen peroxide (0.12 g, 3.6 mmol) were added in sequence, and the mixture was refluxed for 4 h. After cooling to room temperature, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by flash column to obtain a white solid (1.1 g).

[0160] MS m / z(ESI):354[M+1] +

[0161] Step 5: Benzyl 2,6-dibromo-4-cyanoacetate 5f

[0162] Compound 5e (1.0 g, 2.8 mmol, 1.0 eq) was dissolved in DMF (10 ml), potassium acetate (0.33 g, 3.4 mmol, 1.2 eq) was added, and the mixture was reacted at 80°C for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), washed with water (20 ml) and brine (15 ml × 3) in sequence, dried over anhydrous sodium sulfate, concentrated, and purified by flash column (PE-PA / EA=10:1) to obtain a white solid (HHT0130-158-1A, 590 mg).

[0163] MS m / z(ESI):333[M+1] +

[0164] Step 6 2-bromo-4-cyano-6-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)acetic acid benzyl ester 5g

[0165] Compound 5f (540 mg, 1.6 mmol, 1.5 eq) and 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (7) (0.22 g, 1.1 mmol, 1.0 eq) were added to anhydrous 1,4-dioxane (30 ml), and cesium carbonate (0.72 g, 2.2 mmol, 2.0 eq), Pd2(dba)3 (0.10 g, 0.11 mmol, 0.1 eq) and Xantphos (0.13 g, 0.22 mmol, 0.2 eq) were added in sequence, and the mixture was refluxed for 8 h. The mixture was evaporated to dryness under reduced pressure, ethyl acetate (50 ml) was added, and the mixture was washed with water (20 ml) and brine (20 ml) in sequence, concentrated, and purified by flash column to obtain a yellow solid (290 mg).

[0166] MS m / z(ESI):457[M+1] +

[0167] Step 7 (S)-3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(hydroxymethyl)-5-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile 5

[0168] Compound 5g (100 mg, 0.22 mmol, 1.0 eq) and (S)-1-methyl-3-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborololane-2-yl)pyridin-2(1H)-one (0.11 g, 0.22 mmol, 1.0 eq) were added to n-butanol (20 ml) and water (4 ml), and potassium phosphate (93 mg, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol) and XPhos (21 mg, 0.044 mmol) were added in sequence, and the reaction was refluxed for 8 h. Evaporate to dryness under reduced pressure, add ethyl acetate (50 ml), wash with water (20 ml) and saturated brine (20 ml) in sequence, concentrate and purify by flash column to obtain an off-white solid (60 mg).

[0169] MS m / z(ESI):689[M+1] +

[0170] 1H NMR (400MHz, DMSO-d6) δ8.56(t,J=2.5Hz,1H),8.44(s,1H),7.94(d,J=1.7Hz,1H),7.83(d,J=2.9Hz,1H),7.79(d,J=1.7Hz,1 H),7.40–7.33(m,2H),7.24(d,J=9.0Hz,1H),6.51(s,1H),5.09(q,J=4.2Hz,1H),4.60–4.35(m,6H),4.17(dq,J=25.9,7.8,6 .8Hz,3H),3.92–3.81(m,1H),3.67(s,1H),3.58(s,3H),3.39(q,J=6.2Hz,1H),3.09(d,J=12.1Hz,1H),2.93(t,J=9.7Hz,1H) ,2.56(d,J=3.8Hz,2H),2.41(s,2H),2.32(d,J=3.8Hz,2H),2.19(d,J=10.0Hz,1H),1.21(s,6H),0.92(dd,J=6.4,2.3Hz,3H).

[0171] Example 6 (S)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)-4-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile

[0172]

[0173]

[0174] Step 1 2-Bromo-4-chloro-3-formylbenzonitrile 6b

[0175] Compound 6a (5.00 g, 23.1 mmol) was dissolved in THF (50 mL), LDA (15.0 mL, 30.1 mmol) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 0.5 h. DMF (1.89 mL, 25.5 mmol) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 2 h. LCMS showed that the reaction was complete. The reaction was quenched with saturated NH4Cl solution (50 mL), and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 100 / 1 to 1 / 100) to give compound 6b (0.60 g, yield 10%) as a white solid.

[0176] LCMS (ESI-MS) m / z: 245.9 (M+H) + .

[0177] Step 2 2-Bromo-4-chloro-3-(hydroxymethyl)benzonitrile 6c

[0178] Compound 6b (0.60 g, 2.46 mmol) was dissolved in anhydrous MeOH (10 mL), and NaBH4 (0.19 g, 4.92 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched with water (20 mL) and extracted with EA (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA=100 / 1 to 1 / 100) to give compound 6c (0.50 g, yield 82%) as a white solid.

[0179] LCMS (ESI-MS) m / z: 247.9 (M+H) + .

[0180] Step 3 2-Bromo-6-chloro-3-cyanobenzyl acetate 6d

[0181] Compound 6c (0.50 g, 2.03 mmol) was dissolved in DCM (5 mL), and TEA (0.53 mL, 4.06 mmol) and acetyl chloride (0.22 mL, 3.05 mmol) were added under ice bath. Stir at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched with water (10 mL) and extracted with DCM (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography (PE / EA=100 / 1 to 1 / 100) to give compound 6d (0.45 g, yield 77%) as a white solid.

[0182] LCMS (ESI-MS) m / z: 287.9 ​​(M+H) + .

[0183] Step 4: 6-chloro-3-cyano-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)acetic acid benzyl ester 6e

[0184] Compound 6d (0.45 g, 1.56 mmol) was dissolved in dioxane (5 mL), and compound 5 (0.32 g, 1.56 mmol), Pd(AcO)2 (35 mg, 0.16 mmol), Xantphos (90 mg, 0.16 mmol) and Cs2CO3 (1.02 g, 3.13 mmol) were added. The reaction was refluxed for 2 hours under N2 protection. LCMS showed that the reaction was complete. Water (10 mL) was added and extracted with EA (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE / EA=100 / 1 to 1 / 100) to give a light yellow solid compound 6e (0.21 g, yield 33%).

[0185] LCMS (ESI-MS) m / z: 412.2 (M+H) + .

[0186] Step 5 (S)-3-cyano-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-6-(1-methyl-5-((5-(2-methyl-4-(oxa-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)acetate benzyl ester 6f

[0187] Compound 6e (0.16 g, 0.39 mmol) was dissolved in dioxane (3 mL), and compound 7 (0.19 g, 0.39 mmol), Pd(dppf)Cl2 (28 mg, 0.039 mmol) and K3PO4 (0.16 g, 0.78 mmol) were added. Microwave reaction was performed under N2 protection for 2 hours. LCMS showed that the reaction was complete. Water (10 mL) was added and extracted with EA (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE / EA=100 / 1 to 1 / 100) to obtain brown solid compound 6f (80 mg, yield 28%).

[0188] LCMS (ESI-MS) m / z: 367.1 (M+H) + .

[0189] Step 6 (S)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)-4-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile 6

[0190] Compound 6f (80 mg, 0.11 mmol) was dissolved in MeOH (2 mL), and an aqueous solution of NaOH (1 mL, 0.22 M) was added. The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with water (5 mL) and extracted with DCM (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse phase column chromatography (H2O / MeCN = 20 / 1 to 1 / 20) and normal phase column chromatography (DCM / EA = 100 / 1 to 1 / 100) to obtain a white solid compound 6 (10 mg, yield 13%).

[0191] LCMS (ESI-MS) m / z: 689.5 (M+H) + .

[0192] 1H NMR(400MHz, CDCl3)δ8.59(s,1H),7.95–7.86(m,2H),7.77(d,J=4.0Hz,1H),7.56–7.52(m,2H),6.85–6.81(m,2H),4.72–4.47(m,5H),4.39– 4.34(m,1H),4.17–3.96(m,3H),3.70(s,2H),3.67–3.29(m,4H),3.12– 3.07(m,2H),2.60–2.03(m,7H),1.30–1.25(m,9H),0.96–0.86(m,3H).

[0193] Example 7 (S)-4-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)-2-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile

[0194]

[0195] Step 1 4-Bromo-2-chloro-3-formylbenzonitrile 7b

[0196] Compound 7a (4.00 g, 18.5 mmol) was dissolved in THF (50 mL), LDA (12.0 mL, 24.1 mmol) was added dropwise at -78 °C, stirred at -78 °C for 0.5 h, DMF (1.51 mL, 20.4 mmol) was added dropwise at -78 °C, and stirred at -78 °C for 2 h. LCMS showed that the reaction was complete. The reaction was quenched with saturated NH4Cl solution (50 mL), and extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 100 / 1 to 1 / 100) to give white solid compound 2 (0.45 g, yield 10%).

[0197] LCMS (ESI-MS) m / z: 243.9 (M+H+).

[0198] Step 2: 2-Chloro-4-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-formylbenzonitrile 7c

[0199] Compound 7b (0.45 g, 1.84 mmol) was dissolved in DMF (3 mL), and compound 1a (0.32 g, 1.84 mmol), Pd2(dba)3 (0.17 g, 0.18 mmol), Xantphos (0.10 g, 0.18 mmol) and Cs2CO3 (1.20 g, 3.69 mmol) were added. The reaction was refluxed for 2 hours under N2 protection. LCMS showed that the reaction was complete. Water (10 mL) was added to quench the reaction, and EA (10 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE / EA=100 / 1 to 1 / 100) to obtain a light yellow solid compound 7c (0.14 g, yield 21%).

[0200] LCMS (ESI-MS) m / z: 368.2 (M+H) + .

[0201] Step 3 (S)-4-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(formyl)-2-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile 7d

[0202] Compound 7c (0.14 g, 0.38 mmol) was dissolved in dioxane (3 mL), and compound 1f (0.18 g, 0.38 mmol), Pd(dppf)Cl2 (27 mg, 0.038 mmol) and K3PO4 (0.16 g, 0.76 mmol) were added. Microwave reaction was carried out under N2 protection for 2 hours. LCMS showed that the reaction was complete. Water (10 mL) was added to quench the reaction, and EA (10 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA=100 / 1 to 1 / 100) to obtain brown solid compound 7d (20 mg, yield 7%).

[0203] LCMS (ESI-MS) m / z: 687.5 (M+H) + .

[0204] Step 4 (S)-4-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)-2-(1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile 7

[0205] Compound 7d (20 mg, 0.029 mmol) was dissolved in MeOH (2 mL), and NaBH4 (2.2 mg, 0.058 mmol) was added. The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched with water (5 mL) and extracted with DCM (5 mL×3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse phase column chromatography (H2O / MeCN=20 / 1 to 1 / 20) and normal phase column chromatography (DCM / EA=100 / 1 to 1 / 100) to obtain white solid compound 7 (2 mg, yield 10%).

[0206] LCMS (ESI-MS) m / z: 689.5 (M+H) + .

[0207] 1H NMR(400MHz, CDCl3)δ8.39(s,1H),7.88–7.76(m,3H),7.36–7.29(m,2H),6.81(s,2H),5.38–5.30(m,2H),4.71(s,3H),4.53–4.21(m,4H),4.17 –3.99(m,2H),3.70–3.49(m,6H),3.07(s,1H),2.56–2.50(m,3H),2.23 –2.19(m,2H),2.03–1.98(m,2H),1.70–1.60(m,5H),0.97–0.86(m,6H).

[0208] Example 8 2-(3-(Hydroxymethyl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)

[0209]

[0210] Step 1: 4-Chloro-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde 8a

[0211] Compound 1a (1.0 g, 4.9 mmol), 2-bromo-4-chloronicotinaldehyde (1.1 g, 4.9 mmol), palladium acetate (60 mg, 0.25 mmol), Xantphos (140 mg, 0.25 mmol), cesium carbonate (3.2 g, 10 mmol) and dioxane (20 ml) were added to a 100 ml reaction bottle in sequence. After nitrogen replacement 3 times, the temperature was raised to 85 ° C. The reaction solution was stirred for 5 hours under nitrogen protection. LCMS detected that the raw materials were basically reacted. After the reaction solution was cooled to room temperature, it was extracted with DCM / MeOH (10:1, 150 ml x 2), and the organic phase was dried and spin-dried, and separated by column to obtain a light yellow solid compound 2 (800 mg, yield: 47%).

[0212] LCMS (ESI-MS) m / z: 344.2 (M+H) + .

[0213] 1H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.55 (d, J = 5.4Hz, 1H), 7.51 (d, J = 5.4Hz ,1H),6.58(s,1H),4.26–4.15(m,4H),2.55(s,2H),2.38(s,2H),1.18(s,6H).

[0214] Step 2 2-(4-chloro-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)8b

[0215] Compound 8a (700 mg, 2.0 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and methanol (10 ml). Sodium borohydride (160 mg, 4.0 mmol) was added to the reaction system in batches under ice bath conditions. After stirring and reacting for 2 hours at room temperature, LCMS detected that the raw material had reacted completely. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the organic phase was dried and spin-dried to obtain a white solid compound 8b (700 mg. Yield: 100%).

[0216] LCMS (ESI-MS) m / z: 346.2 (M+H) + .

[0217] Step 3: Methyl (4-chloro-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-3-yl)acetate 8c

[0218] Compound 8b (550 mg, 1.6 mmol) was dissolved in dichloromethane (10 ml), triethylamine (900 mg, 9 mmol) and acetic anhydride (1.6 g, 16 mmol, 10 eq) were added dropwise to the reaction system under ice bath conditions, and stirred overnight at room temperature. LCMS detected that the reaction was complete. Water and dichloromethane were added to the reaction solution, and the organic phase was dried and dried by column to obtain white solid compound 8c (600 mg, yield: 97%).

[0219] LCMS (ESI-MS) m / z: 388.2 (M+H) + .

[0220] Step 4: (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-4-yl)boronic acid 8d

[0221] Compound 8c (370 mg, 1.0 mmol), Pd(dppf)(OAc)2 (73 mg, 0.1 mmol), XPhos (47 mg, 0.1 mmol), potassium acetate (300 mg, 3.0 mmol), bisborane (500 mg, 2.0 mmol) and dioxane were added to the reaction flask in sequence. After nitrogen replacement 3 times, the temperature was raised to 70 °C and reacted for 4 hours. LCMS showed that the raw materials were almost completely reacted. After the reaction solution was cooled to room temperature, water and ethyl acetate were added to the reaction solution, and the organic phase was dried and concentrated to dryness to obtain a crude product 8d (500 mg, purity: 80%), which was directly used in the next step.

[0222] LCMS (ESI-MS) m / z: 398.3 (M+H) + .

[0223] Step 5: 5-Chloro-2-(triisopropylsilyl)furo[3,2-b]pyridine 8f

[0224] Compound 8e (3.0 g, 11.7 mmol), triisopropylsilyl acetylene (4.3 g, 24 mmol), cuprous iodide (200 mg, 1.1 mmol), PdCl2(PPh3)2 (700 mg, 1.0 mmol), dioxane (50 ml) and triethylamine (50 ml) were added to the reaction bottle in sequence. After nitrogen replacement 3 times, the temperature was raised to 50 ° C for 2 hours. LCMS showed that the reaction was complete. After the reaction was cooled to room temperature, the reaction solution was diluted with water and ethyl acetate, and the organic phase was dried and concentrated to dryness and passed through a column to obtain a light green solid compound (3.6 g, yield: 100%).

[0225] LCMS (ESI-MS) m / z: 310.2 (M+H)+ .

[0226] 1H NMR (400MHz, Chloroform-d) δ7.69(dd,J=8.6,1.0Hz,1H),7.17(d,J=8.6Hz,1H),7.11(d,J=0.9Hz,1H),1.44–1.34(m,3H),1.12(d,J=7.4Hz,18H).

[0227] Step 6: 5-chloro-7-iodo-2-(triisopropylsilyl)furan[3,2-b]pyridine 8 g

[0228] Dissolve compound 7 (3.1 g, 10 mmol) in anhydrous tetrahydrofuran (20 ml), cool to -65 ° C, add n-butyl lithium (13 mmol, 1.3 eq) dropwise to the reaction system, stir for 1 hour, then dissolve iodine (3.8 g, 15 mmol) in anhydrous tetrahydrofuran (10 ml) and add dropwise to the above reaction system, keep stirring at low temperature for 2 hours. LCMS detection reaction is complete. Add saturated ammonium chloride solution and sodium sulfite solution to the reaction solution to quench the reaction. Add ethyl acetate and water, stir and stand to separate. After the organic phase is dried and concentrated to dryness, separate through a column to obtain a yellow solid compound 8g (4.0 g, yield: 92%).

[0229] 1H NMR (400MHz, Chloroform-d) δ7.59 (s, 1H), 7.19 (s, 1H), 1.40 (ddd, J = 14.8, 8.1, 6.9Hz, 3H), 1.14 (d, J = 7.5Hz, 18H).

[0230] Step 7: 5-chloro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-2-(triisopropylsilyl)furan[3,2-b]pyridin-7-amine 8h

[0231] Compound 8g (560mg, 1.2mmol), 5-(4-methylpiperazine-1-yl)pyridin-2-amine (250mg, 1.30mmol) (Shanghai WuXi AppTec Pharmaceutical Development Co., Ltd.), palladium acetate (40mg, 0.18mmol), Xantphos (40mg, 0.07mmol), cesium carbonate (1.2g, 3.6mmol) and dioxane (15ml) were added to the reaction system in sequence. After nitrogen replacement 3 times, the temperature was raised to 85°C and reacted for 4 hours. LCMS showed that the raw materials were almost completely reacted. After the reaction solution was cooled, water and ethyl acetate were added to dilute the reaction. The organic phase was dried and concentrated to dryness, and separated by column to obtain yellow solid compound 8h (500mg, yield: 78%).

[0232] LCMS (ESI-MS) m / z: 500.4 (M+H) + .

[0233] 1H NMR(400MHz,Chloroform-d)δ8.08(d,J=2.9Hz,1H),7.77(s,1H),7.31(dd,J=8.9,3.0Hz,1H),7.08(s,1H),7.03(dd ,J=8.9,0.7Hz,1H),6.91(s,1H),3.34(s,4H),2.84(s,4H),2.53(s,3H),1.42–1.35(m,3H),1.13(d,J=7.4Hz,18H).

[0234] Step 8: Methyl (2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2-(triisopropylsilyl)furan[3,2-b]pyridin-5-yl)pyridin-3-yl)acetate 8i

[0235] Compound 8h (80 mg, 0.16 mmol), compound 8d (100 mg, crude product, 1.0 eq), K3PO4 (110 mg, 0.5 mmol), Pd(dppf)Cl2 (12 mg, 0.016 mmol), DME (5 ml) and water (1.5 ml) were added to the reaction flask in sequence. After nitrogen replacement 3 times, the temperature was raised to 80 ° C and reacted for 4 hours. After the reaction solution was cooled to room temperature, water and ethyl acetate were added to dilute it. The organic phase was dried and concentrated to dryness to obtain a crude product. The oily compound 8i (30 mg, purity: 80%) was obtained by preparative plate separation.

[0236] Step 9 2-(3-(Hydroxymethyl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2-(triisopropylsilyl)furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)8j

[0237] Compound 8i (30 mg, purity 80%) was dissolved in tetrahydrofuran (6 ml) and water (2 ml), lithium hydroxide (24 mg, 1.0 mmol) was added to the reaction system, stirred at room temperature overnight, LCMS showed that the reaction was complete. Water and ethyl acetate were added to the reaction solution, the organic phase was dried and concentrated to dryness to obtain crude product 8j, which was directly used in the next step.

[0238] LCMS (ESI-MS) m / z: 775.6 (M+H)+.

[0239] Step 10: 2-(3-(hydroxymethyl)-4-(7-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)8

[0240] Compound 8j (25 mg, purity 80%) was dissolved in tetrahydrofuran (5 ml), and TBAF (1.0 M, 0.2 ml) was added dropwise to the reaction system under ice bath conditions, and the reaction was continued with stirring for 2 hours. LCMS showed that the reaction was complete. Ethyl acetate and saturated ammonium chloride solution were added to the reaction solution, the organic phase was dried and concentrated to dryness, and the light yellow solid compound 8 (10 mg, yield: 60%) was obtained by preparative plate separation.

[0241] LCMS (ESI-MS) m / z: 619.4 (M+H) + .

[0242] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.61–8.51(m,2H),8.11(d,J=3.0Hz,1H),7.59–7.55(m,1H),7.51(d,J=5.0H z,1H),7.37(q,J=5.1,4.7Hz,2H),7.23(d,J=5.1Hz,2H),7.12(d,J=5.8Hz,1H),6.56(s,1H),5.32(t,J=4.9Hz,1H) ,4.43(d,J=8.8Hz,1H),4.27(d,J=12.3Hz,1H),4.21(t,J=5.8Hz,1H),3.92(d,J=12.0Hz,1H),3.80(s,1H),3.14(d ,J=8.5Hz,3H),2.79(d,J=4.1Hz,2H),2.58(d,J=8.0Hz,1H),2.42(s,1H),1.99(dd,J=8.5,6.5Hz,2H),1.22(s,6H).

[0243] Example 9 2-(3-(Hydroxymethyl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)

[0244]

[0245]

[0246] Step 1 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 9b

[0247] Compound 9a (2.5 g, 12.3 mmol), tert-butyl piperazine-1-carboxylate (1.9 g, 10 mmol), palladium acetate (110 mg, 0.5 mmol), BINAP (310 mg, 0.5 mmol, 0.05 eq), K3PO4 (6.3 g, 30 mmol, 3.0 eq) and toluene (20 ml) were added to a 100 ml reaction bottle in sequence. After nitrogen replacement 3 times, the temperature was raised to 95 ° C. The reaction solution was stirred for 5 hours under nitrogen protection. LCMS detected that the raw materials were basically reacted. After the reaction solution was cooled to room temperature, it was extracted with DCM / MeOH (10:1, 150 ml x2), and the organic phase was dried, spin-dried, and separated by column to obtain a light yellow solid compound 9b (1.8 g, yield: 58%).

[0248] 1H NMR (400MHz, DMSO-d6) δ8.21(d,J=3.0Hz,1H),8.14(d,J=9.2Hz,1H),7.43(dd,J=9.3,3.1Hz,1H),3.57–3.38(m,8H),1.39(s,9H).

[0249] Step 2 1-(6-Nitropyridin-3-yl)piperazine 9c

[0250] Compound 9b (1.0 g, 3.2 mmol) was dissolved in dichloromethane (10 ml), and TFA (8 ml) was added dropwise to the reaction system under ice bath conditions. After stirring and reacting at room temperature for 2 hours, TLC detected that the reaction of the raw material was complete. The reaction solution was directly spin-dried to obtain yellow oily compound 9c, which was directly used in the next step.

[0251] Step 3 1-(6-nitropyridin-3-yl)-4-(oxetan-3-yl)piperazine 9d

[0252] Compound 9c (1.2 g, 10 mmol) was dissolved in methanol (20 ml), 3-oxetanone (720 mg, 10 mmol), zinc chloride (870 mg, 6.4 mmol) and sodium cyanoborohydride (400 mg g, 6.4 mmol) were added to the reaction system at room temperature, and stirred at 50°C for 4 hours. LCMS detected that the reaction was complete. Water and dichloromethane were added to the reaction solution, and the organic phase was dried and passed through a column to obtain a yellow solid compound 9d (800 mg, yield: 94%).

[0253] 1H NMR(400MHz,Chloroform-d)δ8.15(d,J=9.1Hz,1H),8.12(d,J=3.0Hz,1H),7.19(dd,J=9.2,3.0Hz,1H) ,4.70(t,J=6.5Hz,2H),4.62(t,J=6.1Hz,2H),3.57–3.52(m,1H),3.50–3.45(m,4H),2.53–2.48(m,4H).

[0254] Step 4: 5-(4-(Oxetane-3-yl)piperazin-1-yl)pyridin-2-amine 9e

[0255] Compound 9d (800 mg, 3.0 mmol) was dissolved in methanol (20 ml), palladium carbon (10% w, 100 mg) was added to the reaction system, hydrogen was replaced 3 times, and the reaction was stirred for 4 hours. TLC showed that the raw material was completely reacted. The reaction solution was filtered through diatomaceous earth and dried to obtain a white solid compound 9e (700 mg, yield: 98%).

[0256] LCMS (ESI-MS) m / z: 235.2 (M+H) + .

[0257] Step 5: 5-chloro-N-(5-(4-(oxetan-3-yl)piperazine-1-yl)pyridin-2-yl)-2-(triisopropylsilyl)furan[3,2-b]pyridin-7-amine 9 g

[0258] Compound 9e (800 mg, 1.8 mmol), compound 9f (420 mg, 1.8 mmol, 1.0 eq), palladium acetate (20 mg, 0.09 mmol), Xantphos (50 mg, 0.09 mmol), cesium carbonate (1.1 g, 3.6 mmol) and dioxane (20 ml) were added to the reaction bottle in sequence. After nitrogen replacement 3 times, the temperature was raised to 85 ° C for 4 hours. LCMS showed that the raw materials reacted completely. After the reaction solution was cooled, ethyl acetate and water were added to dilute the reaction solution. The organic phase was dried and concentrated to dryness, and the yellow solid compound 9g (800 mg, yield: 82%) was obtained by column separation.

[0259] LCMS (ESI-MS) m / z: 542.4 (M+H) + .

[0260] Step 6: (2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-2-(triisopropylsilyl)furan[3,2-b]pyridin-5-yl)pyridin-3-yl)acetate 9h

[0261] Compound 9g (150 mg, 0.28 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-4-yl)boric acid (200 mg. Purity: 87%), Pd(dppf)Cl2 (20 mg, 0.028 mmol), K3PO4 (180 mg, 0.84 mmol), dioxane (6 ml) and water (2 ml) were added to the reaction bottle in sequence. After nitrogen replacement 3 times, the temperature was raised to 80°C and reacted for 4 hours. The reaction solution was separated and purified by the preparation plate to obtain compound 9h (20 mg, purity: 90%, yield: 10%).

[0262] LCMS (ESI-MS) m / z: 859.6 (M+H)+.

[0263] Step 7 2-(3-(hydroxymethyl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-2-(triisopropylsilyl)furan[3,2-b]pyridin-5-yl)pyridin-2-yl-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)9i

[0264] Compound 9h (20 mg, purity: 90%) was dissolved in tetrahydrofuran (6 ml) and water (2 ml), and lithium hydroxide (24 mg, 1.0 mmol) was added to the reaction solution. The reaction was allowed to react overnight at room temperature. TLC showed that the reaction was complete. After the reaction solution was diluted with ethyl acetate and water, the organic phase was dried and then spin-dried to obtain the crude product 9i, which was directly used in the next step.

[0265] Step 8 2-(3-(hydroxymethyl)-4-(7-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)furan[3,2-b]pyridin-5-yl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)9

[0266] Compound 9i (20 mg, purity 90%) was dissolved in tetrahydrofuran (5 ml), and TBAF (1.0 M, 0.2 ml) was added dropwise to the reaction system under ice bath conditions, and the reaction was continued with stirring for 2 hours. LCMS showed that the reaction was complete. Ethyl acetate and saturated ammonium chloride solution were added to the reaction solution, the organic phase was dried and concentrated to dryness, and the light yellow solid compound 9 (5 mg, yield: 60%) was obtained by preparative plate separation.

[0267] LCMS (ESI-MS) m / z: 661.4 (M+H) + .

[0268] 1H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 8.52–8.48 (m, 2H), 8.30 (d, J = 2.2Hz, 1H), 7.96 (d, J = 3.0Hz, 1H), 7. 47–7.40(m,2H),7.21(d,J=9.0Hz,1H),7.17(s,1H),7.10(d,J=2.2Hz,1H),6.63(s,2H),6.52(s,1H),5. 32–5.28(m,2H),5.18–5.14(m,1H),4.54(t,J=6.5Hz,2H),4.44(t,J=6.0Hz,2H),4.39(t,J=5.5Hz,2H), 4.17(t,J=5.3Hz,2H),3.11(t,J=5.0Hz,4H),2.39(d,J=7.8Hz,4H),1.97(d,J=7.7Hz,4H).1.20(s,6H).

[0269] Example 10 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0270]

[0271] A synthetic method similar to that of Example 1 was used to replace tert-butyl (S)-3-methylpiperazine-1-carboxylate with tert-butylpiperazine-1-carboxylate to obtain the title product 10 in a yield of 19%.

[0272] 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2. 8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H) ,4.52(t,J=6.5Hz,2H),4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3 .53–3.40(m,1H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),1.22(s,6H).

[0273] LCMS (ESI-MS) m / z: 668.8 (M+H) + .

[0274] Example 11 2-(5-((5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-fluoro-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0275]

[0276] A synthetic method similar to that of Example 1 was used to replace tert-butyl (S)-3-methylpiperazine-1-carboxylate with 2-oxa-7-azaspiro[3.5]nonane to obtain the title product 11 in a yield of 26%.

[0277] 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7. 45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H),4.52(t,J=6.5Hz,2H), 4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.08(t,J=5. 0Hz, 4H), 2.57 (q, J = 8.9Hz, 2H), 2.42–2.35 (m, 2H), 1.65-1.43 (m, 4H), 1.22 (s, 6H).

[0278] LCMS (ESI-MS) m / z: 653.8 (M+H) + .

[0279] Example 12 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0280]

[0281] A synthetic method similar to that of Example 1 was used to replace tert-butyl (S)-3-methylpiperazine-1-carboxylate with 2-methyl-2,7-diazaspiro[3.5]nonane to obtain the title product 12 in a yield of 29%.

[0282] 1H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J= 2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.93(t,J=5.1Hz, 1H),4.52(t,J=6.5Hz,2H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3.08(t,J=5.0H z,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),2.21(s,3H),1.65-1.43(m,4H),1.22(s,6H).

[0283] LCMS (ESI-MS) m / z: 666.8 (M+H) + .

[0284] Example 13 9-Fluoro-2-(5-((5-(2-hydroxy-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)amino)-3'-(hydroxymethyl)-1-methyl-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0285]

[0286] A synthetic method similar to that of Example 1 was used to replace tert-butyl (S)-3-methylpiperazine-1-carboxylate with 2-methyl-2,7-diazaspiro[3.5]nonane to obtain the title product 13 in a yield of 17%.

[0287] 1H NMR(400MHz,DMSO-d6)δ1H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2.8Hz,1 H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J=5.1Hz,1H),4.55(td,J =6.5,2.9Hz,2H),4.29-4.19(m,1H),4.25-4.12(m,3H),3.82(d,J=11.1Hz,1H),3.67(d,J=5.5Hz,1H) ,3.60(s,3H),3.40(t,J=6.2Hz,4H),2.45(s,2H),2.36-2.28(m,2H),2.09-1.75(m,8H),1.22(s,6H).

[0288] LCMS (ESI-MS) m / z: 667.8 (M+H) + .

[0289] Example 14 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0290]

[0291] A synthetic method similar to that of Example 1 was used to replace tert-butyl (S)-3-methylpiperazine-1-carboxylate with 1-methylpiperazine to obtain the title product 14 in a yield of 21%.

[0292] 1H NMR (400MHz, DMSO-d6) δ8.61 (d, J = 2.3Hz, 1H), 8.48 (d, J = 5.0Hz, 1H),8.44(s,1H),7.83(d,J=2.8Hz,1H),7.45(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.24(d,J=9.0Hz,1H),4.94(t,J =5.1Hz,1H),4.39(d,J=5.1Hz,2H),3.58(s,3H),3.08(t,4H),2.41-2.30(m,11H),,2.39-2.19(m,4H),1.22(s,6H).

[0293] LCMS (ESI-MS) m / z: 626.7 (M+H) + .

[0294] Example 15 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((4-(4-(oxabutane-3-yl)piperazin-1-yl)phenyl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0295]

[0296] A synthetic method similar to that of Example 1 was used to obtain the title product 15 in a yield of 19%, by replacing tert-butyl (S)-3-methylpiperazine-1-carboxylate with tert-butylpiperazine-1-carboxylate and 5-chloro-2-nitropyridine with 1-bromo-4-chlorobenzene.

[0297] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.44(s,1H),7.83(d,J=2. 8Hz,1H),7.45(d,J=2.3Hz,1H),7.26(d,J=9.0Hz,2H),7.04(d,J=9.0Hz,2H),4.93(t,J=5.1Hz,1 H),4.52(t,J=6.5Hz,2H),4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H), 3.53–3.40(m,1H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),1.22(s,6H).

[0298] LCMS (ESI-MS) m / z: 667.8 (M+H) + .

[0299] Example 16 9-Fluoro-2-(3'-(hydroxymethyl)-1-methyl-5-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0300]

[0301] A synthetic method similar to that of Example 1 was used to obtain the title product 16 in a yield of 23%, by replacing tert-butyl (S)-3-methylpiperazine-1-carboxylate with tert-butylpiperazine-1-carboxylate and 5-chloro-2-nitropyridine with 2-bromo-5-chloropyridine.

[0302] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.3Hz,1H),8.47(d,J=5.0Hz,1H),8.41(s,1H),7.82(d,J=2. 9Hz,1H),7.44(d,J=2.3Hz,1H),7.37–7.30(m,2H),7.21(d,J=9.0Hz,1H),4.93(t,J=5.1Hz,1H) ,4.52(t,J=6.5Hz,2H),4.50–4.33(m,4H),4.31–4.12(m,3H),3.89–3.79(m,1H),3.60(s,3H),3 .53–3.40(m,1H),3.08(t,J=5.0Hz,4H),2.57(q,J=8.9Hz,2H),2.42–2.35(m,6H),1.22(s,6H).

[0303] LCMS (ESI-MS) m / z: 668.8 (M+H) + .

[0304] Example 17 (S)-9-bromo-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0305]

[0306] The intermediate 1b was synthesized by a synthetic method similar to that of Example 1 to obtain the title product 17 in a yield of 29%.

[0307] 1 H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.3Hz,1H),8.46(d,J=5.0Hz, 1H),8.42(s,1H),7.82(d,J=2.9Hz,1H),7.43(d,J=2.3Hz,1H),7.38–7.30(m,2H),7.24–7.20(m,1H),4.93 (t,J=5.1Hz,1H),4.62–4.32(m,6H),4.21(d,J=10.2Hz,3H),3.82(d,J=6.4Hz,1H),3.65(d,J=5.9Hz,1H),3 .59(s,3H),3.43–3.33(m,1H),3.08(d,J=11.5Hz,1H),2.93(t,J=9.9Hz,1H),2.69–2.50(m,3H),2.37-2.23 (m,4H),2.17(t,J=9.7Hz,1H),1.21(d,J=2.9Hz,6H),0.91(d,J=6.3Hz,3H).LCMS(ESI-MS)m / z:743.7(M+H) + .

[0308] Example 18 (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxadiazole-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-1-carbonyl-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-9-carbonitrile

[0309]

[0310] Step 1: 7,7-dimethyl-1-carbonyl-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-9-carbonitrile

[0311] Compound 1b (0.5 g, 1.77 mmol) was dissolved in toluene (10 mL), and cuprous cyanide (0.16 g, 1.77 mmol) and tetrakistriphenylphosphine palladium (50 mg) were added. The reaction solution was stirred at 100 ° C for 3 hours under nitrogen protection. After cooling, it was washed with saturated brine and extracted with ethyl acetate (50 × 2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 18a (280 mg) with a yield of 69.1%.

[0312] MS m / z(ESI):230(M+1) +

[0313] The subsequent steps were similar to the reactions after step 5 in Example 1 to obtain the title product 18 in a yield of 19%.

[0314] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.4Hz,1H),8.48(d,J=5.2Hz,1H),8.44(s,1H),7.81(d,J =2.8Hz,1H),7.40–7.34(m,3H),7.24–7.22(m,1H),4.99(s,1H),4.55–4.38(m,6H),4.30–4.2 8(m,3H),3.90(s,1H),3.67–3.65(m,1H),3.59(s,3H),3.38–3.34(m,1H),3.09–3.05(m,1H), 2.95–2.90(m,1H),2.66–2.65(m,2H),2.31–2.13(m,6H),1.22(s,6H),0.91(d,J=6.4Hz,3H).

[0315] LCMS (ESI-MS) m / z: 689.8 (M+H) + .

[0316] Example 19 (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxadiazole-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-1-carbonyl-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-9-carbonitrile

[0317]

[0318] Step 1: 7,7-dimethyl-9-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0319] Compound 1a (0.5 g, 2.45 mmol) was dissolved in DMF (10 mL), and diiododifluoromethane (1.48 g, 4.9 mmol) was added. The reaction solution was irradiated with strong light and stirred for 18 hours under nitrogen protection. After cooling, it was washed with saturated brine and extracted with ethyl acetate (50×2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 19a (180 mg) with a yield of 27%.

[0320] MS m / z(ESI):230(M+1) +

[0321] The subsequent steps were similar to the reactions after step 5 in Example 1 to obtain the title product 19 in a yield of 16%.

[0322] 1 H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1 H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.17–3.01(m,6H),2. 81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.46(s,3H),2.33(s,3H),2.25(s,3H),2.12(s,3H),1.97(td,J=13.4,12.8 ,4.0Hz,2H),1.81(d,J=13.9Hz,2H),1.78(d,J=12.5Hz,2H),1.67–1.53(m,3H),1.28–1.22(m,4H),0.86(t,J=7.0Hz,3H).

[0323] LCMS (ESI-MS) m / z: 732.8 (M+H) + .

[0324] Example 20 (S)-9-ethoxy-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridinyl-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0325]

[0326] Step 1: 9-ethoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0327] Compound 1b (0.5 g, 1.77 mmol) was dissolved in dichloromethane (10 mL), and sodium ethoxide (0.16 g, 1.77 mmol) was added. The reaction solution was sealed under nitrogen protection and stirred at 50 ° C for 18 hours. After cooling, it was washed with saturated brine and extracted with ethyl acetate (50×2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 20a (210 mg) with a yield of 47.8%.

[0328] MS m / z(ESI):248.3(M+1) +

[0329] The subsequent steps were similar to the reactions after step 5 in Example 1 to obtain the title product 20 in a yield of 30%.

[0330] 1H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6. 65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),4.07(m,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2. 81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0H z,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.38(m,2H),1.27–1.21(m,4H),0.86(t,J=7.0Hz,3H).

[0331] LCMS (ESI-MS) m / z: 708.9 (M+H) + .

[0332] Example 21 (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-methoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0333]

[0334] A similar synthesis method to Example 20 was used to obtain the title product 21 in a yield of 35%, by replacing sodium ethoxide with sodium methoxide.

[0335] 1H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1 H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.90(d,J=1 1.0Hz,2H),3.83(s,3H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7 .2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4, 12.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.27–1.21(m,4H),0.86(t,J=7.0Hz,3H).

[0336] LCMS (ESI-MS) m / z: 694.8 (M+H) + .

[0337] Example 22 (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-9-propoxy-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0338]

[0339] A similar synthesis method to Example 20 was used to replace sodium ethoxide with sodium propoxide to obtain the title product 22 in a yield of 26%.

[0340] 1H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65( d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.99(m,2H),390(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3 H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.8 2(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.72(m,2H),1.69–1.56(m,3H),1.27–1.21(m,4H),0.99(m,3H),0.86(t,J=7.0Hz,3H).

[0341] LCMS (ESI-MS) m / z: 722.9 (M+H) + .

[0342] Example 23 (S)-9-cyclopropyloxy-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0343]

[0344] A synthetic method similar to that of Example 20 was used to obtain the title product 23 in a yield of 17%, by replacing sodium ethoxide with sodium cyclopropoxide.

[0345] 1H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H), 6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),390(d,J=11.0Hz,2H),3.37(m,3H),3.19–3.01(m,6H),2.81(s,3H),2.76(d, J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J =13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.27–1.21(m,4H),0.86(t,J=7.0Hz,3H),0.58(m,2H),0.34(m,2H).

[0346] LCMS (ESI-MS) m / z: 720.9 (M+H) + .

[0347] Example 24 (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxadiazole-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-isopropoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0348]

[0349] A similar synthesis method to Example 23 was used to replace sodium ethoxide with sodium isopropoxide to obtain the title product 24 in a yield of 25%.

[0350] 1H NMR (400MHz, Methanol-d4) δ7.38 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 1.8 Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H),6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),4.69( m,1H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50( s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,12.8,4.0Hz,2H),1.82(d,J=13.9Hz, 2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.31(m,6H),1.27–1.21(m,4H),0.99(m,3H),0.86(t,J=7.0Hz,3H).

[0351] LCMS (ESI-MS) m / z: 722.9 (M+H) + .

[0352] Example 25 (S)-9-amino-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0353]

[0354] Step 1: 9-amino-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0355] Compound 1b (0.5 g, 1.77 mmol) was dissolved in ammonia methanol solution (10 mL), and the reaction solution was heated at 80 ° C under nitrogen protection and sealed for 3 hours. After cooling, it was washed with saturated brine and extracted with ethyl acetate (50 × 2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 25a (156 mg) with a yield of 40.1%.

[0356] MS m / z(ESI):219(M+1) +

[0357] The subsequent steps were similar to the reactions after step 5 in Example 1 to obtain the title product 25 in a yield of 11%.

[0358] 1 H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H) ,6.65(d,J=1.5Hz,1H),6.09(s,1H),5.82(s,2H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m, 6H),2.81(s,3H),2.76(d,J=7.2Hz,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,1 2.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.28–1.21(m,4H),0.88(t,J=7.0Hz,3H).

[0359] LCMS (ESI-MS) m / z: 679.8 (M+H) + .

[0360] Example 26 (S)-2-(3'-(Hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxadiazole-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-9-isopropoxy-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0361]

[0362] A similar synthesis method to Example 25 was used to replace the methanol solution of ammonia with methylamine hydrochloride to obtain the title product 26 in a yield of 24.6%.

[0363] 1H NMR (400MHz, Methanol-d4) δ7.38(d,J=1.9Hz,1H),7.25(d,J=1.8Hz,1H),7.07(d,J=7.6Hz,1H),6.85(dd,J=7.7,1.6Hz,1H) ,6.65(d,J=1.5Hz,1H),6.09(s,1H),4.47(s,2H),3.90(d,J=11.0Hz,2H),3.36(d,J=11.7Hz,2H),3.19–3.01(m,6H),2.81(s, 3H),2.76(d,J=7.2Hz,2H),2.72(s,2H),2.50(s,1H),2.41(s,3H),2.33(s,3H),2.23(s,3H),2.14(s,3H),1.98(td,J=13.4,1 2.8,4.0Hz,2H),1.82(d,J=13.9Hz,2H),1.77(d,J=12.5Hz,2H),1.69–1.56(m,3H),1.28–1.22(m,4H),0.88(t,J=7.0Hz,3H).

[0364] LCMS (ESI-MS) m / z: 693.9 (M+H) + .

[0365] Example 27 (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxabutane-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-carbonyl-1,6-dihydro-[3,4'-bipyridyl]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one-9-deuterated

[0366]

[0367] Step 1: 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one-9-deuterated

[0368] Compound 1b (0.5 g, 1.77 mmol) was dissolved in tetrahydrofuran, sodium deuterated borohydride was added to the reaction solution under nitrogen protection, and stirred for 3 hours in an ice bath. The mixture was washed with saturated brine and extracted with ethyl acetate (50×2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 27a (160 mg) with a yield of 44.2%.

[0369] MS m / z(ESI):206.3(M+1) +

[0370] The subsequent steps were similar to the reactions after step 5 in Example 1 to obtain the title product 26 in a yield of 21%.

[0371] 1H NMR (400MHz, DMSO-d6) δ8.64(d,J=22.6Hz,2H),8.47(d,J=5.0Hz,1H),7.92(s,1 H),7.45(dd,J=9.7,2.6Hz,2H),7.36–7.24(m,2H),4.83–4.60(m,4H),4.40(q,J =11.7Hz,3H),4.23–4.04(m,3H),3.79(d,J=11.5Hz,1H),3.56(s,3H),3.18–3.0 5(m,3H),2.54(d,J=8.8Hz,2H),2.42(s,2H),1.18(d,J=5.6Hz,8H),0.90(s,3H).

[0372] MS m / z(ESI):666.8[M+H] + .

[0373] Biological Experiment Example:

[0374] Experiment 1: Study on the activity of compounds inhibiting BTK kinase

[0375] The BTK kinase activity of the compound was determined using the mobility shift method, and the reaction system was (kinase solution, ATP, kinase substrate 2). After the compound and enzyme were incubated for 30 minutes, the conversion rate was read using the Caliper EZ reader, the compound inhibition rate was determined using the calculation formula, and the data was fitted using Graphad to obtain the IC value of the compound of the present invention. 50 value.

[0376] Experimental Results

[0377] The compound of the present invention has a significant inhibitory effect on BTK kinase, with a 50% inhibition concentration of BTK less than 0.75 nM, and has a better selectivity than ibrutinib.

[0378] Table 2 Study on the activity of compounds inhibiting BTK kinase

[0379] Compound No. <![CDATA[BTK(IC 50 ,nM)]]> H01 0.23 H02 0.59 H03 0.14 H04 0.26 H05 0.69 H06 0.41 H07 0.38 H08 0.23 H09 0.71 H10 0.21 H11 0.26 H12 0.49 H13 0.18 H14 0.27 H15 0.68 H16 0.17 H17 0.73 H18 0.65 H19 0.52 H20 0.55 H21 0.38 H22 0.74 H23 0.51 H24 0.65 H25 0.44 H26 0.46 Ibrutinib 0.78

[0380] Experiment 2: Inhibitory effect of compounds on cell proliferation

[0381] 1. Experimental purpose and methods

[0382] This assay measures the effect of compounds on cell proliferation.

[0383] The inhibitory effect of the compound on tumor cell proliferation was determined. Tumor cells (A20 5E6 cells) were cultured to a certain number and then plated in 96 wells. Different concentrations of the compound of the present invention were added to the culture plate according to the experimental requirements. The inhibitory effect on tumor cells was observed after 1 h, 2 h, 4 h, 8 h, and 24 h. CCK8 was added and incubated for 2 h, and the absorbance value was detected to determine the inhibitory effect of the compound on cell proliferation. Graphad was used to fit the data to obtain the IC value of the compound. 50 value.

[0384] 2. Experimental results

[0385] The compound of the present invention can effectively inhibit the proliferation of tumor cells, and the effect is better than that of ibrutinib.

[0386] Table 3 Inhibitory effect of compounds on cell proliferation

[0387] Compound No. <![CDATA[IC 50 (μM)]]> H01 0.024 H02 0.023 H03 0.061 H04 0.026 H05 0.023 H06 0.031 H07 0.040 H08 0.029 H09 0.031 H10 0.021 H11 0.013 H12 0.013 H13 0.019 H14 0.047 H15 0.023 H16 0.047 Ibrutinib 0.087

[0388] Experiment 3: Effect of Compounds on Alleviating Rheumatoid Arthritis

[0389] 1. Experimental purpose and methods

[0390] The purpose of this experiment is to test the effect of the compound on the rat arthritis model induced by type II collagen. The rats were injected intradermally at the base of the tail twice on day 0 and day 7 to establish the model, and the clinical scores were performed. The animals with successful modeling (clinical score>3 points) were randomly assigned to various dosing groups for treatment. Various indicators were tested at the same time, including clinical scores, toe volume measurements (twice a week), etc.

[0391] 2. Experimental results

[0392] The compound of the present invention can effectively alleviate the clinical score of arthritis of animals and reduce the volume of toes after administration for 14 days, and alleviate the progression of arthritis, and the effect is better than that of ibrutinib.

[0393] Experiment 4: Effects of Compounds on Lymphoma

[0394] 1. Experimental purpose and methods

[0395] The purpose of this experiment is to test the effect of the compound on lymphoma. A20 5E6 cells were cultured and inoculated subcutaneously in SCID nude mice. The tumor volume was measured twice a week. After the tumor grew to a certain volume, the animals with successful modeling were randomly assigned to each dose group for treatment. At the same time, the tumor size and body weight changes were observed every day.

[0396] 2. Experimental results

[0397] The compound of the present invention can effectively reduce the size of animal solid tumors, alleviate the progression of tumors, and improve the body weight of animals, and the effect is better than that of ibrutinib.

[0398] Experiment 5: Effects of Compounds on Acute Pneumonia

[0399] 1. Experimental purpose and methods

[0400] The purpose of this experiment is to test the effect of compounds on acute pneumonia.

[0401] The animals were anesthetized with chloral hydrate, and then given lipopolysaccharide to chemically induce an acute pneumonia model. The animals were divided into a control group and a model group. The bronchoalveolar lavage fluid and lung tissue of the animals were collected at different time periods after inhalation of lipopolysaccharide, and the lung injury and other indicators of the animals were monitored by a respiratory function instrument. After the tissues were collected, tissue sections and staining were performed, and the cell counts of the bronchoalveolar lavage fluid and the corresponding inflammatory factors were determined.

[0402] 2. Experimental results

[0403] After administration, the compound of the present invention can effectively improve the infiltration of inflammatory cells in HE staining compared with the control group, the lymphocytes, mononuclear macrophages and neutrophils in the bronchoalveolar lavage fluid are significantly reduced compared with the control group, and the IL-1β content in the tissue and blood is also significantly reduced compared with the control group, and the effect is better than ibrutinib.

[0404] Experiment 6: Effects of Compounds on Systemic Lupus Erythematosus

[0405] 1. Experimental purpose and methods

[0406] The purpose of this experiment is to test the pharmacological effects of compounds on spontaneous systemic lupus erythematosus in MRL / lpr mice.

[0407] After 7 days of adaptation, serum was collected from MRL / lpr mice to determine the antinuclear antibody content in the blood, and the mice were divided into groups for drug administration. Blood samples were collected at 4, 8, 16, and 20 weeks to determine antinuclear antibodies, anti-single-stranded deformed DNA antibodies, anti-tissue protein, urea nitrogen, creatinine, and urine protein in the blood. The efficacy of the compound on systemic lupus erythematosus was observed.

[0408] 2. Experimental results

[0409] The compound of the present invention can effectively reduce the content of relevant indicators in the blood of animals and effectively alleviate the progress of systemic lupus erythematosus in animals.

[0410] Experiment 7: Inhibitory effect of compounds on hERG potassium channel current

[0411] 1. Experimental purpose and methods

[0412] The purpose of this experiment is to use electrophysiological manual patch clamp to detect the effect of compounds on hERG potassium channels.

[0413] HEK293 cells overexpressing hERG potassium channels were cultured in a 37°C 5% CO2 incubator using a medium consisting of DMEM / 15% fetal bovine serum / 1% penicillin-streptomycin. During the experiment, the cells were transferred to a cell bath embedded in an inverted microscope platform, perfused with extracellular fluid, and the experiment could be started after the cells were stabilized for 5 minutes. The membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466Lambrcht, Pfalz,

[0414] Germany).

[0415] The experiment was performed in whole-cell recording mode, and the current value was recorded according to the preset electrophysiological stimulation scheme. The drug to be tested was perfused and recorded from low to high concentrations. PATCHMASTER V2X60 (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany) was used for data acquisition, and Origin 8.5 (Origin Lab Corporation, Northampton, MA) software was used for analysis and statistics.

[0416] 2. Experimental results

[0417] Compounds of the present invention

[0418] hERG IC 50 >40μM, good cardiac safety.

[0419] Experiment 8. Pharmacokinetic results of compounds

[0420] 1. Experimental purpose and methods

[0421] The purpose of this experiment is to test the content of compounds in plasma and tissues.

[0422] The compound levels in plasma and tissues of SD rats were measured before administration and 15, 30 minutes, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, 24 hr, and 48 hr after administration.

[0423] 2. Experimental results

[0424] T on rats 1 / 2 Between 3-4hr.

[0425] Experiment 9. Results of acute toxicity test of compounds

[0426] 1. Experimental purpose and methods

[0427] The purpose of this experiment is to test the toxic effects of compounds in mice.

[0428] The mice were given different doses of the compound once and observed for 14 days, and the animal deaths, poisoning reactions, weight changes, diet, appearance, behavior, etc. were recorded. At the end point, the animals were dissected, and the organs were removed for histopathological examination.

[0429] 2. Experimental results

[0430] LD of the compounds of the present invention 50 >1000mg / kg, good safety. Compared with the control group, the mice in the drug group had no abnormal weight and behavior within 14 days from the date of drug administration, and no obvious organ lesions were found in the end-point anatomy. The compound of the present invention did not show obvious toxicity. No obvious abnormal indicators were found in blood analysis.

[0431] Experiment 10: Results of pre-toxicity tests of compounds

[0432] 1. Experimental purpose and methods

[0433] The purpose of this experiment is to test the toxic effects of compounds in rats after long-term administration.

[0434] Rats were given different high doses of compounds for a long time for 21 days, and the weight and related physiological signs of the animals were observed every day, and the death of the animals, poisoning reactions, weight changes, diet, appearance, behavior, etc. were recorded. After 21 days, the animals were dissected at the end point, and blood samples were collected for blood routine, blood biochemistry and coagulation tests, and organs were taken for histopathological examination.

[0435] 2. Experimental results

[0436] LD of the compounds of the present invention 50 >100mg / kg, good safety. Compared with the control group, the animals in the drug group showed no abnormal body weight, behavior and physiological changes within 21 days from the date of drug administration, and no obvious organ lesions were found in the end-point anatomy, and the compounds of the present invention did not show obvious toxicity. Blood analysis did not find abnormalities in related indicators in the animals in the drug group.

[0437] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound represented by the general formula (I), or its mesoform, racemate, enantiomer, diastereomer, and pharmaceutically acceptable salt thereof, wherein X is N; R0 is hydrogen; R2 and R3 are independently C 1-3 alkyl; R is a hydroxyl group; A is R4 is a straight chain C 1-6 Alkyl or branched C 3-6 alkyl; R5 is hydrogen or C 1-3 alkyl; X1 is CH or N; T is R1 is hydrogen, deuterium, halogen, cyano, trifluoromethyl, C 0-6 Substituted amino, C 1-6 Alkyl, C 1-6 Alkoxy; T3 is hydroxyl or C 1-6 alkyl; T4 is C 1-6 Alkyl or 3-6 membered heterocycloalkyl.

2. The compound according to claim 1 or its mesoform, racemate, enantiomer, diastereomer, and pharmaceutically acceptable salt thereof, characterized in that: T is 3. A compound, or its racemate, racemate, enantiomer, diastereomer, and pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4. A method for preparing a compound of the general formula (I) as defined in any one of claims 1 to 2, wherein the compound of the general formula (I) is prepared by the following scheme: Scenario 1: When A is R is hydroxyl, R1 is halogen or C 1-6 When the alkyl group is present, the synthetic route of the compound represented by the general formula (I) is as follows: Scenario 2: When A is When R is hydroxyl and R1 is hydrogen, the synthetic route of the compound represented by general formula (I) is as follows: in, The catalyst described in Scheme 1 is selected from tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, palladium acetate, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 1,10-phenanthroline and cuprous iodide; the reducing agent 1 is lithium aluminum tetrahydride, borane tetrahydrofuran, borane dimethyl sulfide, and reduced iron powder; the reducing agent 2 is sodium borohydride, potassium borohydride, sodium triacetylborohydride, and sodium cyanoborohydride; The catalyst described in Scheme 2 is selected from tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, palladium acetate, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 1,10-phenanthroline and cuprous iodide; the reducing agent 2 is sodium borohydride, potassium borohydride, sodium triacetylborohydride, and sodium cyanoborohydride.

5. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 3 or its racemate, racemate, enantiomer, diastereomer, and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers and / or diluents.

6. Use of the compound according to any one of claims 1 to 3 or its mesomer, racemate, enantiomer, diastereomer, and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 5 in the preparation of a medicament for preventing and / or treating Bruton's tyrosine kinase-mediated related diseases.

7. The use according to claim 6, wherein the Bruton's tyrosine kinase-mediated related disease is autoimmune disorder, cancer or inflammatory disease.

8. The use according to claim 7, wherein the cancer is esophageal cancer, lung cancer, colorectal cancer, pancreatic cancer, thyroid cancer, lymphoma or leukemia, and the autoimmune disease or inflammatory disease is arthritis, systemic lupus erythematosus, inflammatory bowel inflammation, Crohn's disease, multiple sclerosis, asthma, thrombocytopenic purpura, chronic obstructive pulmonary disease, psoriasis, organ transplant rejection, allergy or rhinitis.

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