TECHNICAL FIELD

The present invention relates to a bromodomain inhibitor compound, a preparation method thereof, a pharmaceutical composition containing the same and use thereof. Specifically, the present invention relates to a bromodomain inhibitor compound, its pharmaceutically acceptable salts, enantiomers, diastereomers, atropisomers, racemates, polymorphs, solvates, or isotopically labeled compounds (including deuterium substituted compounds), a preparation method thereof, a pharmaceutical composition containing the same, and pharmaceutical use thereof.

BACKGROUND ART

The bromodomain refers to a conserved protein fold connected with N-acetylated lysine residues, which is found in certain proteins. There are currently 46 human bromodomain-containing proteins, which are divided into eight families based on their sequence and structural similarities. Among others, the BET family includes BRD2, BRD3, BRD4, and BRDT. These proteins have two highly conserved bromodomains (BDT and BD2) that can recognize and bind acetylated histones at the N-terminus, and a highly conserved bromodomain that is involved in protein interactions regulated by non-BRD proteins at the C-terminus. The BET family proteins other than BRDT are widely expressed in the human body and have multiple cell functions. One of the most important functions of BET family proteins is to bind with acetylated histones, thereby recruiting regulatory proteins to chromosomal regions, such as the catalytic subunit of NuRD recombinant complex, histone demethylase JMJD6 and SWI/SNF nucleosome remodeling complex or methyltransferase NSD3 (Rahman, et al. Molecular and cellular biology 2011, 31 (13), 2641-52), etc., to combine acetylation of histones and function of chromatin to play the role of identifying genes. BET family proteins can also interact with acetylated transcription factors such as NF-KB, etc. to promote the binding of nuclear chromatin to other proteins (Shi, et al. Molecular cell 2014, 54 (5), 728-36).

Genomic data analysis shows that there is overlap part between the binding sites of chromatin and BRD4, BRD3 and BRD2, but there are significant differences in functions due to their own difference (Anders et al. Nat. Biotech. 2014; 32:92-6). For example, the deletion of BRD4 will kill the embryos of mice, indicating that BRD4 protein plays a vital role in the important physiological process of mouse growth and development (Houzelstein et al. Molecular and Cellular Biology 2002; 22:3794-802); physiological functional defects of BRD3 protein deletions are currently not reported but it plays an important role in the maturation of red blood cells (Lamonica, et al. Proceedings of the National Academy of Sciences of the United States of America 2011; 108:E159-E68); the mice with BRD2 deletion can survive, but have obvious obesity (Wang et al. Vitamins and hormones 2013; 91:49-75); the deletion of the first Broman region of BRDT can lead to incorrect reorganization of chromatin and abnormal transcriptional regulation, causing sperm defects (Berkovits et al. Current topics in developmental biology 2013; 102:293-326).

Therefore, there is currently a medical need to develop compounds that can inhibit the binding of the bromodomains of the BET family with their homologous acetylated lysine proteins for the treatment of cancer, inflammatory diseases, kidney diseases, diseases involving metabolism or fat accumulation, and some viral infections, and for providing methods for male contraception. At the same time, a large number of experiments have shown that although the BET family has similar structure, their physiological functions are quite different. Therefore, it is necessary to develop selective small molecule inhibitors for specific proteins in the BET family to avoid physiological dysfunction caused by the inhibition of other BET family proteins and reduce the adverse reactions of small molecule compounds. In summary, the development of inhibitors involving bromodomains is currently very hot in the industry and is conducive to the related new drug development.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically labeled compound (including deuterium substituted compound) thereof,



is a single bond or a double bond;

Rxis hydrogen, C1-C3alkyl, or C1-C3haloalkyl;

Ryis hydrogen, C1-C3alkyl, or C1-C3haloalkyl;

X1is N or CRx1, wherein Rx1is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen or CN;

Y1is N, CRy1or CRy1Ry2, wherein Ry1and Ry2are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, halogen, CN;

Y2is N, CR3or CRy3Ry4, wherein Ry3and Ry4are each independently hydrogen, CN, C1-C6alkyl, C1-C6haloalkyl, —(C1-C6alkylene)-OR2a, —C(O)—Rax1, —(C1-C6alkylene)—C(O)—Rax1, —C(O)ORax1, —(C1-C6alkylene)—C(O)NHRax1, —(C1-C6alkylene)—N(Rax1)Rax2, —C(O)N(Rax1)Rax2, Ga, or —(C1-C6alkylene)-Ga;

Rax1and Rax2at each occurrence are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, Ga, or —(C1-C6alkylene)-Ga;

particularly, Y1and Y2are not N simultaneously; and when Y1or Y2is N,is a double bond;

A1is N or CR1, A2is N or CR2, A3is N or CR3, A4is N or CR4, with the proviso that none, one, two or three of A1, A2, A3and A4is/are N;

R1is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, CN, or NO2;

R2, R3and R4are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, CN, NO2, G2a,


—OR2a, —OC(O)R2d, —OC(O)NR2bR2c, —SR2a, —S(O)2R2d, —S(O)2NR2bR2c, —C(O)R2d, —C(O)OR2a, —C(O)NR2bR2c, —NR2bR2c, —N(R2e)C(O)R2d, —N(R2e)S(O)2R2d, —N(R2e)C(O)OR2d, —N(R2e)C(O)NR2bR2c, —N(R2e)S(O)2NR2bR2c, —(C1-C6alkylene)-G2a, —(C1-C6alkylene)—OR2a, —(C1-C6alkylene)—OC(O)R2d, —(C1-C6alkylene)—OC(O)NR2bR2c, —(C1-C6alkylene)—S(O)2R2d, —(C1-C6alkylene)—S(O)2NR2bR2c, —(C1-C6alkylene)—C(O)R2d, —(C1-C6alkylene)—C(O)OR2a, —(C1-C6alkylene)—C(O)NR2bR2c, —(C1-C6alkylene)—NR2bR2c, —(C1-C6alkylene)—N(R2e)C(O)R2d, —(C1-C6alkylene)—N(R2e)S(O)2R2d, —(C1-C6alkylene)—N(R2e)C(O)OR2a, —(C1-C6alkylene)—N(R2e)C(O)NR2bR2c, —(C1-C6alkylene)—N(R2e)S(O)2NR2bR2c, —(C1-C6alkylene)—CN, —S(═O)(═NH)R2d, —(C1-C6alkylene)—S(═O)(═NH)R2d; wherein C1-C6alkylene is unsubstituted or substituted with 1 to 6 substituents selected from CN, OH and C1-C3alkyl; R2a, R2b, R2cand R2eat each occurrence are each independently hydrogen, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, G2b, C1-C6alkyl, or C1-C6alkyl substituted by one selected from —ORz1, —NRz1Rz2, —C(O)ORz1, —C(O)NRz1Rz2, —S(O)2Rz1, —S(O)2NRz1Rz2and G2b;

R2dat each occurrence is independently C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, G2b, C1-C6alkyl, or C1-C6alkyl substituted by one selected from —ORz1, —NRz1Rz2, —C(O)ORz1, —C(O)NRz1Rz2, —S(O)2Rz1, —S(O)2NRz1Rz2and G2b; Rz1and Rz2at each occurrence are each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl;

Ga, G2aand G2bat each occurrence are each independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, which are each independently unsubstituted or substituted by 1, 2, 3, 4, or 5 Rvs;

L1is absent, or is —CH2—, —C(O)—, —C(H)(OH)—, —(CH2)mO—, —(CH2)mS(O)n—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHS(O)2—, —S(O)2NH— or —(CH2)mN(Rz)—, wherein n is 0, 1, or 2; m is 0 or 1; Rzis hydrogen, C1-C3alkyl, C1-C3haloalkyl; (C2-C3alkylene)—OH, or unsubstituted cyclopropyl;

G1is C1-C6alkyl, alkoxyalkyl, G1aor —(C1-C6alkylene)-G1a; wherein each G1ais independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, and each G1ais independently unsubstituted or substituted with 1, 2, 3, 4, or 5 Rws;

Rvand Rwat each occurrence are each independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, —CN, oxo (═O), —ORh, —OC(O)Ri, —OC(O)NRjRk, —SRh, —S(O)2Rh, —S(O)2NRjRk, —C(O)Rh, —C(O)-monocyclic heterocyclyl, —C(O)-monocyclic heteroaryl, —C(O)ORh, —C(O)NRjRk, —NRjRk, —N(Rh)C(O)Ri, —N(Rh)S(O)2Ri, —N(Rh)C(O)ORi, —N(Rh)C(O)NRjRk, —(C1-C6alkylene)—ORh, —(C1-C6alkylene)—OC(O)Ri, —(C1-C6alkylene)—OC(O)NRjRk, —(C1-C6alkylene)—S(O)2Rh, —(C1-C6alkylene)—S(O)2NRjRk, —(C1-C6alkylene)—C(O)Rh, —(C1-C6alkylene)—C(O)ORh, —(C1-C6alkylene)—C(O)NRjRk, —(C1-C6alkylene)—NRjRk, —(C1-C6alkylene)—N(Rh)C(O)Ri, —(C1-C6alkylene)—N(Rh)S(O)2Ri, —(C1-C6alkylene)—N(Rh)C(O)ORi, —(C1-C6alkylene)—N(Rh)C(O)NRjRk, or —(C1-C6alkylene)—CN;

Rh, Rj, Rkat each occurrence are each independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; and

Riat each occurrence is independently C1-C6alkyl, or C1-C6haloalkyl.

Preferably, the compound of formula I is a compound represented by formula Ia, Ib, Ic, or Ie:



is a single bond or a double bond;

Rx, Ry, Rx1, Ry1, Ry2, Ry3, Ry4, Y1, Y2, A, A2, A3, A4, L1and G1at occurrence have the same definition as those in the formula I described above.

Preferably, the compound of formula I is a compound represented by formula Id or If:



wherein, A1, A2, A3, A4, L1and G1at occurrence have the same definition as those in the formula I described above;

Y2is N or CH;

Ryis C1-C3alkyl;

Rx1is H, CH3or halogen.

Preferably, the compound of formula I is a compound represented by formula Ig or Ih:



wherein, A2has the same definition as that in the formula I described above;

L1is O or NH;

Y2is CH or N;

Rx1is H, CH3or halogen;

A4is CH or N;

G1is G1aor —(CH2)-G1a; wherein each G1ais independently aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, and each G1ais independently unsubstituted or substituted with 1 or 2 Rws;

Rwhas the same definition as that in the formula I described above.

Preferably, the compound of formula I is a compound represented by formula Ii or Ij:



wherein, Y2is N or CH;

L1is O or NH;

A4is CH or N;

G1is pyridyl,


or phenyl substituted with 1 or 2 halogens;

R2is —S(O)2R2d, —NHS(O)2R2d, —S(O)2NR2bR2or —(CH2)—S(O)2R2d; wherein R2dis an unsubstituted C1-C3alkyl, and R2band R2care each independently hydrogen or an unsubstituted C1-C3alkyl.

Preferably, the compound of formula I is selected from the group consisting of the following compounds:



Preferably, the isotopically labeled compound is, for example, a deuterium-substituted compound. The isotopically labeled compounds may be used in applications such as metabolic detection.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically labeled compound thereof as described above, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of treating or preventing a disease or disorder or condition that is improved by inhibiting BET. The method includes administering to a subject a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically labeled compound thereof, alone or in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention provides use of the compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically labeled compound thereof or the pharmaceutical composition in preparation of a medicament for treating a disease or disorder or condition in a subject.

Some methods or uses involve the treatment or prevention of an inflammatory disease or a cancer or acquired immunodeficiency syndrome (AIDS).

In another aspect, the method or use relates to a cancer selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, adverse proliferative changes (dysplasia and metaplasia), embryonic cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, primary thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, (Hodgkin's and Non-Hodgkin's) lymphoma, malignant tumors and hyperproliferative disorders of bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell derived lymphoma, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat adenoma, thyroid cancer, primary macroglobulinemia, testicular tumor, uterine cancer, and nephroblastoma. In certain embodiments, the method or use further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is an anticancer agent. In a particular embodiment, the additional therapeutic agent is selected from cytarabine, bortezomib and 5-azacytidine.

In another aspect, the disease or disorder or condition is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, organs transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, localized pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Gauer's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's Granuloma. In certain embodiments, the method or use further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the disease or disorder or condition is selected from the group consisting of diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal stage glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubulointerstitial nephritis. In certain embodiments, the method or use further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the disease or disorder or condition is acute kidney injury or a related condition, wherein the acute kidney injury or the related condition is selected from the group consisting of acute kidney injury or related conditions induced by ischemia-reperfusion, cardiotonics and major surgical procedures, percutaneous coronary intervention, radiocontrast agents, sepsis, pneumonia, or drug poisoning. In certain embodiments, the method further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the disease or disorder or condition is AIDS. In certain embodiments, the method or use further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the disease or disorder or condition is obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy. In certain embodiments, the method or use further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the invention provides a method of preventing pregnancy comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or isotopically labeled compound thereof. The present invention provides use of the compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically labeled compound thereof in preparation of a medicament for preventing pregnancy. In certain embodiments, the method or use further comprises administering or adding a therapeutically effective amount of at least one additional therapeutic agent. The compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically labeled compound thereof according to the present invention achieves the object of preventing pregnancy by inhibiting sperm production in an individual.

According to another aspect of the invention, provided is a method for preparing the compound of the invention, wherein the method is as shown in Scheme 1 below.



The compound of formula I may be prepared by the general procedure described in Scheme 1, that is, an aryl halide, aryl methanesulfonate or aryl trifluoromethanesulfonate is treated with an arylboronic acid or a derivative (eg, a borate) thereof under Suzuki coupling conditions. As shown in scheme I, the compound of formula (A), wherein R101is Br, Cl, I, methanesulfonate or trifluoromethanesulfonate, is coupled with the compound of formula (B), wherein R102is a boronic acid or a derivative (eg, borate) thereof, or the compound of formula (A), wherein R101is a boronic acid or a derivative (eg, borate) thereof, is coupled with the compound of formula (B), wherein R102is Br, Cl, I, methanesulfonate or trifluoromethanesulfonate, to provide the compound of formula I. Generally, the coupling reaction is performed in the presence of a palladium catalyst, a base, and optionally a ligand, in a suitable solvent at an elevated temperature (for example, about 80 to 150° C.). The reaction can be promoted by microwave radiation. Examples of the palladium catalyst include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), allylpalladium(II) chloride dimer, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium(II) acetate. Examples of the suitable base that may be used include, but are not limited to, a carbonate or phosphate of sodium, potassium and cesium, and cesium fluoride. Examples of the suitable ligand include, but are not limited to 2-dicyclohexylphosphino-2,4,6-tri-i-propyl-biphenyl (X-Phos), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryl-adamantane, sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate hydrate and 1,1′-bis(diphenylphosphino)ferrocene. Non-limiting examples of the suitable solvent include methanol, acetonitrile, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene and water, or the mixture thereof.

Alternatively, the compound of formula (C), wherein R103is boronic acid or a derivative (eg, borate) thereof, is coupled with the compound of formula (A), wherein R101is Br, Cl, I, methanesulfonate or trifluoromethanesulfonate, to prepare a compound of formula D, then the fluorine atom in formula (D) is replaced with a suitable alcohol, amine or thiol of formula G1-L1-H, wherein L is O, NH or S, to provide a compound of formula I. The replacement of fluorine with an alcohol, amine or thiol can be performed in a solvent in the presence of a base at a temperature of about 30 to 140° C., the solvent is, for example, but not limited to, dimethyl sulfoxide, dimethyl formamide, dioxane or tetrahydrofuran. The base is, for example, but not limited to, cesium carbonate, potassium carbonate, or sodium hydride.

The compound of formula (A), whereinis a double bond, Rxis hydrogen, Y1is CRy1, and Y2is CH, may be prepared by a general synthetic method shown in Scheme 2.



The compound of formula (1) is treated by the compound of formula (1A), wherein X is halogen or OMs, to give a N-substituted compound of formula (2), the solvent is, for example, but not limited to, N-methylpyrrolidone, DMF or acetonitrile, the reaction temperature is about 60 to 150° C., the base used is, for example, but not limited to, sodium hydride, sodium hydroxide or potassium t-butoxide. The ester group is then hydrolyzed under a basic condition to give a carboxylic acid of formula (3), wherein the used base is, for example, but not limited to, lithium hydroxide, potassium hydroxide or sodium hydroxide. A condensation reaction is performed with NH3or ammonium chloride in the presence of a condensing agent to give an amide (4), wherein the condensing agent is selected from the group consisting of, for example, but not limited to, carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, o-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate and 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, the condensation reaction may be performed in an organic solvent in the presence of a base, the base is, for example, but not limited to, triethylamine, diisopropylethylamine or 1,5-diazabicyclo[5.4.0]undec-5-ene, the organic solvent is, for example, but not limited to, dichloromethane, chloroform, N,N-dimethylformamide or tetrahydrofuran. Then, a cyclization reaction is performed through acid treatment at a reaction temperature of about 100 to 130° C., to give the compound of formula (5), wherein the used acid is, for example, but not limited to, glacial acetic acid and hydrochloric acid. Finally, a halogenation is performed through treatment with a halogenating agent to give a halide (6A), wherein the used halogenating agent is, for example, but not limited to, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine or iodine. Alternatively, the halide (6A) may be further coupled with bis(pinacolato)diboron under palladium catalysts to give a borate (6B).

The compound of formula (A), whereinis a single bond, Rxis hydrogen, Y1is CRy1Ry2, and Y2is CRy3Ry4may be prepared by the general synthetic method shown in Scheme 3.



The ester group of formula (1) is hydrolyzed under a basic condition to give the carboxylic acid of formula (7), wherein the used base is, for example, but not limited to, lithium hydroxide, potassium hydroxide or sodium hydroxide. The carboxylic acid is condensated with an amine of formula (8) (in the formula (8), X is halogen or OMs) in the present of a condensing agent to give an amide (9), the condensing agent is selected from the group consisting of, for example, but not limited to, carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, o-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate and 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, the condensation may be performed in an organic solvent in the presence of a base, the base includes, for example, but not limited to, triethylamine, diisopropylethylamine and 1,5-diazabicyclo[5.4.0]undec-5-ene, the organic solvent is, for example, but not limited to, dichloromethane, chloroform, N,N-dimethylformamide or tetrahydrofuran. Then, cyclization is performed under a basic condition to give a compound of formula (10), wherein the used base is, for example, but not limited to, triethylamine or diisopropylethylamine. Finally, halogenation is performed by treating with a halogenating agent to give a compound of formula (11A), wherein the used halogenating agent is, for example, but not limited to, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine or iodine. Alternatively, the halide (11A) may be further coupled with bis(pinacolato)diboron under palladium catalysis to give a borate (11B).

The compound of formula (A), whereinis a double bond, Rxis hydrogen, Y2is CH, and Y1is N, may be prepared by a general synthetic method shown in Scheme 4.



The compound of formula (1) is treated with a base, and reacted with diphenylphosphorylhydroxylamine (CAS: 72804-96-7) to give the compound of formula (12), wherein the used base is, for example, but not limited to, lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) or lithium diisopropylamide (LDA), the reaction temperature is about −78 to 10° C. The compound of formula (12) is then reacted with formamide at a high temperature of about 100 to 200° C. to give a cyclized product (13). Finally, halogenation is performed by treating with a halogenating reagent to give the compound (14A), wherein the used halogenating reagent is, for example, but not limited to, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine or iodine. Alternatively, the halide (14A) may be further coupled with bis(pinacolato)diboron under palladium catalysis to give a borate (14B).

The compound of formula (A), whereinis a double bond, Rxis hydrogen, Y2is N, and Y1is CRy1, may be prepared by a general synthetic method shown in Scheme 5.



The hydrazide of Formula (15), which may be prepared by reacting the compound of formula (1) with hydrazine hydrate, is directly cyclized with the compound of formula (16) at an elevated temperature to give the product (17), or (15) is first reacted with (16) to give a precursor for cyclization, which is then cyclized under a basic condition to give the cyclized product (17), wherein the reaction temperature is about 50 to 150° C. Then, halogenation is performed by treating with a halogenating agent to give the compound of formula (18A), wherein the used halogenating agent is, for example, but not limited to, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine or iodine. Alternatively, the halide (18A) may be further coupled with bis(pinacolato)diboron under palladium catalysis to give a borate (18B).

The compound of formula (A), wherein Rxis C1-C3alkyl or C1-C3haloalkyl, may be prepared by the general synthetic method shown in Scheme 6.



The compound of formula (19) is alkylated with a halide or methanesulfonate in the present of a base to give the product of formula (20), wherein the base is, for example, but not limited to, sodium hydride, cesium carbonate or potassium carbonate, the alkylation reaction may be conducted in an organic solvent, wherein the solvent is, for example, but not limited to, dimethylformamide or dimethylsulfoxide. The compound (20) is then treated with a halogenating reagent to conduct a halogenation reaction to give the compound (21A), wherein the used halogenating agent is, for example, but not limited to, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine or iodine. Alternatively, the halide (21A) may be further coupled with bis(pinacolato)diboron under palladium catalysis to give a borate (21B).

When R102in the compound of formula (B) is a borate, the synthesis may be performed by the general synthetic method shown in Scheme 7.



The halide (22A) may be coupled with bis(pinacolato)diboron under palladium catalysis to give a borate (22B). Among others, the halide (22A) are commercially available or prepared according to a conventional method known in the art (for example, reference is made toJ Med. Chem.,2017, 60, 8369; WO 2015058160; US 2014275026). The coupling reaction is performed in the presence of a palladium catalyst, a base, and optionally, a ligand, in a suitable solvent at an elevated temperature (for example, about 80 to 150° C.). Examples of the palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), allylpalladium (II) chloride dimer, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl2), palladium (II) acetate. Examples of the suitable base that may be used include, but are not limited to, carbonate, phosphate or acetate of sodium, potassium and cesium, and cesium fluoride. Examples of the suitable ligand include, but are not limited to, 2-dicyclohexylphosphino-2,4,6-tri-i-propyl-biphenyl (X-Phos), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryl-adamantane, sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate hydrate and 1,1′-bis(diphenylphosphino)ferrocene. Non-limiting examples of the suitable solvent include methanol, acetonitrile, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene and water, or the mixture thereof.

The optimal reaction conditions and reaction time for each individual step can vary according to the specific reactants used and the substituents present in all reactants. Unless otherwise specified, the solvent, the temperature and other reaction conditions can be easily selected by those skilled in the art. Specific steps are provided in Synthetic Examples. The reaction can be further processed in a conventional manner, for example by removing the solvent from the residue, and further purified by a method generally known in the art, for example, but not limited to, crystallization, distillation, extraction, grinding and chromatography. Unless otherwise stated, the starting materials and reactants are commercially available or may be prepared by those skilled in the art from commercially available materials using a method described in chemical literatures.

Routine tests, including appropriate adjustment of the reaction conditions, the reagents and sequence of the synthetic route, the protection of any chemical functional groups (which may not be compatible with the reaction conditions) and deprotection at an appropriate point in the reaction sequence of the method, are included within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art, and examples thereof may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (Third Edition), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the invention can be achieved by methods similar to those described in the synthetic schemes described above and in the specific examples.

If a starting material is not commercially available, it may be prepared by steps selected from the group consisting of standard organic chemical techniques, techniques similar to the synthesis of known structural analogs, or techniques similar to the above schemes or steps described in Synthetic Examples. When an optically active form of the compound of the present invention is required, it may be obtained by performing one of the steps described herein using an optically active starting material (e.g., prepared by asymmetric induction of an appropriate reaction step), or by resolving a stereoisomer mixture of a compound or intermediate by using a standard procedure (e.g., chromatographic separation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of the compound of the present invention is required, it may be obtained by performing one of the steps described herein using a pure geometric isomer as a starting material, or by resolving a geometric isomer mixture of a compound or intermediate by using a standard procedure, such as chromatographic separation.

