Nitrogen-containing heterocyclic compounds, methods for their preparation, and their use in medicine

Abstract

This disclosure relates to nitrogen-containing heterocyclic compounds, their preparation methods, and their pharmaceutical applications. Specifically, this disclosure relates to a nitrogen-containing heterocyclic compound of general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and their use as therapeutic agents, particularly as BET inhibitors, and in the preparation of medicaments for the treatment and / or prevention of BET-mediated or dependent diseases or conditions.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a nitrogen-containing heterocyclic compound, its preparation method, and its pharmaceutical application. Specifically, this disclosure relates to a nitrogen-containing heterocyclic compound of general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a therapeutic agent, particularly as a BET inhibitor, and in the preparation of medicaments for treating and / or preventing BET-mediated or dependent diseases or conditions. Background Technology

[0002] The bromodomain and extraterminal domain (BET) family of proteins is a widely expressed epigenetic reader, including the ubiquitous BRD2, BRD3, and BRD4, as well as the germline-only BRDT. All BET family proteins contain two highly homologous tandem bromodomains (BD1 and BD2) and an ET domain, with BRD4 also having a distinctive C-terminal domain.

[0003] BET proteins are mainly distributed on chromatin near histone acetylation sites. They utilize their BD1 and BD2 domains to recognize and bind acetylated lysine residues on histones, acting as scaffold proteins to recruit transcription factors and other proteins to promoters and enhancers, thus playing a crucial role in normal development and diseases such as tumors, inflammation, and viral infections. BRD4 primarily recruits positive transcription elongation factor b (P-TEFb) through its C-terminal domain. P-TEFb proteins interact with cell cycle-dependent protein kinase 9 (CDK9) and increase the transcriptional activity of RNA polymerase II through phosphorylation, activating the expression of downstream genes. BRD2, BRD3, and BRDT mainly recruit other transcription activators, such as HDAC and GATA1, through their ET domains, exerting transcriptional regulatory functions.

[0004] The main physiological functions of BET proteins are regulating the cell cycle, inflammatory responses, and maintaining higher-order chromatin structure. Knockout of the BRD2 and BRD4 genes leads to early embryonic death in mice. In adult mice, BRD4 knockdown results in epidermal hyperplasia, hair loss, decreased small intestinal cell diversity, and reduced stem cell count.

[0005] BET family proteins are closely related to tumors, and some important proto-oncogenes such as MYC, BCL2, and CDK6 are regulated by BET proteins. Studies have shown that BET inhibitors can reduce the expression of proto-oncogenes and have a significant inhibitory effect on tumor growth.

[0006] First-generation BET inhibitors have the same affinity for both the BD1 and BD2 domains, limiting their clinical application due to side effects and short duration of clinical response. Selective BET inhibitors have shown good efficacy and low toxicity in preclinical studies and are becoming a new development direction. For example, the selective BD2 inhibitor ABBV-744 is currently in Phase 1 clinical trials for the treatment of myelofibrosis (MF). Preclinical data show that ABBV-744 is mainly effective against acute myeloid leukemia (AML) and androgen receptor-positive prostate cancer cells, while normal small intestinal cells are unaffected. In enzalutamide-sensitive and enzalutamide-resistant tumor models, ABBV-744 significantly inhibited tumor growth at low doses (ACS Chem Biol, 2015, 10(8):1770-1777; Nat Rev Cancer, 2012, 12(7):465-77; Nature, 2020, 578(7794):306-310).

[0007] The purpose of this disclosure is to provide a class of selective BD2 inhibitors for the targeted treatment of malignant tumors.

[0008] Currently published patent applications for BET inhibitors include WO2017177955A1 and

[0009] WO2015058160A1. Summary of the Invention

[0010] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

[0011]

[0012] in:

[0013] X is a nitrogen atom or CR 5 ;

[0014] R 5 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, and hydroxyalkyl groups;

[0015] G 4 Nitrogen atom or CR 6a ;

[0016] G 1 G 2 and G 3 Whether the same or different, and each independently consisting of a nitrogen atom or a CR 6 ;

[0017] R 6a and R 6Whether identical or different, each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7 R 8 hydroxyl and

[0018] L is selected from covalent bonds, oxygen atoms, sulfur atoms, and (CH2). r and NH;

[0019] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0020] Each R x The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxy, hydroxyalkyl, -NR 7 R 8 -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -S(O) t R 7 R 8 and -S(O) t NR 7 R 8 ;

[0021] R 1 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, and hydroxyalkyl groups;

[0022] R 2 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7 R 8 hydroxyl group, -C(O)R 9 -C(O)OR 9 -C(O)NR 7 R 8 -S(O) t R 7 R 8 -S(O) t NR 7 R 8 cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 10 R 11 It is substituted by one or more substituents selected from nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0023] R 3 and R 4 The same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 10 R 11 It is substituted by one or more substituents selected from nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0024] Or R 3 and R 4 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, wherein each cycloalkyl or heterocyclic group is independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 10 R 11 It is substituted by one or more substituents selected from nitro, hydroxy, and hydroxyalkyl;

[0025] R 7 R 8 R 10 and R 11 The same or different, and each independently selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; or R 7 and R 8 R 10 and R 11 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the formed heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0026] R 9 Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0027] r can be 0, 1, 2, 3, 4, 5, or 6;

[0028] n is 0, 1, 2, 3, or 4; and

[0029] t can be 0, 1, or 2.

[0030] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein G4 For CR 6a And R 6a for L, ring A, R x And n is as defined in general formula (I).

[0031] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is an oxygen atom.

[0032] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] X, ring A, G 1 To G 3 R 1 To R 4 R x And n is as defined in general formula (I).

[0036] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, cyano, -NR 7 R 8 , hydroxyl group and -C(O)NR 7 R 8 R 7 and R 8 As defined in general formula (I); preferably, R 2 -C(O)NR 7 R 8 R 7 and R 8 As defined in general formula (I); more preferably, R 2 -C(O)NR 7 R 8 ;R 7 and R 8 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 2 -C(O)NR 7 R 8 ;R7 and R 8 One is a hydrogen atom, and the other is a carbon atom. 1-6 Alkyl; most preferably, R 2 -C(O)NR 7 R 8 ;R 7 and R 8 One of them is a hydrogen atom, and the other is an ethyl atom.

[0037] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 1 G 2 and G 3 All are CR 6 And R 6 It is a hydrogen atom.

[0038] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0039]

[0040] in:

[0041] X, ring A, R 1 R 3 R 4 R 7 R 8 R x And n is as defined in general formula (I).

[0042] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; preferably, ring A is phenyl or pyridyl; more preferably, ring A is phenyl.

[0043] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or its pharmaceutically acceptable salt, wherein X is a nitrogen atom or CR 5 And R 5 It is a hydrogen atom.

[0044] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 1 C 1-6 Alkyl; more preferably, R 1 It is a methyl group.

[0045] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Whether the atoms are the same or different, they are each independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 3 and R 4 All are C 1-6 Alkyl; more preferably, R 3 and R 4 All are methyl groups.

[0046] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 Hydroxyalkyl; preferably, each R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; more preferably, each R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

[0047] In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (II) or general formula (III) or their pharmaceutically acceptable salts, wherein each R x They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 Hydroxyalkyl; and n is 0, 1, 2 or 3; preferably, each R x They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; and n is 1, 2 or 3; more preferably, each R x They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; and n is 3; most preferably, each R x They may be the same or different, and each is independently a fluorine atom or a methyl group; and n is 3.

[0048] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups are each independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 The alkoxy group is substituted with one or more substituents in the haloalkoxy group; preferably, R 7 and R 8 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 7 and R 8 One is a hydrogen atom, and the other is a carbon atom. 1-6 Alkyl; most preferably, R 7 and R 8 One of them is a hydrogen atom, and the other is a methyl group.

[0049] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II) or general formula (III) or its pharmaceutically usable salt thereof, wherein n is 1, 2 or 3; preferably, n is 3.

[0050] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom or CR 5 And R 5 It is a hydrogen atom; ring A is a phenyl group; R 1 C 1-6 Alkyl; R 3 and R 4 All are C 1-6 Alkyl; R 7 and R 8 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each Rx They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; n is 1, 2 or 3.

[0051] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom or CR 5 And R 5 It is a hydrogen atom; ring A is a phenyl group; R 1 Methyl; R 3 and R 4 All are methyl; R 7 and R 8 One is a hydrogen atom, and the other is a carbon atom. 1-6 Alkyl groups; each R x They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl group; and n is 3.

[0052] Table A lists typical compounds disclosed herein, including but not limited to:

[0053]

[0054] Another aspect of this disclosure relates to compounds of general formula (IIIa) or salts thereof.

[0055]

[0056] in:

[0057] R y Selected from hydroxyl, C 1-6 Alkoxy and halogen; preferably, R y C 1-6 Alkoxy;

[0058] X, ring A, R 1 R 3 R 4 R x And n is as defined in general formula (III).

[0059] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0060]

[0061] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0062]

[0063] Compounds of general formula (IIIa) or their salts and compound NHR 7 R 8 The compound or its salt reacts to give the compound of general formula (III) or its pharmaceutically usable salt;

[0064] in:

[0065] R y Selected from hydroxyl, C 1-6 Alkoxy and halogen; preferably, R y C 1-6 Alkoxy;

[0066] X, ring A, R 1 R 3 R 4 R 7 R 8 R x And n is as defined in general formula (III).

[0067] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) of this disclosure and a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0068] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, in the preparation of medicaments for inhibiting BET.

[0069] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, in the preparation of medicaments for inhibiting BD1 and / or BD2, preferably in the preparation of medicaments for inhibiting BD2.

[0070] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for treating and / or preventing diseases or conditions selected from tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, kidney diseases, viral infections, and neurological diseases.

[0071] This disclosure also relates to a method of inhibiting BET, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0072] This disclosure also relates to a method of inhibiting BD1 and / or BD2, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0073] This disclosure also relates to a method of inhibiting BD2, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0074] This disclosure also relates to a method of treating and / or preventing a disease or condition selected from tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, kidney diseases, viral infections, and neurological diseases, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as shown in Table A.

[0075] This disclosure further relates to a compound of general formula (I), general formula (II), general formula (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0076] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, which are used as BET inhibitors.

[0077] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, which are used as BD1 and / or BD2 inhibitors.

[0078] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, which are used as BD2 inhibitors.

[0079] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (III) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of diseases or conditions selected from tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, kidney diseases, viral infections, and neurological diseases.

[0080] The diseases or conditions described in this disclosure are BET-mediated diseases or conditions, preferably mediated by BD1 and / or BD2, and more preferably mediated by BD2.

[0081] The diseases or conditions described in this disclosure are preferably selected from: cancer, Addison's disease, gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous dermatitis, chronic obstructive pulmonary disease (COPD), dermatitis, eczema, giant cell arteritis, glomerulonephritis (such as membranous glomerulonephritis), hepatitis, autoimmune hypophysitis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, myositis (such as myocarditis), organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Goran's arteritis, toxic shock, thyroiditis, type I diabetes, uveitis, vitiligo, vasculitis, essential thrombocytosis, erythropoietinosis. The following conditions are included: cellular polycythemia, Wegener's granulomatosis, acquired immunodeficiency syndrome (AIDS), obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, ischemia-reperfusion-induced kidney disease, kidney disease induced by cardiac and major surgery, kidney disease induced by percutaneous coronary intervention, kidney disease induced by radioactive contrast agents, kidney disease induced by sepsis, kidney disease induced by pneumonia, kidney disease induced by drug toxicity, diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, polycystic kidney disease, and tubulointerstitial nephritis; the inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis.

[0082] The cancers mentioned are preferably selected from: prostate cancer (such as hormone-insensitive prostate cancer), acute leukemia (such as acute lymphoblastic leukemia, acute myeloid leukemia, acute granulocytic leukemia, and acute T-cell leukemia), chronic leukemia (such as chronic lymphocytic leukemia, chronic granulocytic leukemia, and chronic myeloid leukemia), myeloid leukemia, myelofibrosis, erythroleukemia, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, embryonal carcinoma, endometrial cancer, endothelial sarcoma (such as lymphangiosarcoma), ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, and gliomas (such as glioblastoma, gliosarcoma, and oligodendroglioma). Heavy chain disease, angioblastoma, liver cancer, leiomyosarcoma, liposarcoma, lung cancer (such as non-small cell lung cancer (such as lung adenocarcinoma and lung squamous cell carcinoma) and small cell lung cancer), lymphangiosarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myeloma, myxosarcoma, neuroblastoma, midline carcinoma of NUT, bone cancer, nasopharyngeal carcinoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, thyroid cancer, pineal tumor, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, gastric cancer, squamous cell carcinoma, synovoma, sweat gland carcinoma, Waldenström macroglobulinemia, and Wilms' tumor; more preferably, the cancers are selected from prostate cancer, acute myeloid leukemia, and myelofibrosis; the myeloma is preferably multiple myeloma.

[0083] The active compound can be formulated into a form suitable for administration via any appropriate route, preferably in a unit dose manner or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0084] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0085] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0086] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0087] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0088] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0089] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0090] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0091] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0092] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0093] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0094] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0095] Terminology Explanation

[0096] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0097] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0098] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkylene containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0099] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Preferably, it is an alkenyl compound containing 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C14-C14-C14). 2-12 Alkenyl), more preferably alkenyl containing 2 to 6 carbon atoms (i.e., C14-C ... 2-6 Alkenyl). The alkenyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0100] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. Preferably, the alkynyl group (i.e., C14) contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12). 2-12 Alkyne group), more preferably an alkyne group containing 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 (Alkyne). The alkynyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0101] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) (i.e., 3 to 12-membered cycloalkyl), more preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0102] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds (i.e., 5- to 20-membered spirocycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered spirocycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spirocycloalkyl). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, 5 / 6-membered, or 6 / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0103]

[0104] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds (i.e., 5- to 20-membered fused cycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered fused cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, and other polycyclic fused cycloalkyls, preferably bicyclic or tricyclic, more preferably 3- / 4-membered, 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 4-membered, 5- / 5-membered, 5- / 6-membered, 6- / 3-membered, 6- / 4-membered, 6- / 5-membered, and 6- / 6-membered bicyclic alkyls. Non-limiting examples of fused cycloalkyls include:

[0105]

[0106] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds (i.e., 5- to 20-membered bridged cycloalkyl). Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered bridged cycloalkyl), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0107]

[0108] The cycloalkyl ring comprises a cycloalkyl group (including monocycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group, and non-limiting examples include indenyl. Tetrahydronaphthyl and benzocycloheptanyl etc.; preferred indene and tetrahydronaphthyl

[0109] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0110] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0111] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent containing 3 to 20 ring atoms (i.e., a 3 to 20-membered heterocyclic group), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., to form sulfoxide or sulfone), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclic groups); more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 are heteroatoms (e.g., 1, 2, and 3) (i.e., 3 to 8-membered heterocyclic groups); even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclic groups). Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0112] The term "spiroheterocyclic group" refers to a 5- to 20-membered (i.e., 5- to 20-membered heterocyclic group) polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered spiroheterocyclic group), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spiroheterocyclic group). Spiroheterocyclic groups are classified into monospirocyclic groups or polyspirocyclic groups (such as bispirocyclic groups) according to the number of shared spiro atoms between rings, with monospirocyclic groups and bispirocyclic groups being more preferred. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, or 6 / 6 monospirocyclic heterocyclic group. Non-limiting examples of spirocyclic groups include:

[0113]

[0114] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group (i.e., a 5- to 20-membered fused heterocyclic group), in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. The sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered fused heterocyclic group (i.e., a 6- to 14-membered fused heterocyclic group), more preferably a 7- to 10-membered fused heterocyclic group (e.g., 7, 8, 9, or 10-membered fused heterocyclic group). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, and tetracyclic groups, etc., preferably bicyclic or tricyclic, and more preferably ternary / quadricyclic, ternary / pentacyclic, ternary / hexacyclic, quadricyclic / quadricyclic, quadricyclic / pentacyclic, quadricyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, and pentacyclic / pentacyclic bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0115]

[0116] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds (i.e., a 5- to 14-membered bridged heterocyclic group), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered (i.e., a 6- to 14-membered bridged heterocyclic group), more preferably a 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., a 7- to 10-membered bridged heterocyclic group). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0117]

[0118] The heterocyclic ring comprises a heterocyclic group (including monocyclic heterocyclic groups, spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0119] wait.

[0120] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0121] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system (i.e., 6- to 14-membered aryl), preferably 6- to 10-membered (e.g., 6, 7, 8, 9, or 10-membered) (i.e., 6- to 10-membered aryl), such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0122]

[0123] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0124] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen (i.e., 5 to 14-membered heteroaryls). The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) (i.e., 5 to 10-membered heteroaryls), more preferably 5 or 6-membered (i.e., 5 or 6-membered heteroaryls), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl ring fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0125]

[0126]

[0127] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0128] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0129] The term "amino protecting group" is used to protect the amino group by means of an easily removable group, ensuring that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, p-methoxybenzyl, tert-butyldimethylsilyl (TBS), etc. These groups may optionally be substituted with 1-3 substituents selected from halogens, alkoxy groups, or nitro groups.

[0130] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect the hydroxyl group and react on other functional groups of a compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0131] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0132] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0133] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0134] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0135] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0136] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0137] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0138] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0139] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0140] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0141] The term "hydroxyl group" refers to -OH.

[0142] The term "thiol" refers to -SH.

[0143] The term "amino" refers to -NH2.

[0144] The term "cyano" refers to -CN.

[0145] The term "nitro" refers to -NO2.

[0146] The term "oxo" or "oxo" refers to "=O".

[0147] The term "carbonyl" refers to C=O.

[0148] The term "carboxyl group" refers to -C(O)OH.

[0149] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0150] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0151] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include, for example, keto-enol tautomers, imine-enamine tautomers, lactam-lactamimide tautomers, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0152]

[0153] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0154]

[0155] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0156] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0157] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0158] In the compounds disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to indicate that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0159] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0160] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0161] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0162] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0163] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0164] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0165] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0166] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0167] The method for synthesizing the compounds disclosed herein

[0168] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0169] Option 1

[0170] The method for preparing the compound of formula (III) or its pharmaceutically acceptable salt thereof, comprising the following steps:

[0171]

[0172] Compounds of general formula (IIIa) or their salts and compound NHR 7 R 8 The compound or its salt reacts under heating conditions to give the compound of general formula (III) or its pharmaceutically usable salt;

[0173] in:

[0174] R y Selected from hydroxyl, C 1-6 Alkoxy and halogen; preferably, R y C 1-6 Alkoxy;

[0175] X, ring A, R 1 R 3 R 4 R 7 R 8 R x And n is as defined in general formula (III).

[0176] In the above synthesis scheme, the reaction temperature is 50-100℃, preferably 60-70℃.

[0177] The above synthesis is preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. Detailed Implementation

[0178] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0179] Example

[0180] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE NEO 400M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard.

[0181] MS measurements were performed using an Agilent 1290-6125 single quadrupole (ESI) mass spectrometer.

[0182] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1290DAD HPLC system and a Thermo U3000 HPLC system (Waters Sunfire C18 4.6*75mm, 3.5μm column).

[0183] Thin-layer chromatography (TLC) uses HPTLC Silica Gel 60GF254 or PLC Silica Gel 60GF254 silica gel plates from Shanghai Haohong Biomedical Technology Co., Ltd. The silica gel plates used for thin-layer chromatography (TLC) have a diameter of 0.2 mm to 0.25 mm, while the diameter used for TLC separation and purification of products is 0.9 mm to 1.0 mm.

[0184] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0185] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0186] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0187] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0188] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0189] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0190] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0191] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0192] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, and D: ethyl acetate / dichloromethane / n-hexane. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0193] Example 1

[0194] N-Ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxamide

[0195]

[0196] first step

[0197] 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)prop-2-ol 1b

[0198] Compound 2-(3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)prop-2-ol 1a (4 g, 11.4 mmol, prepared by the method disclosed in Example 35c on page 95 of patent application WO2017177955A1) and 1,4-dioxane (40 mL) were added to a reaction flask and stirred until homogeneous. Then, pinacol diboronate (4.3 g, 17 mmol, Shanghai Mairui Chemical Technology Co., Ltd.) and [ 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.8 g, 1.1 mmol, Xi'an Kaili New Material Co., Ltd.) and potassium acetate (3.2 g, 32.6 mmol) were added to the reaction system. The mixture was purged with nitrogen three times, heated to 95 °C and reacted for 4 hours. After natural cooling to room temperature, the mixture was filtered, the filter cake was washed with dioxane, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 1b (2.5 g, yield 54.8%).

[0199] MS m / z(ESI):383.2.2[M-17].

[0200] Step 2

[0201] 5-((2,2-dimethoxyethyl)(methyl)aminocarbonyl)-1H-pyrazole-3-carboxylic acid ethyl ester 1c

[0202] Tetrahydrofuran (150 mL) was added to the reaction flask and cooled to 0 ± 5 °C. Trimethylaluminum (70 mL) was added dropwise to the reaction system. After the addition was complete, compound 2,2-dimethoxy-N-methylethane-1-amine (17 g, 0.14 mol, Shanghai Hanhong Chemical Technology Co., Ltd.) was added dropwise. After the addition was complete, compound 1H-pyrazole-3,5-dicarboxylic acid diethyl ester (10 g, 47.2 mmol, Leyan) was added dropwise. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with water (30 mL) and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1c (10.2 g, yield: 75.8%).

[0203] MS m / z(ESI):285.9[M+1].

[0204] Step 3

[0205] 7-Hydroxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester 1d

[0206] Compound 1c (10.2 g, 35.1 mmol), 3M hydrochloric acid (10.2 mL), and acetone (51 mL) were added to a reaction flask, stirred to dissolve, heated to 50 °C, stirred for 4 hours, allowed to cool naturally to room temperature, and the pH was adjusted to 7–8 with sodium carbonate aqueous solution. The mixture was concentrated under reduced pressure, and ethyl acetate (100 mL) was added for separation. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with eluent system B to give the title compound 1d (1.7 g, yield: 20.3%).

[0207] MS m / z(ESI):240.1[M+1].

[0208] Step 4

[0209] 5-Methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester 1e

[0210] Compound 1d (2 g, 8.4 mmol), p-methylphenylsulfonyl chloride (2.4 g, 12.6 mmol, Maclean), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.1 g, 33.6 mmol, Shanghai Mairui Chemical Technology Co., Ltd.), and dichloromethane (20 mL) were added to a reaction flask and stirred at room temperature for 6 hours. The reaction was quenched with water (50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with eluent system A to give title compound 1e (1.7 g, yield: 91.8%).

[0211] MS m / z(ESI):222.0[M+1].

[0212] Step 5

[0213] 7-Bromo-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester 1f

[0214] Compound 1e (1 g, 4.5 mmol) was added to N,N-dimethylformamide (6 mL), and the mixture was purged with nitrogen three times. N-bromosuccinimide (0.81 g, 4.5 mmol, lysine) dissolved in N,N-dimethylformamide (4 mL) was added dropwise to the above reaction system. The mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (40 mL) and dichloromethane (20 mL) were added and the mixture was separated. The aqueous phase was extracted with dichloromethane (30 mL). The organic phases were combined and washed successively with water (100 mL × 4) and saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1f (1.1 g, yield: 78.57%).

[0215] MS m / z(ESI):300.0[M+1].

[0216] Step 6

[0217] 1 g of ethyl 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropane-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate

[0218] Compound 1f (1 g, 3.3 mmol), compound 1b (1.6 g, 4.0 mmol), tetrakis(triphenylphosphine)palladium (0.4 g, 0.33 mmol, Rico), and potassium carbonate (1.4 g, 9.9 mmol) were added to 1,4-dioxane (10 mL) and water (1.5 mL). The mixture was purged with nitrogen three times, heated to 85 °C, and reacted for 5 hours. After natural cooling to room temperature, the mixture was filtered, and the filter cake was washed with 1,4-dioxane. The filtrates were combined, concentrated under reduced pressure, and then water (20 mL) and ethyl acetate (20 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1 g (1.5 g, yield: 91.46%) of the title product.

[0219] MS m / z(ESI):476.1[M-17].

[0220] Step 7

[0221] N-Ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxamide

[0222] 1 g (0.15 g, 0.3 mmol) of compound was added to 5 mL of 70% ethylamine aqueous solution, heated to 65 °C and reacted for half an hour. After cooling to room temperature, ethylamine was removed under reduced pressure, and water (5 mL) was added. The pH was adjusted to 5 with 3 M hydrochloric acid, and ethyl acetate (20 mL × 2) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography using eluent system A to give title compound 1 (28 mg, yield: 18.67%).

[0223] MS m / z(ESI):475.1[M-17].

[0224] 1 H NMR (400MHz, DMSO-d6): δ8.09(m,1H),7.62(d,1H),7.48-7.46(m,1H),7.44(s,1H),7.41(s,1H),6.9 7(d,2H),6.30(d,1H),3.53(s,3H),3.29-3.22(m,2H),2.02(s,6H),1.46(s,6H),1.09-1.06(m,3H).

[0225] Example 2

[0226] N-Ethyl-4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropane-2-yl)phenyl)-2-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxamide

[0227]

[0228] first step

[0229] 2-Cyano-N-(2,2-Dimethoxyethyl)-N-methylacetamide 2a

[0230] 2M trimethylaluminum (150 mL, 300 mmol) was dissolved in dry tetrahydrofuran (250 mL), purged three times with nitrogen, and cooled to 0 °C. Compound 2,2-dimethoxy-N-methylethane-1-amine (35 g, 292.6 mmol, Anegig) was added dropwise to the reaction system. After the addition was complete, compound methyl 2-cyanoacetate (10 g, 100.9 mmol) was added dropwise to the reaction system. After the addition was complete, the ice bath was removed, and the reaction was allowed to proceed for 16–18 hours. The reaction was quenched with water (50 mL), and then ethyl acetate (100 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with eluent system B to give the title compound 2a (13 g, yield: 70.0%).

[0231] MS m / z(ESI):187.0[M+1].

[0232] Step 2

[0233] 5-((2,2-dimethoxyethyl)(methyl)aminocarbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester 2b

[0234] Compound 2a (13 g, 0.091 mol), ethyl propargyl ester (6.9 g, 70.4 mmol, Leyan), and 1,10-phenanthroline (5.0 g, 27.7 mmol, Mairuier) were added to 1,4-dioxane (130 mL), heated to 100 °C, and reacted for 2 hours. The mixture was then allowed to cool naturally to room temperature. After removing the solvent under reduced pressure, a saturated ammonium chloride solution (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography using eluent system A to give the title compound 2b (15 g, yield: 75.3%).

[0235] MS m / z(ESI):284.9[M+1].

[0236] Step 3

[0237] 4-Hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid ethyl ester 2c

[0238] Compound 2b (15 g, 0.053 mol) and 3M hydrochloric acid (20 mL) were added to acetone (150 mL), stirred until homogeneous, heated to 50 °C and reacted for 2.5 hours. The mixture was then allowed to cool naturally to room temperature, and the solvent was removed under reduced pressure. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (500 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with eluent system B to give the title compound 2c (3 g, yield 23.7%).

[0239] MS m / z(ESI):239.2[M+1].

[0240] Step 4

[0241] 2-Methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxylic acid ethyl ester 2d

[0242] Compound 2c (0.9 g, 3.8 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.78 mmol, Maclean) were added to dichloromethane (15 mL), and 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene (2.29 g, 15 mmol) was slowly added dropwise. After stirring for 3 hours, water (15 mL) was added, and dichloromethane (30 mL) was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with eluent system A to give the title compound 2d (0.6 g, yield: 71.0%).

[0243] MS m / z(ESI):221.1[M+1].

[0244] Step 5

[0245] 4-Bromo-2-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxylic acid ethyl ester 2e

[0246] Compound 2d (0.6 g, 2.7 mmol) and N-bromosuccinimide (0.48 g, 2.7 mmol, lysuccinimide) were added to dichloromethane (6 mL) and reacted for 1 hour. The mixture was then purified by thin-layer chromatography using solvent system B to give the title compound 2e (40 mg, yield: 4.9%).

[0247] MS m / z(ESI):299.0[M+1].

[0248] Step 6

[0249] 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropane-2-yl)phenyl)-2-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxylic acid ethyl ester 2f

[0250] Compound 2e (160 mg, 0.54 mmol), compound 1b (195 mg, 0.65 mmol), potassium carbonate (180 mg, 1.62 mmol), and tetrakis(triphenylphosphine)palladium (0.05 g, 0.054 mmol) were added to 1,4-dioxane (150 mL), followed by the addition of water (20 mL). The mixture was purged three times with nitrogen, heated to 85 °C, and reacted for 18 hours. After natural cooling to room temperature, water (15 mL) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (70 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product, crude product 2f (230 mg). The product was used directly in the next reaction without purification.

[0251] MS m / z(ESI):493.2[M+1].

[0252] Step 7

[0253] N-Ethyl-4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropane-2-yl)phenyl)-2-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxamide

[0254] Compound 2f (65 mg, 0.13 mmol) was added to 70% ethylamine aqueous solution (7 mL), heated to 60 °C and reacted for 24 hours. After cooling to room temperature, the solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, washed twice with water, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by thin-layer chromatography using solvent system B to give title compound 2 (22 mg, yield: 34.5%).

[0255] MS m / z(ESI):474.2[M-17].

[0256] 1 H NMR (400MHz, DMSO-d6): δ8.22(m,1H),7.62(d,1H),7.61(m,1H),7.52(s,1H),7.43(s,1H),7.08(s ,1H),7.00(d,2H),6.40(d,1H),3.20(s,2H),3.45(s,3H),1.99(s,6H),1.46(s,6H),1.07(m,3H).

[0257] Biological evaluation

[0258] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0259] Test Example 1: BRD4 BD1 or BD2 Binding Inhibition Experiment

[0260] 1. Experimental Objective

[0261] The binding of the BD1 or BD2 domains of BRD4 to the substrate was detected using HTRF, and the IC50 of the compound inhibiting the binding was determined. 50 Evaluate its selectivity for BD1 or BD2.

[0262] 2. Experimental Methods

[0263] Dilute BRD4 BD1 (Panchao Biotechnology, prokaryotic expression) or BRD4 BD2 protein (Panchao Biotechnology, prokaryotic expression) and the compound separately with binding buffer (Cisbio, 62DLBDDF), add them to a 384-well plate (Corning, 4513), vortex to mix (Haimen Qilinbeier, MH-I), centrifuge at 1000 rpm (Xiangyi Centrifuge Instrument Co., Ltd., L-530) for 1 minute, and incubate at 25 degrees Celsius (Shanghai Jinghong Experimental Equipment Co., Ltd., DMP-9052) for 30 minutes.

[0264] Dilute the substrate (BET Bromodomain Ligand, synthesized by GIL Biochemical) with binding buffer, add to the incubated test plate, vortex to mix, and centrifuge at 1000 rpm for 1 minute. Dilute Euanti-GST antibody (Cisbio, 61HI2KLA) and APC-conjugated streptavidin (Cisbio, 611SAXLA) with test buffer (Cisbio, #62DB1FDG), add to the incubated test plate, vortex to mix, centrifuge at 1000 rpm for 1 minute, and incubate overnight at 25 degrees Celsius.

[0265] After incubation, use a microplate reader (BMG, PHERAstar FS) to... The reader panel reads signals at 665 / 620nm. The data is analyzed and processed using Graphpad Prism 6.

[0266] The inhibitory effects of the disclosed compounds on BRD4 BD1 or BD2 are shown in Table 1.

[0267] Table 1 shows the inhibitory effects of the disclosed compounds on BRD4 BD1 or BD2.

[0268]

[0269] Conclusion: The compound disclosed herein exhibits selective inhibitory activity against BRD4 BD2.

[0270] Test Example 2: Cell Proliferation Inhibition Experiment

[0271] 1. Experimental Objective

[0272] The inhibitory effect of the compounds on the proliferation of LNCap or MV-4-11 cells was detected based on IC50. 50 Evaluate the activity of the compound.

[0273] 2. Experimental Methods

[0274] LNcap (ATCC, CRL-1740) or MV-4-11 (ATCC, CRL-9591) cells were digested with 0.25% trypsin (Invitrogen, 25200-072) and collected for counting. Cells were resuspended in RPMI-1640 (Gibco, 11875119) or IMDM (Gibco, 12440061) medium containing 10% fetal bovine serum (Gibco, 10099-141). Cells were placed at 2000 cells per well in 96-well plates (Corning, 3903) and incubated at 37°C with 5% CO2 (thermoscientific, HERAcell 240i). After 24 hours of culture, serially diluted compounds were added, and the plates were incubated at 37°C with 5% CO2 for 3 days. Remove the culture plate, add CellTiter-Glo (Promega, G7573), incubate at room temperature in the dark for 10 minutes, affix a white sealing film (PE, 6005199) to the bottom, and read the cold light signal value using a microplate reader (BMG, PHERAstar FS). Analyze the data using Graphpad Prism6.

[0275] The inhibitory effects of the disclosed compounds on the proliferation of LNCap or MV-4-11 cells are shown in Table 2.

[0276] Table 2 shows the inhibitory effect of the disclosed compounds on the proliferation of LNCap or MV-4-11 cells.

[0277]

[0278] Conclusion: The compound disclosed herein has an inhibitory effect on the proliferation of LNCap and MV-4-11 cells.

Claims

1. A compound of general formula (III) or a pharmaceutically acceptable salt thereof; in: X is a nitrogen atom or CR 5 And R 5 It is a hydrogen atom; Ring A is phenyl; R 1 C 1-6 alkyl; R 3 and R 4 All are C 1-6 alkyl; R 7 and R 8 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl; Each R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 hydroxyalkyl; and n can be 0, 1, 2, 3, or 4.

2. The compound of formula (III) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a methyl group.

3. The compound of formula (III) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 All are methyl groups.

4. The compound of formula (III) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

5. The compound of formula (III) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R x They may be the same or different, and each is independently a fluorine atom or a methyl group.

6. The compound of general formula (III) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the following compounds: and .

7. A compound of general formula (IIIa) or a salt thereof, in: R y Selected from hydroxyl, C 1-6 Alkoxy groups and halogens; X, cyclic A, R 1 R 3 R 4 R x and n as defined in claim 1.

8. The compound or a salt thereof according to claim 7, wherein, R y C 1-6 Alkyl group.

9. The compound or a salt thereof according to claim 7 or 8, wherein the compound is selected from the following compounds: and .

10. A method for preparing a compound of general formula (III) according to claim 1, comprising: Compounds of general formula (IIIa) or their salts and compound NHR 7 R 8 Or its salt reaction yields the compound of general formula (III) or its pharmaceutically usable salt; in: R y Selected from hydroxyl, C 1-6 Alkoxy groups and halogens; X, cyclic A, R 1 R 3 R 4 R 7 R 8 R x and n as defined in claim 1.

11. A method for preparing a compound of general formula (III) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein: R y C 1-6 Alkyl group.

12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for inhibiting BET.

14. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for inhibiting BD2.

15. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 12 in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is selected from tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, kidney diseases, viral infections and neurological diseases.

16. The use according to claim 15, wherein the disease or condition is selected from cancer, Addison's disease, gout, ankylosing spondylitis, asthma, atherosclerosis, bullous dermatitis, chronic obstructive pulmonary disease, dermatitis, eczema, glomerulonephritis, hepatitis, autoimmune hypophysitis, inflammatory bowel disease, multiple sclerosis, myositis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, toxic shock, thyroiditis, type I diabetes, uveitis, vitiligo, vasculitis, essential thrombocytosis, and erythrocytosis. Polycystic nephropathy, acquired immunodeficiency syndrome, obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, ischemia-reperfusion induced kidney disease, kidney disease induced by cardiac and major surgery, kidney disease induced by percutaneous coronary intervention, kidney disease induced by radioactive contrast agents, kidney disease induced by sepsis, kidney disease induced by pneumonia, kidney disease induced by drug toxicity, diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, polycystic kidney disease, and tubulointerstitial nephritis.

17. The use according to claim 16, wherein the vasculitis is selected from Behcet's disease, giant cell arteritis, Kawasaki disease, polyarteritis nodosa, Goyan's arteritis, and Wegener's granulomatosis.

18. The use according to claim 16, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

19. The use according to claim 16, wherein the cancer is selected from: prostate cancer, acute leukemia, chronic leukemia, myeloid leukemia, myelofibrosis, erythroleukemia, acoustic neuroma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, colorectal cancer, craniopharyngioma, cystadenocarcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, germ cell testicular cancer, glioma, heavy chain disease, angioblastoma, liver cancer, leiomyosarcoma, lipoma. Liposarcoma, lung cancer, lymphangiosarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myeloma, neuroblastoma, midline carcinoma of NUT, bone cancer, nasopharyngeal carcinoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, thyroid cancer, pineal tumor, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, skin cancer, gastric cancer, squamous cell carcinoma, synovial sarcoma, sweat gland carcinoma, Waldenström macroglobulinemia, and Wilms' tumor.

20. The use according to claim 19, wherein the cancer is selected from prostate cancer, acute myeloid leukemia, myelofibrosis, diffuse large B-cell lymphoma, follicular lymphoma, seminoma, and embryonal carcinoma.

21. The use according to claim 19, wherein the myeloma is multiple myeloma.

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