1. A method of inhibiting BET proteins in a mammal by administering a therapeutically effective amount of a compound of Formula I:
or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,
wherein:
W1 is selected from N and CR1;
W2 is selected from N and CR2;
W3 is selected from N and CR3;
W4 is selected from N and CR4;
each W may be the same or different from each other;
A is selected from N and CH;
R1 and R4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, amino, hydroxyl, and halogen;
R2 and R3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;
two adjacent substituents selected from R1, R2, R3, and R4 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;
AR1 is a group selected from the following:
and
B is a group selected from the following:
each ring system may be substituted with one or more substituents independently selected from R10 and R11:
R5 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;
R6 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, and halogen;
R7 is selected from hydrogen, alkyl, \u2014SO2R12, \u2014C(O)NR12R13, and \u2014C(O)R12;
R8 and R9 are independently selected from hydrogen, aryl, alkenyl, alkyl, \u2014SO2R12, \u2014C(O)NR12R13, and \u2014C(O)R12;
R10 and R11 are independently selected from hydrogen, halogen, alkyl, alkoxy, aryl, and hydroxyl;
R12 and R13 are independently selected from hydrogen, aryl, and alkyl;
Y is selected from NH, O, and S; and
two adjacent substituents selected from R5, R6, R8, R9, R10, and R11 may be connected in a 5- or 6-membered ring to form a carbocycle or heterocycle.
2. The method according to claim 1,
wherein R1 and R4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino;
wherein R2 and R3 are independently selected from hydrogen, alkyl, alkoxy, and halogen;
wherein at least one of R1, R2, R3, and R4 is not hydrogen;
wherein R5 is selected from hydrogen, alkyl, alkoxy, and halogen;
wherein R6 is selected from hydrogen and alkoxy optionally substituted with a hydroxyl or amino; and
wherein Y is N.
3. The compound according to claim 2,
wherein AR1 is selected from
wherein B is selected from
wherein R7 is selected from hydrogen and alkyl;
wherein R8 and R9 are independently selected from hydrogen and alkyl;
wherein R10 and R11 are independently selected from hydrogen and halogen; and
wherein R12 and R13 are independently selected from hydrogen and alkyl.
4. The method according to claim 1, wherein the compound is selected from:
2-(3-(4-Isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-(4-Isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;
2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(6-(4-Isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;
Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate;
2-(6-(4-(1-Hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide;
2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid;
3-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoic acid;
2-(5-(2-(Isopropylamino)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one bis(trifluoroacetate);
2-(5-(2-Hydroxyethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one acetate;
2-(6-(4-Isopropylpiperazin-1-yl)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;
5,7-Dimethoxy-2-(6-morpholinopyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;
2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;
5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;
5,7-Dimethoxy-2-(6-(4-propionylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one dihydrochloride;
2-(3-(4-Isopropylpiperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
7-Fluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Hydrochloride;
7-(Benzyloxy)-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Hydrochloride;
2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxy-7-phenylquinazolin-4(3H)-one;
8-(Benzyloxy)-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-5-methoxyquinazolin-4(3H)-one;
4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N-isopropylpiperazine-1-carboxamide Hydrochloride;
2-(6-(4-Isopropyl-2-oxopiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;
2-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;
2-(3-Chloro-5-(piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; and
stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof.
5. The method according to claim 1, wherein R6 is selected from the group represented by Formula II:
wherein:
D is selected from O and S;
E is selected from O, N, and S;
R14 and R15 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein if E is O or S, only one of R14 and R15 is present; and
n is selected from 1, 2, and 3.
6. The method according to claim 5
wherein D is O;
wherein n=1;
wherein R14 and R15 are independently selected from hydrogen, and alkyl; and
wherein R6 is selected from hydrogen, methoxy,
7. The method of claim 1, further comprising treating a disease, disorder, or condition characterized by dysregulation of cell cycle control, inflammatory cytokine expression, viral transcription, hematopoietic differentiation, insulin transcription, or adipogenesis.
8. The method of claim 7, wherein the disease, disorder, or condition is an autoimmune disease.
9. The method of claim 8, wherein the autoimmune disease is selected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosing spondylitis, Anti-GBMAnti-TBM nephritis, Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura, Behcet’s Disease, Bullous pemphigoid, Castleman’s Disease, Celiac Disease, Churg-Strauss syndrome, Crohn’s Disease, Cogan’s syndrome, Dry eye syndrome, Essential mixed cryoglobulinemia, Dermatomyositis, Devic’s Disease, Encephalitis, Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giant cell arteritis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (Wegener’s), Graves’ Disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, Type I diabetes, Interstitial cystitis, Kawasaki’s Disease, Leukocytoclastic vasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Sjogren’s syndrome, Takayasu’s arteritis, Transverse myelitis, Ulcerative colitis, Uveitis, and Vitiligo.
10. The method of claim 7, wherein the disease, disorder, or condition is an inflammatory disease.
11. The method of claim 10, wherein the inflammatory disease or disorder is selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections.
12. The method of claim 7, wherein the disease, disorder, or condition is a cardiovascular disease.
13. The method of claim 7, wherein the disease, disorder, or condition is insulin resistance diabetes.
14. The method of claim 7, wherein the disease, disorder, or condition is a neurological disorder.
15. The method of claim 7, wherein the disease, disorder, or condition is HIV.
16. The method of claim 7, wherein the disease, disorder, or condition is cancer.
17. The method according to claim 16,
wherein R1 and R4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino;
wherein R2 and R3 are independently selected from hydrogen, alkyl, alkoxy, and halogen;
wherein at least one of R1, R2, R3, and R4 is not hydrogen;
wherein R5 is selected from hydrogen, alkyl, alkoxy, and halogen;
wherein R6 is selected from hydrogen and alkoxy optionally substituted with a hydroxyl or amino; and
wherein Y is N.
18. The compound according to claim 17,
wherein AR1 is selected from
wherein B is selected from
wherein R7 is selected from hydrogen and alkyl;
wherein R8 and R9 are independently selected from hydrogen and alkyl;
wherein R10 and R11 are independently selected from hydrogen and halogen; and
wherein R12 and R13 are independently selected from hydrogen and alkyl.
19. The method according to claim 16, wherein the compound is selected from:
2-(3-(4-Isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-(4-Isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;
2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(6-(4-Isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;
Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate;
2-(6-(4-(1-Hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2yl)-pyridin-2-yl)piperazin-1-yl)propanamide;
2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid;
3-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoic acid;
2-(5(2-(Isopropylamino)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one bis(trifluoroacetate);
2-(5-(2-Hydroxyethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one acetate;
2-(6-(4-Isopropylpiperazin-1-yl)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin -4(3H)-one;
5,7-Dimethoxy-2-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;
5,7-Dimethoxy-2-(6-morpholinopyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;
2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;
5,7-Dimethoxy-2-(6-(4-methylsulfonyl)piperazin-1-yl)pyridin-2-yl)quinazolin -4(3H)-one Hydrochloride;
5,7-Dimethoxy-2-(6-(4-propionylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one dihydrochloride, 2-(3(4-Isopropylpiperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
7-Fluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H) -one Hydrochloride;
7-(Benzyloxy)-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinzolin -4(3H)-one Hydrochloride;
2-(6-(4-Isopropylpiperazin-1-yl)pyrdin-2-yl)-5-methoxy-7-phenyiquinazolin-4(3H) -one;
8-(Benzyloxy)-2-(3-(4-isopropylpiperazin-1 -yl)phenyl)-5-methoxyquinazolin -4(3)-one;
4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N -isopropylpiperazine-1-carboxamide Hydrochloride;
2-(6-(4-Isopropyl-2-oxopiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin -4(3H)-one Hydrochloride;
2-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin -4(3H)-one;
5,7-Dimethoxy-2-(6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2yl)quinazolin-4(3H)-one;
2-(3-Chloro-5-(piperazin-1yl)-phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H) -one; and
stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof.
20. The method according to claim 16, wherein R6 is selected from the group represented by Formula II:
wherein:
D is selected from O and S;
E is selected from O, N, and S;
R14 and R15 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein if E is O or S, only one of R14 and R15 is present; and
n is selected from 1, 2, and 3.
21. The method according to claim 20
wherein D is O;
wherein n =1;
wherein R14 and R15 are independently selected from hydrogen, and alkyl; and
wherein R6 is selected from hydrogen, methoxy,
22. The method of claim 16, wherein the cancer is a midline carcinoma.
23. The method of claim 16, wherein the cancer exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoproteins.
24. The method of claim 23, wherein the cancer is characterized by overexpression of c-myc.
25. The method of claim 23, wherein the cancer is characterized by is characterized by overexpression n-myc.
26. The method of claim 16, wherein the cancer is characterized by recruitment of pTEFb to regulate oncogenes.
27. The method of claim 16, wherein the cancer is characterized by upregulation of at least one of CDK6, Bcl2, TYRO3, MYB and hTERT.
28. The method of claim 16, wherein the cancer is associated with a viral infection.
29. The method of claim 16, wherein the cancer is selected from B-acute lymphocytic leukemia, Burkitt’s lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, neuroblastoma, oesophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer and head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt’s lymphoma, Hodgkin’s lymphoma, follicular lymphomas, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barret’s adenocarcinoma, hepatoma, pro-myelocytic leukemia, chronic lymphocytic leukemia, and mantle cell lymphoma.
30. The method of claim 16, wherein the compound of Formula I is administered in combination with another anticancer agent.
31. The method of claim 30, wherein the anticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A combined dual anaerobic process of biomethanation comprising;
two or more different anaerobic digesters for biogas generation in dual phase using mixed andor multiple solid feeds as substrates;
a culture preparation tankunit for preparing feed from non digested feed material for the said process;
a filtration unitpercolation unit for draining excess water from the non digested feed material; and
a manure preparation unit for preparing manure from the non digested feed material.
2. A process as claimed in claim 1, wherein the first or solid state methane digester comprises:
a gas collecting fixed dome or other device to gather biogas generated from the reaction mixture;
a reaction chamber for biomethanation process;
a vertical perforated unit (tube) at the internal base of solid state methane digester to facilitate;
a spray recirculation unit or other arrangement for circulation connected to the other or liquid state methane digester to facilitate percolation of lechates from the feed into the digester and maintaining the required temperature for the microbial activity for biogas generation;
control valves for controlling flow of biogas from the digesters into a common biogas collecting unit; and
a solidslurry handling pump to control the flow of lechates from the liquid state methane digester to the solid state methane digester;
wherein the number of said state methane digester varies depending on the retention time of the biomass used for biomethanation process or other design constraints.
3. A process as claimed in claim 1, wherein the lechates produced from the solid state methane digester are utilized to generate biogas into another or liquid state methane digester with addition of desired microbes wherein the leachates are gathered due to the percolating structure preferably a mesh like structure present in the solid state methane digester.
4. A process as claimed in claim 3, wherein the lechates produced are recirculated through the anaerobic digesters to enchance microbial degradation of substrates and increase biogas production.
5. A process as claimed in claim 1, wherein the solid non digested feed material is collected a in culture preparation unit to produce a culture for the biomethanation process.
6. A process as claimed in claim 1, wherein manure is produced in a manure preparation unit through the step of filtration of non digested material until a desired quality of carbon to nitrogen ration is obtained.
7. A process as claimed in claim 1, wherein mixed andor multiple solid feeds can be used as substrates for anaerobic digestion to produce biogas and manures.
8. A process as claimed in claim 1, wherein the biomethanation process reduces the overall hydraulic retention time to 5 to 20 days required for the biomethanation process, thereby reducing the size of the biogas digester by at least 50 percent of equivalent capacity.
9. A process as claimed in claim 1, wherein the substrates used include at least any of agro residues, and oilcakes.
10. A process as claimed in claim 1, wherein the first or solid state methane digester process is self sustaining producing, biogas, fuel and manure with minimum effluent slurry.
11. A process as claimed in claim 1 wherein the oilcakes include at least one of any of the following:
paddy stray, wheat straw, maize, Napier grass, press mud, castor, sal, food waste, biodegradable municipal waste and alike.