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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

• the invention provides novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of diseases and conditions associated with bromodomain and extra terminal domain (BET) proteins.
• BET bromodomain and extra terminal domain
• PTMs Post-translational modifications
• Histone acetylation at specific lysine residues is a PTM that is regulated by histone acetylases (HATs) and deacetylases (HDACs).
• HATs histone acetylases
• HDACs deacetylases
• Histone acetylation controls gene expression by recruiting protein complexes that bind directly to acetylated lysine via bromodomains.
• Sanchez, R. and M.M. Zhou "The role of human bromodomains in chromatin biology and gene transcription," Curr Opin Drug Discov Devel 12(5):659-65 (2009).
• One such family, the bromodomain and extra terminal domain (BET) proteins comprises Brd2, Brd3, Brd4, and BrdT, each of which contains two bromodomains in tandem that can independently bind to acetylated lysines, as reviewed in Wu, S.Y. and CM. Chiang, "The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation," J Biol Chem 282(18):13141-5 (2007).
• BET inhibitors have been shown to have a broad spectrum of anti-inflammatory effects in vitro including the ability to decrease expression of pro-inflammatory cytokines such as IL- ⁇ , MCP-1, TNF-ot, and IL-6 in activated immune cells.
• pro-inflammatory cytokines such as IL- ⁇ , MCP-1, TNF-ot, and IL-6 in activated immune cells.
• the mechanism for these anti-inflammatory effects may involve BET inhibitor disruption of Brd4 co-activation of NF-KB-regulated pro-inflammatory cytokines and/or displacement of BET proteins from cytokine promoters, including IL-6. Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic,” Nature 468(7327):1119-23 (2010);
• BET inhibitors may be useful in inflammatory disorders characterized by specific programs of T cell differentiation.
• a BET inhibitor prevented endotoxin- or bacterial sepsis-induced death and cecal ligation puncture-induced death in mice, suggesting utility for BET inhibitors in sepsis and acute inflammatory disorders. Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic," Nature 468(7327):1119-23 (2010).
• a BET inhibitor has been shown to ameliorate inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIV-associated nephropathy, in part through inhibition of Brd4 interaction with NF- ⁇ .
• BET inhibitors may be useful in the treatment of a variety of chronic autoimmune disorders
• one aspect of the invention provides compounds, compositions, and methods for treating autoimmune and/or inflammatory diseases by administering one or more compounds of the invention or pharmaceutical compositions comprising one or more of those compounds.
• autoimmune and inflammatory diseases, disorders, and syndromes that may be treated using the compounds and methods of the invention include but are not limited to, inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis (Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIVassociated Kidney Disease by BRD4 Inhibition," J Biol Chem 287(34):8840-51 (2012)), osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agamma
• BET inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions.
• one aspect of the invention provides compounds, compositions, and methods for treating inflammatory conditions including but not limited to, acute gout, nephritis including lupus nephritis, vasculitis with organ involvement, such as glomerulonephritis, vasculitis, including giant cell arteritis, Wegener's granulomatosis, polyarteritis nodosa, Behcet's disease, Kawasaki disease, and Takayasu's arteritis.
• BET inhibitors may be useful in the prevention and treatment of diseases or conditions that involve inflammatory responses to infections with bacteria, viruses, fungi, parasites, and their toxins, such as, but not limited to sepsis, sepsis syndrome, septic shock (Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic,” Nature 468(7327):1119-23 (2010)), systemic
• inflammatory response syndrome SIRS
• multi-organ dysfunction syndrome toxic shock syndrome
• acute lung injury acute lung injury
• adult respiratory distress syndrome ARDS
• acute renal failure fulminant hepatitis
• burns post-surgical syndromes
• sarcoidosis Herxheimer reactions
• encephalitis myelitis
• meningitis malaria
• SIRS associated with viral infections, such as influenza, herpes zoster, herpes simplex, and coronavirus.
• Belkina, A.C. and G.V. Denis "BET domain co-regulators in obesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77 (2012).
• one aspect of the invention provides compounds, compositions, and methods for treating these inflammatory responses to infections with bacteria, viruses, fungi, parasites, and their toxins described herein.
• Cancer is a group of diseases caused by dysregulated cell proliferation.
• Therapeutic approaches aim to decrease the numbers of cancer cells by inhibiting cell replication or by inducing cancer cell differentiation or death, but there is still significant unmet medical need for more efficacious therapeutic agents.
• Cancer cells accumulate genetic and epigenetic changes that alter cell growth and metabolism, promoting cell proliferation and increasing resistance to programmed cell death, or apoptosis. Some of these changes include inactivation of tumor suppressor genes, activation of oncogenes, and modifications of the regulation of chromatin structure, including deregulation of histone PTMs.
• One aspect of the invention provides compounds, compositions, and methods for treating human cancer, including, but not limited to, cancers that result from aberrant translocation or overexpression of BET proteins (e.g., NUT midline carcinoma (NMC) (French, C.A., "NUT midline carcinoma,” Cancer Genet Cytogenet 203(l):16-20 (2010) and B-cell lymphoma (Greenwald, R.J., et al., "E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia,” Blood 103(4):1475-84 (2004)).
• NMC tumor cell growth is driven by a translocation of the Brd4 or Brd3 gene to the nutlin 1 gene.
• the present disclosure provides a method for treating human cancers, including, but not limited to, cancers dependent on a member of the myc family of oncoproteins including c-myc, MYCN, and L-myc. Vita, M. and M. Henriksson, "The Myc oncoprotein as a therapeutic target for human cancer,” Semin Cancer Biol 16(4):318-30 (2006).
• cancers include Burkitt's lymphoma, acute myelogenous leukemia, multiple myeloma, and aggressive human medulloblastoma. Vita, M. and M. Henriksson, "The Myc oncoprotein as a therapeutic target for human cancer," Semin Cancer Biol 16(4):318-30 (2006). Cancers in which c-myc is overexpressed may be particularly susceptible to BET protein inhibition; it has been shown that treatment of tumors that have activation of c-myc with a BET inhibitor resulted in tumor regression through inactivation of c- myc transcription.
• Embodiments of the invention include methods for treating human cancers that rely on BET proteins and pTEFb (Cdk9/CyclinT) to regulate oncogenes (Wang, S. and P.M. Fischer, "Cyclin- dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology," Trends Pharmacol Sci 29(6):302-13 (2008)), and cancers that can be treated by inducing apoptosis or senescence by inhibiting Bcl2, cyclin-dependent kinase 6 (CDK6) (Dawson, M.A., et al., "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia," Nature 478(7370):529-33 (2011)), or human telomerase reverse transcriptase (hTERT) (Delmore, J.E., et al., "BET bromodomain inhibition as a therapeutic
• Inhibition of BET proteins may also result in inhibition of enhancer and/or super-enhancer known to drive transcriptional programs associated with several human disease etiologies (Hnisz, D. et al. "Super-enhancers in the control of cell identity and disease," Cell 155:934-947 (2013); Loven, J. et al. "Selective inhibition of tumor oncogenes by disruption of super-enhancers.” Cell 153: 320-334 (2013); Whyte, W.A. et al. "Master transcription factors and mediator establish super-enhancers at key cell identity genes," Cell 153:307-319 (2013)).
• the MYC oncogene is an example of a gene associated with a super enhancer that is disrupted by BET-bromodomain inhibitors. See, e.g., Loven (2013).
• one aspect of the invention provides compounds, compositions, and methods for treating such diseases and disorders, including cancers associated with a super-enhancer or enhancer that may be disrupted with a BET inhibitor.
• BET inhibitors may be useful in the treatment of cancers including, but not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia (see, e.g., Loven (2013)), acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia (Dawson, M.A., et al., "Inhibition of BET recruitment to chromatin as an effective treatment for MLL- fusion leukaemia," Nature 478(7370):529-33 (2011); Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains," Proc Natl Acad Sci USA 108(40):16669-74 (2011); Zuber, J., e
• BET Bacillus et al.
• HTLV-1 human T cell leukemia virus 1
• NF-kappaB nuclear factor kappaB
• J Biol Chem 288:36094- 36105 (2013) aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma (Knoechel, B. et al.
• gonadoblastoma gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (Lwin, T. et al.
• a microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas J Clin Invest 123:4612-4626 (2013)
• invasive lobular carcinoma intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia (Mertz, J.
• BET bromodomain protein inhibition is a therapeutic option for medulloblastoma
• the BET bromodomain inhibitor I-BET151 acts downstream of Smoothened to abrogate the growth of Hedgehog driven cancers," J Biol Chem 289(51):35494-35502 (2014); Tang, Y. et al.
• pancreatic cancer (Sahai, V. et al. "BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen,” Mol Cancer Ther 13:1907-1917 (2014)), pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's
• one aspect of the inventions provides compounds, compositions, and/or methods for treating wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
• one aspect of the inventions provides compounds, compositions,
• BET inhibitors of the invention may be useful in the treatment of cancers that are resistant to current and future cancer treatments, as BET proteins are involved in the mechanisms of resistance of several anti-cancer treatment, including chemotherapy (Feng, Q., et al. "An epigenomic approach to therapy for tamoxifen-resistant breast cancer” Cell Res 24:809-819 (2014)), immunotherapy (Emadali, A., et al. "Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls ituximab response and tumour growth in aggressive lymphoid cancers," EMBO Mol Med 5:1180-1195 (2013))., hormone-deprivation therapies (Asangani, I. A. et al.
• BET inhibitors may be useful in the treatment of benign proliferative and fibrotic disorders, including benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma, and cardiac fibrosis. Tang, X.
• one aspect of the invention provides compounds, compositions, and methods for treating such benign proliferative and fibrotic disorders.
• Cardiovascular disease is the leading cause of mortality and morbidity in the United States. Roger, V.L., et al., "Heart disease and stroke statistics-2012 update: a report from the American Heart Association,” Circulation 125(l):e2-e220 (2012).
• Atherosclerosis an underlying cause of CVD, is a multifactorial disease characterized by dyslipidemia and inflammation. BET inhibitors are expected to be efficacious in atherosclerosis and associated conditions because of aforementioned anti-inflammatory effects as well as ability to increase transcription of ApoA-l, the major constituent of HDL.
• one aspect of the invention provides compounds, compositions, and methods for treating cardiovascular disease, including but not limited to atherosclerosis.
• Up-regulation of ApoA-l is considered to be a useful strategy in treatment of atherosclerosis and CVD.
• BET inhibitors have been shown to increase ApoA-l transcription and protein expression.
• BET inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of ApoA-l and HDL such as hypercholesterolemia, dyslipidemia, atherosclerosis (Degoma, E.M. and D.J. Rader, "Novel HDL-directed pharmacotherapeutic strategies," Nat Rev Cardiol 8(5):266-77 (2011)), and Alzheimer's disease and other neurological disorders.
• Dregoma, E.M. and D.J. Rader “Novel HDL-directed pharmacotherapeutic strategies,” Nat Rev Cardiol 8(5):266-77 (2011)
• Alzheimer's disease and other neurological disorders include Alzheimer's disease and other neurological disorders.
• Ell, D.A., et al. "Apolipoproteins in the brain: implications for neurological and psychiatric disorders," Clin Lipidol 51(4):555-573 (2010).
• one aspect of the invention provides compounds, compositions, and methods for treating cardiovascular disorders by upregulation of ApoA-l.
• BET inhibitors may be useful in the prevention and treatment of conditions associated with ischemia-reperfusion injury such as, but not limited to, myocardial infarction, stroke, acute coronary syndromes (Prinjha, R.K., J. Witherington, and K. Lee, "Place your BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci 33(3):146-53 (2012)), renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, hypertension, pulmonary, renal, hepatic, gastro-intestinal, or peripheral limb embolism. Accordingly, one aspect of the invention provides compounds, compositions, and methods for prevention and treatment of conditions described herein that are associated with ischemia-reperfusion injury.
• Brd2 interacts with PPARy and opposes its transcriptional function. Knockdown of Brd2 in vitro promotes transcription of PPARy-regulated networks, including those controlling adipogenesis. Denis, G.V., et al, "An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis," FEBS Lett 584(15):3260-8 (2010). In addition Brd2 is highly expressed in pancreatic ⁇ -cells and regulates proliferation and insulin transcription. Wang, F., et al., "Brd2 disruption in mice causes severe obesity without Type 2 diabetes," Biochem J 425(l):71-83 (2010).
• one aspect of the invention provides compounds, compositions, and methods for treatment and prevention of metabolic disorders, including but not limited to obesity-associated inflammation, type II diabetes, and insulin resistance.
• BET inhibitors may be useful in the prevention and treatment of episome-based DNA viruses including, but not limited to, human papillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiency virus (Belkina, A.C. and G.V. Denis, "BET domain co-regulators in obesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77 (2012)), adenovirus, poxvirus, hepatitis B virus, and hepatitis C virus. Host-encoded BET proteins have been shown to be important for transcriptional activation and repression of viral promoters.
• Brd4 interacts with the E2 protein of human papilloma virus (HPV) to enable E2 mediated transcription of E2-target genes.
• HPV human papilloma virus
• GLAl latent nuclear antigen 1
• KSHV Kaposi's sarcoma-associated herpes virus
• RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus
• PLoS Pathog 7(10):el002334 (2011) a BET inhibitor reactivated HIV in models of latent T cell infection and latent monocyte infection, potentially allowing for viral eradication by complementary anti-retroviral therapy.
• the invention also provides compounds, compositions, and methods for treatment and prevention of episome-based DNA virus infections.
• one aspect of the invention provides compounds, compositions, and methods for treatment and/or prevention of a viral infection, including, but not limited to infection by HPV, KSHV, EBV, HIV, HBV, HCV, adenovirus, poxvirus herpes virus, or a malignancy associated with that infection.
• CNS diseases are characterized by disorders in epigenetic processes. Brd2 haplo-insufficiency has been linked to neuronal deficits and epilepsy. Velisek, L, et al., "GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy," PLoS One 6(8): e23656 (2011). SNPs in various bromodomain-containing proteins have also been linked to mental disorders including schizophrenia and bipolar disorders. Prinjha, R.K., J. Witherington, and K.
• BRDT is the testis-specific member of the BET protein family which is essential for chromatin remodeling during spermatogenesis.
• Gaucher, J., et al. "Bromodomain-dependent stage-specific male genome programming by Brdt," EMBO J 31(19):3809-20 (2012); Shang, E., et al., "The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain- containing proteins, is essential for male germ cell differentiation," Development 134(19):3507-15 (2007).
• testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTR truncation in round spermatids.
• Another aspect of the invention provides compounds, compositions, and methods for male contraception.
• Monocyte chemotactic protein-1 (MCP-1, CCL2) plays an important role in cardiovascular disease. Niu, J. and P.E. Kolattukudy, "Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications," Clin Sci (Lond) 117(3):95-109 (2009). MCP-1, by its chemotactic activity, regulates recruitment of monocytes from the arterial lumen to the subendothelial space, where they develop into macrophage foam cells, and initiate the formation of fatty streaks which can develop into atherosclerotic plaque.
• MCP-1 and cardiovascular disease are well-established. Niu, J. and P.E. Kolattukudy, "Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications," Clin Sci (Lond) 117(3):95-109 (2009). MCP-1 and its receptor are overexpressed by endothelial cells, smooth muscle cells, and infiltrating monocytes/macrophages in human atherosclerotic plaque. Nelken, N.A., et al., "Monocyte chemoattractant protein-1 in human atheromatous plaques," 7 Clin Invest 88(4):1121-7 (1991).
• MCP-1 cardiovascular risk factors
• measures of coronary atherosclerosis burden and the incidence of coronary heart disease (CHD).
• CHD patients with among the highest levels of MCP-1 are those with acute coronary syndrome (ACS), de Lemos, J. A., et al.,
• MCP-1 also promotes tissue inflammation associated with autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). MCP-1 plays a role in the infiltration of macrophages and lymphocytes into the joint in RA, and is overexpressed in the synovial fluid of RA patients. Koch, A.E., et al., "Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis," 7 Clin Invest 90(3):772-9 (1992). Blockade of MCP-1 and MCP-1 signaling in animal models of RA have also shown the importance of MCP-1 to macrophage accumulation and proinflammatory cytokine expression associated with RA.
• RA rheumatoid arthritis
• MS multiple sclerosis
• MCP-1 is overexpressed by a variety of cell types in the brain during disease progression and contributes to the infiltration of macrophages and lymphocytes which mediate the tissue damage associated with MS.
• one aspect of the invention provides compounds, compositions, and methods for treating cardiovascular, inflammatory, and autoimmune conditions associated with MCP-1 and CCR2.
• the invention provides compounds that are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising one or more of those compounds, and use of these compounds or compositions in the treatment and prevention of diseases and conditions, including, but not limited to, cancer, autoimmune, and cardiovascular diseases.
• One embodiment of the invention provides compounds of Formula I and methods of administering a therapeutically effective amount of those compounds to a mammal (e.g., a human) in need thereof:
• X is selected from CH and N;
• Y is selected from -NH, -NR ib and oxygen
• Z is selected from N, and -CH-;
• Ri a and Ri b are independently selected from alkyl (Ci-C 6 ), carbocycle (C 3 -Ci 0 ), heterocycle (C 2 - Cio) optionally substituted with 1 to 3 groups selected from R 4 ;
• R 2 is selected from aryl (C 5 -Ci 0 ) and heteroaryl (C 5 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 ;
• R 3 is selected from carbocycle (C 3 -C 10 ) and heterocycle (C 2 -C 10 ) optionally substituted with 1 to 5 groups selected from R 5 ; each R 4 is independently selected from deuterium, alkyl (Ci-C 6 ) (such as methyl, ethyl, propyl, isopropyl, butyl), cycloalkyl (C 3 -C 8 ) (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); alkoxy (Ci-C 6 ) (such as methoxy, ethoxy, isopropoxy), amino (such as - NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu -NMe 2 , NMeEt, -NEt 2 , -NEtBu), -NHC(0)NH-alkyl(C !
• halogen such as F, CI
• amide such as -NHC(0)Me, -NHC(0)Et, -C(0)NHMe, - C(0)NEt 2 , -C(O)NiPr), -CF 3 , -CN, -N 3 , ketone (such as acetyl, -C(0)Et, -C(O)Pr), -S(O)- alkyl(Ci-C 4 ) (such as -S(0)Me, -S(O)Et), -S0 2 -alkyl(Ci-C 6 ) (such as -S0 2 Me, -S0 2 Et, - S0 2 Pr), thioalkyl(Ci-C 6 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH, and ester (such as - C(0)OMe, -C(0)OEt, -C(
• a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients is provided.
• cardiovascular disease refers to diseases, disorders and conditions of the heart and circulatory system that are mediated by BET inhibition.
• cardiovascular diseases including cholesterol- or lipid-related disorders, include, but are not limited to, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholesterolemia, familial combined hyperlipidemia,
• hypoalphalipoproteinemia hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery
• Atherosclerosis rheumatic heart disease
• stroke thrombotic disorder
• transitory ischemic attacks and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes mellitus, syndrome X, impotence, multiple sclerosis, Parkinson's disease, and inflammatory diseases.
• inflammatory diseases refers to diseases, disorders, and conditions that are mediated by BET inhibition.
• exemplary inflammatory diseases include, but are not limited to, arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina, and small artery disease.
• COPD chronic obstructive pulmonary disease
• cancer refers to diseases, disorders, and conditions that are mediated by BET inhibition.
• exemplary cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas and activated, anaplastic large cell lymphoma, neuroblastoma and primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, breast cancer, NMC (NUT-midline carcinoma), acute myeloid leukemia (AM L), acute B lymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell lymphoma, melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocytic leukemia (PML), non-Hodg
• Neuroblastoma neuroblastoma
• medulloblastoma medulloblastoma
• lung carcinoma NSCLC, SCLC
• colon carcinoma NSCLC, SCLC
• Subject refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.
• treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
• treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
• treatment or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
• treatment or “treating” refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.
• prevention or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder.
• a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
• -CONH 2 is attached through the carbon atom.
• optionally or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which is does not.
• optionally substituted aryl encompasses both “aryl” and “substituted aryl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non- feasible and/or inherently unstable.
• hydrate refers to a crystal form with either a stoichiometric or non- stoichiometric amount of water is incorporated into the crystal structure.
• alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C 2 -C 8 )alkenyl.
• alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2- butenyl, and 4-(2-methyl-3-butene)-pentenyl.
• alkoxy refers to an alkyl group attached to an oxygen (-O-alkyl-).
• Alkoxy also include an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”) groups.
• alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-8 carbon atoms, referred to herein as (Ci.CgJalkoxy.
• Exemplary alkoxy groups include, but are not limited to methoxy and ethoxy.
• alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as (Ci_C 8 )alkyl.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2- propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l- pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
• alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C 2 -C 8 )alkynyl.
• alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2- pentynyl, and 4-butyl-2-hexynyl.
• amide refers to the form -NR a C(0)(Rb)- or -C(0)NRbR c , wherein R a , Rb and R c are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
• the amide can be attached to another group through the carbon, the nitrogen, Rj-,, or R c .
• the amide also may be cyclic, for example Rj-, and R c , may be joined to form a 3- to 8-membered ring, such as 5- or 6-membered ring.
• amide encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof.
• amide also encompasses an amide group attached to a carboxy group, e.g., -amide-COOH or salts such as -amide-COONa, an amino group attached to a carboxy group (e.g., -amino-COOH or salts such as -amino-COONa).
• amine or “amino” as used herein refers to the form -NR ⁇ Rg or -NfR j jjRg-, where
• Rj and R e are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyi, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen.
• the amino can be attached to the parent molecular group through the nitrogen.
• the amino also may be cyclic, for example any two of Rj and R e may be joined together or with the N to form a 3- to 12-membered ring (e.g., morpholino or piperidinyl).
• the term amino also includes the corresponding quaternary ammonium salt of any amino group.
• Exemplary amino groups include alkylamino groups, wherein at least one of Rj or R e is an alkyl group.
• Rd and Re each may be optionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.
• aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system.
• the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls.
• aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyi, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
• Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
• Exemplary aryl groups also include, but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryl.”
• arylalkyi refers to an alkyl group having at least one aryl substituent (e.g., -aryl-alkyl-).
• exemplary arylalkyi groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )arylalkyl.”
• carboxylate refers to the form -R g OC(0)N(Rh)-, -R g OC(0)N(Rh)Rj-, or -OC(0)NR
• Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates (e.g., wherein at least one of g ; R
• Carbocycle refers to an aryl or cycloalkyi group.
• carboxy also includes "carboxycarbonyl,” e.g. a carboxy group attached to a carbonyl group, e.g., -C(0)-COOH or salts, such as -C(0)-COONa.
• cyano refers to -CN.
• cycloalkoxy refers to a cycloalkyi group attached to an oxygen.
• cycloalkyi refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as "(C 3 - C 8 )cycloalkyl,” derived from a cycloalkane.
• exemplary cycloalkyi groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
• Cycloalkyi groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyi, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyi groups can be fused to other cycloalkyi saturated or unsaturated, aryl, or heterocyclyl groups.
• dicarboxylic acid refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof.
• Exemplary dicarboxylic acids include alkyl dicarboxylic acids.
• Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyi, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
• Dicarboxylic acids include, but are not limited to succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid, and terephthalic acid.
• Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides (for example, succinic anhydride and succinimide).
• esters refers to the structure -C(0)0-, -C(0)0-Rj_, -R ⁇ CiOjO-Rj., or -R
• Rj and R ⁇ can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyi, ether, haloalkyl, heteroaryl, and heterocyclyl.
• R ⁇ can be a hydrogen atom, but Rj cannot be a hydrogen atom.
• the ester may be cyclic, for example the carbon atom and Rj, the oxygen atom and , or Rj and R ⁇ may be joined to form a 3- to 12- membered ring.
• esters include, but are not limited to, alkyl esters wherein at least one of Rj or Rk is alkyl, such as -0-C(0)-alkyl, -C(0)-0-alkyl-, and -alkyl-C(0)-0-alkyl-.
• Exemplary esters also include aryl or heteoraryl esters, e.g. wherein at least one of j or Rk is a heteroaryl group such as pyridine, pyridazine, pyrimidine and pyrazine, such as a nicotinate ester.
• Exemplary esters also include reverse esters having the structure -R
• Exemplary reverse esters include succinate, D-argininate, L-argininate, L-lysinate and D-lysinate.
• Esters also include carboxylic acid anhydrides and acid halides.
• halo or halogen as used herein refer to F, CI, Br, or I.
• haloalkyl refers to an alkyl group substituted with one or more halogen atoms. "Haloalkyls” also encompass alkenyl or alkynyl groups substituted with one or more halogen atoms.
• heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.
• Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyi, carbamate, carboxy, cyano, cycloalkyi, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non- aromatic rings.
• heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
• heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C 2 - C 5 )heteroaryl.”
• heterocycle refers to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Heterocycles can be aromatic (heteroaryls) or non-aromatic.
• Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyi, carbamate, carboxy, cyano, cycloalkyi, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
• substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyi, carbamate, carboxy, cyano, cycloalkyi, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycly
• Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
• Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, o
• hydroxyalkyl refers to a hydroxy attached to an alkyl group.
• hydroxyaryl refers to a hydroxy attached to an aryl group.
• ketone refers to the structure -C(0)- n (such as acetyl, -C(0)CH 3 ) or -R n- C(0)-R 0- .
• the ketone can be attached to another group through R n or R 0 .
• R n or R 0 can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R n or R 0 can be joined to form a 3- to 12-membered ring.
• monoester refers to an analogue of a dicarboxylic acid wherein one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or salt of a carboxylic acid.
• monoesters include, but are not limited to, to monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.
• phenyl refers to a 6-membered carbocyclic aromatic ring.
• the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
• Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyi, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
• thioalkyl refers to an alkyl group attached to a sulfur (-S-alkyl-).
• alkyl alkenyl, alkynyl, “alkoxy”, “amino” and “amide” groups can be optionally substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyi, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N.
• the substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
• a suitable substitution on an optionally substituted substituent refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates useful for preparing them.
• suitable substitutions include, but are not limited to: Ci_ 8 alkyl, alkenyl or alkynyl; Ci_ 6 aryl, C 2 _ 5 heteroaryl; C 37 cycloalkyl; Ci_ 8 alkoxy; C 6 aryloxy; -CN; -OH; oxo; halo, carboxy; amino, such as -N H(Ci_ 8 alkyl), -N(Ci_ 8 alkyl) 2 , -NH((C 6 )aryl), or -N((C 6 )aryl) 2 ; formyl; ketones, such as -CO(Ci_ 8 alkyl), -CO((C 6 aryl) esters, such as -C0 2 (Ci_ 8 alkyl
• compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
• composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• prodrugs as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure.
• a discussion is provided in Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
• Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i
• salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
• stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols " “ or "S,” depending on the configuration of substituents around the stereogenic carbon atom.
• Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
• Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
• Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• Geometric isomers can also exist in the compounds of the present disclosure.
• the present disclosure encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
• Substituents around a carbon-carbon double bond are designated as being in the "Z” or "E” configuration wherein the terms "Z” and "E” are used in accordance with l UPAC standards.
• structures depicting double bonds encompass both the E and Z isomers.
• Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
• the arrangements of substituents around a carbocyclic ring are designated as “cis” or “trans.”
• the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
• Certain embodiments of the invention provide compounds of Formula I, which include compounds of Formula la, compositions and formulations containing such compounds, and methods of using and making such compounds.
• Some embodiments relate to a compound according to Formula I :
• X is selected from CH and N;
• Y is selected from -NH, -N- i b and oxygen
• Z is selected from N, and -CH-;
• Ria and Ri b are independently selected from alkyl (Ci-C 6 ), carbocycle (C 3 -Ci 0 ), and heterocycle (C 2 -C 10 ) optionally substituted with 1 to 3 groups selected from R 4 ;
• R 2 is selected from aryl (C 5 -Ci 0 ) and heteroaryl (C 5 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 ;
• R 3 is selected from carbocycle (C 3 -C 10 ) and heterocycle (C 2 -C 10 ) optionally substituted with 1 to 5 groups selected from R 5 ; each R 4 is independently selected from deuterium, alkyl (Ci-C 6 ) (such as methyl, ethyl, propyl, isopropyl, butyl), cycloalkyl (C 3 -C 8 ) (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkoxy (Ci-C 6 ) (such as methoxy, ethoxy, isopropoxy), amino (such as - NH 2 , -N HMe, -N H Et, -N HiPr, -N HBu -NMe 2 , NMeEt, -N Et 2 , -N EtBu), -N HC(0)NH-alkyl(C!- C 6 ), halogen (such as
• Some embodiments provide compound of Formula la, which are a subset of compounds of Formula I, compositions and formulations containing such compounds, and methods of using and making such compounds:
• R la is selected from alkyl (C ⁇ Q), carbocycle (C 3 -C 10 ), and heterocycle (C 2 -C 10 ) optionally substituted with 1 to 3 groups selected from 4 ; is selected from aryl (C 5 -Ci 0 ) and heteroaryl (C 5 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 ; is selected from carbocycle (C 3 -Ci 0 ) and heterocycle (C 2 -Ci 0 ) optionally substituted with
• alkyl such as methyl, ethyl, propyl, isopropyl, butyl
• cycloalkyl C 3 -C 8
• alkoxy such as methoxy, ethoxy, isopropoxy
• amino such as - NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu -NMe 2 , NMeEt, -NEt 2 , -NEtBu
• halogen such as F, CI
• amide such as -NHC(0)Me, -NHC(0)Et, -C(0)NHMe, - C(0)NEt 2 , -C(O)N
• halogen such as F, CI
• amide such as -NHC(0)Me, -NHC(0)Et, - C(0)NHMe, -C(0)NEt 2 , -C(O)NiPr
• Q-Cs such as acetyl, -C(0)Et, -C(O)Pr
• -C 4 such as -S(0)Me, -S(O)Et), -SOz-alkyKQ-Cs) (such as - S0 2 Me, -S0 2 Et, -S0 2 Pr), thioalkyl(Ci-C 6 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH, and ester (such as -C(0)OMe, -C(0)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, CI, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo, and/or thio- oxo.
• each R 4 in Formula I or Formula la is independently selected from deuterium, alkyl (Ci-C 6 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (Ci-C 6 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu -NMe 2 , NMeEt, - NEt 2 , -NEtBu), -NHC(0)NH-alkyl(C !
• halogen such as F, CI
• amide such as -NHC(0)Me, -NHC(0)Et, - C(0)NHMe, -C(0)NEt 2 , -C(O)NiPr), -CF 3 , -CN, -N 3 , ketone (such as acetyl, -C(0)Et, -C(O)Pr), -S(O)- alkyl(C C 4 ) (such as -S(0)Me, -S(O)Et), -S0 2 -alkyl(C 1 -C 6 ) (such as -S0 2 Me, -S0 2 Et, -S0 2 Pr), thioalkyl(C C 6 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH, and ester (such as -C(0)OMe, -C(0)OEt, -C(O)OB
• X is N; and Y, Z, R l3 , R lb , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• X is CH; and Y, Z, R ia , R ib , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Y is -NR lb ; and X, Z, R la , R lb , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Y is -NH; and X, Z, R ia , R ib , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Y is oxygen; and X, Z, R ia , Ri b , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Z is N; and X, Y, i a , i b , R2, R3, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Z is CH; and X, Y, R la , R lb , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R ia is selected from alkyl (Ci-C 6 ), carbocycle (C 3 -C 6 ), heterocycle (C 2 -C 5 ) optionally substituted with 1 to 3 groups selected from R 4 ; and X, Y, Z, Rib, R2, R3, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R ia is selected from alkyl (Ci-C 6 ) and carbocycle (C 3 -C 6 ) optionally substituted with 1 to 3 groups selected from R 4 ; and X, Y, Z, R lb , R 2 , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R la is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 3 groups selected from R 4 :
• X, Y, Z, R ib , R2, R3, R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R ia is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 3 groups selected from R 4 :
• X, Y, Z, R ib , R2, R3, R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Ri a is , which may be optionally substituted with 1 to 3 groups selected from R 4 ; and X, Y, Z, R ib , R2, R3, R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein. [0098] In some embodiments according to Formula I or Formula la, R la is and X, Y, Z, R lb , R :
• R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R ia is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 3 groups selected from R 4 :
• X, Y, Z, R ib , R2, R3, R4, and R 5 are as defined in any one or combination of paragraphs 83-156 herein.
• R ib is selected from alkyl (Ci-C 6 ); and X, Y, Z, R ia , R2, R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R ib is selected from methyl and ethyl; and X, Y, Z, Ria, R2, R3, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• Ri b is methyl; and X, Y, Z, R ia , R 2 , R3, R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 2 is selected from optionally substituted bicyclic aryl and bicyclic heteroaryl groups; and X, Y, Z, R ia , Ri b , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 2 is selected from aryl (C 5 -C 10 ) optionally substituted with 1 to 5 groups selected from R 5 ; and X, Y, Z, R la , R lb , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 2 is selected from heteroaryl (C 5 - C10) optionally substituted with 1 to 5 groups selected from R 5 ; and X, Y, Z, R ia , Ri b , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 2 is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5 :
• R 2 is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5 :
• X, Y, Z, R la , R lb , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 2 is selected from, but not limited to, the following structures:
• R 2 is selected from, but not limited to, the following structures: , which may be optionally substituted with
• R 2 is selected from, but not limited to, the following structures:
• X, Y, Z, R l3 , R lb , R 3 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 2 is / ; and X, Y, Z,
• Ria, Rib, R3, and R 4 are as defined in any one or combination of paragraphs 83-124 herein.
• R 3 is selected from carbocycle (C 3 - C10) optionally substituted with 1 to 5 groups selected from R 5 ; and X, Y, Z, R ia , R ib , R2, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 3 is selected from aryl groups (C5-C10) optionally substituted with 1 to 5 groups selected from R 5 ; and X, Y, Z, R ia , R ib , R2, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 3 is selected from heterocycle (C 2 -Cio) optionally substituted with 1 to 5 groups selected from R 5 ; and X, Y, Z, R ia , R ib , R2, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein. [0115] In some embodiments according to Formula I or Formula la, R 3 is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 5 groups selected fr
• X, Y, Z, R l3 , R lb , R 2 , R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 3 is selected from, but not limited to, the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5 :
• X, Y, Z, R ia , R ib , R2, R4, and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 3 is selected from, but not limited to, the following structures:
• R 3 is selected from, but not limited to, the following structures:
• R 3 is selected from phenyl groups which may be optionally substituted with 1 to 5 groups selected from R 5 ; and X, Y, Z, R la , R lb , R 2 , R 4 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• R 3 is an unsubstituted phenyl group; and X, Y, Z, R ia , R ib , R2, R4, and R 5 are as defined in any one or combination of paragraphs 83- 124 herein.
• each R 4 is independently selected from deuterium, alkyl (Ci-C 6 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (Ci-C 6 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -N H 2 , -N HMe, -N HEt, -NHiPr, -N HBu -NMe 2 , N MeEt, - NEt 2 , -NEtBu), -NH ojN H-alky Ci-Cg), halogen (such as F, CI), amide (such as -NHC(0)Me, -NHC(0)Et, - C(0)N HMe, -C(0)N Et 2 , -C(O)NiPr), -CF 3 , -CN, -N 3 , ketone (such as ace
• each R 4 is independently selected from deuterium, alkyl (Ci-C 3 ) (such as methyl, ethyl, propyl), alkoxy (Ci-C 3 ) (such as methoxy, ethoxy), and halogen (such as F, CI); and X, Y, Z, R ia , R ib , R 2 , R 3 , and R 5 are as defined in any one or combination of paragraphs 83-124 herein.
• alkyl such as methyl, ethyl, propyl
• alkoxy such as methoxy, ethoxy
• halogen such as F, CI
• each R 4 is independently selected from cycloalkyl (C 3 -C 8 ) (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); and X, Y, Z, R ia , Ri b , R 2 , R 3 , and R 4 are as defined in any one or combination of paragraphs 83-124 herein.
• cycloalkyl C 3 -C 8
• X, Y, Z, R ia , Ri b , R 2 , R 3 , and R 4 are as defined in any one or combination of paragraphs 83-124 herein.
• each R 5 is independently selected from deuterium, alkyl (Ci-C 6 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (Ci-C 6 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -N H 2 , -N HMe, -N HEt, -NHiPr, -N HBu -NMe 2 , N MeEt, - NEt 2 , -NEtBu), -NHCiOjN H-alkyKCi-Cs), halogen (such as F, CI), amide (such as -NHC(0)Me, -NHC(0)Et, - C(0)N HMe, -C(0)N Et 2 , -C(O)NiPr), -CF 3 , -CN, -N 3 , ketone (such as
• the compound of Formula I or Formula la is selected from:
• the compound of Formula I is 4-cyclopropyl-l-methyl-3-(5-(l-methyl- l/-/-indazol-6-yl)-2-phenyl-l/-/-imidazol-4-yl)-l/-/-l,2,4-triazol-5(4/-/)-one or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
• the pharmaceutically acceptable salt of a compound of Formula I is selected from a hydrochloride or dihydrochloride salt.
• the pharmaceutically acceptable salt of a compound of Formula I or Formula la is selected from:
• the pharmaceutically acceptable salt of a compound of Formula I is 4- cyclopropyl-l-methyl-3-(5-(l-methyl-lH-indazol-6-yl)-2-phenyl-lH-imidazol-4-yl)-lH-l,2,4-triazol- 5(4H)-one hydrochloride.
• Another aspect of the invention provides a method for inhibition of BET protein function by binding to bromodomains, and their use in the treatment and prevention of diseases and conditions in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula I or Formula la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
• BET inhibitor compounds of Formula I or Formula la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof may be used as therapeutics for inflammatory disorders in which IL-6 and/or IL-17 have been implicated in disease.
• the following autoimmune diseases are amenable to therapeutic use of BET inhibition by administration of a compound of Formula I or Formula la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof because of a prominent role of IL-6 and/or IL-17: Acute Disseminated Encephalomyelitis (T.
• McKinley et al. "TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,” J Immunol 181(6):4089-97 (2008)), Ankylosing spondylitis (A. Taylan et al., “Evaluation of the T helper 17 axis in ankylosing spondylitis,” Rheumatol Int 32(8):2511-5 (2012)), Anti-GBM/Anti-TBM nephritis (Y.
• Fujioka et al. "The analysis of mRNA expression of cytokines from skin lesions in Churg-Strauss syndrome," J Dermatol 25(3):171-7 (1998)), Crohn's Disease (V. Holtta et al., "IL-23/IL-17 immunity as a hallmark of Crohn's disease,” Inflamm Bowel Dis 14(9):1175-84 (2008)), Cogan's syndrome (M. Shibuya et al., “Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis,” Mod Rheumatol (2012)), Dry eye syndrome (C. De Paiva et al., "IL-17 disrupts corneal barrier following desiccating stress," Mucosal Immunol 2(3):243-53 (2009)), Essential mixed cryoglobulinemia (A.
• the invention includes compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; pharmaceutical compositions comprising one or more of those compounds; and methods of using those compounds or compositions for treating these diseases.
• Acute and chronic (non-autoimmune) inflammatory diseases characterized by increased expression of pro-inflammatory cytokines, including IL-6, MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition. These include, but are not limited to, sinusitis (D. Bradley and S.
• the invention includes compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; pharmaceutical compositions comprising one or more of those compounds; and methods of using those compounds or compositions for treating these diseases.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used for treating rheumatoid arthritis (RA) and multiple sclerosis (MS). Strong proprietary data exist for the utility of BET inhibitors in preclinical models of RA and MS. R.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof may be used for treating sepsis and associated afflictions.
• BET inhibition has been shown to inhibit development of sepsis, in part, by inhibiting IL-6 expression, in preclinical models in both published (E. Nicodeme et al., Nature 468(7327):1119-23 (2010)) and proprietary data.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancer.
• Cancers that have an overexpression, translocation, amplification, or rearrangement c-myc or other myc family oncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition. J. Delmore et al., Cell 146(6):904-17 (2010); J. Mertz et al., Proc Natl Acad Sci USA 108(40):16669-74 (2011).
• cancers include, but are not limited to, 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
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers that result from an aberrant regulation (overexpression, translocation, etc) of BET proteins.
• BET proteins include, but are not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation to nutlin 1 gene) (C. French Cancer Genet Cytogenet 203(1): 16- 20 (2010)), B-cell lymphoma (Brd2 overexpression) (R. Greenwald et al., Blood 103(4):1475-84 (2004)), non-small cell lung cancer (BrdT overexpression) (C. Grunwald et al., "Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer," IntJ Cancer
• BET inhibitors decrease Brd-dependent recruitment of pTEFb to genes involved in cell proliferation
• BET inhibitor compounds of Formula I or Formula la because BET inhibitors decrease Brd-dependent recruitment of pTEFb to genes involved in cell proliferation, BET inhibitor compounds of Formula I or Formula la,
• stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers that rely on pTEFb
• cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma (W. Tong et al., "Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma," J Clin Oncol 28(18):3015-22 (2010)), follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas and activated, anaplastic large cell lymphoma (C. Bellan et al., "CDK9/CYCLIN Tl expression during normal lymphoid differentiation and malignant
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers in which BET-responsive genes, such as CDK6, Bcl2, TYR03, MYB, and hTERT are up-regulated.
• BET-responsive genes such as CDK6, Bcl2, TYR03, MYB, and hTERT are up-regulated.
• cancers include, but are not limited to, pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers for which exist published and, for some, proprietary, in vivo and/or in vitro data showing a direct effect of BET inhibition on cell proliferation.
• NMC NUT-midline carcinoma
• AML acute myeloid leukemia
• B-ALL acute B lymphoblastic leukemia
• Burkitt's Lymphoma B-cell Lymphoma
• Melanoma mixed lineage leukemia, multiple myeloma, pro-myelocytic leukemia (PML), and non-Hodgkin's lymphoma.
• PML pro-myelocytic leukemia
• PML non-Hodgkin's lymphoma.
• the compounds of the invention have a demonstrated BET inhibition effect on cell proliferation in vitro for the following cancers: Neuroblastoma, Medulloblastoma, lung carcinoma (NSCLC, SCLC), and colon carcinoma.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be combined with other therapies, chemotherapeutic agents, or antiproliferative agents to treat human cancer and other proliferative disorders.
• the list of therapeutic agents which can be combined with BET inhibitors in cancer treatment includes, but is not limited to, 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, Ifosf
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat benign proliferative and fibrotic disorders, including benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, juvenile polyposis syndrome, idiopathic fibroma, juvenile polyposi
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cardiovascular diseases that are generally associated with including dyslipidemia, atherosclerosis, hypercholesterolemia, and metabolic syndrome (A. Belkina and G. Denis, Nat Rev Cancer 12(7):465-77 (2012); G.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof may be used to treat non- cardiovascular disease characterized by deficits in ApoA-1, including Alzheimer's disease.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used in patients with insulin resistance and type II diabetes.
• the anti-inflammatory effects of BET inhibition would have additional value in decreasing inflammation associated with diabetes and metabolic disease.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used as therapeutics for cancers that are associated with viruses including Epstein-Barr Virus (EBV), hepatitis virus (HBV, HCV), Kaposi's sarcoma associated virus (KSHV), human papilloma virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV).
• EBV Epstein-Barr Virus
• HBV hepatitis virus
• KSHV Kaposi's sarcoma associated virus
• HPV human papilloma virus
• Merkel cell polyomavirus and human cytomegalovirus
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy.
• diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy.
• BET inhibitor compounds of Formula I or Formula la, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used as reversible, male contraceptive agents.
• testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTR truncation in round spermatids
• compositions of the present disclosure comprise at least one compound of Formula I or Formula la, or tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof formulated together with one or more pharmaceutically acceptable carriers.
• These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
• Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
• such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
• the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
• the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
• a unit-dose formulation for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
• Other pharmacologically active substances may also be present including other compounds.
• the formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.
• conventional nontoxic solid carriers include, for example,
• compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
• an excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
• suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
• a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
• Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
• Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.
• Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula I or Formula la or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although
• compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.
• Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
• Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
• Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
• the active compound i.e., at least one compound of Formula I or Formula la or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof
• the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
• a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 ⁇ g to about 1000 mg.
• intermittent administration such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed.
• Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
• physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
• a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
• the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
• the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration.
• Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
• Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
• Compositions that exhibit large therapeutic indices are preferable.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
• a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
• the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
• a compound of Formula I or Formula la or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered in combination with another therapeutic agent.
• the other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present disclosure alone.
• the therapeutic agent can be, for example, a statin; a PPAR agonist, e.g., a thiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; a bile-acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; a cholesteryl ester transfer protein (CETP), an ion-exchange resin; an antioxidant; an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrophostine; a sulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug; an HDL enhancer; a regulator of the apolipoprotein
• a compound of Formula I or Formula la or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered in combination with one or more anti-inflammatory agents.
• Anti-inflammatory agents can include immunosuppressants, TNF inhibitors, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDS), and the like.
• NSAIDs non-steroidal anti-inflammatory drugs
• DARDS disease-modifying anti-rheumatic drugs
• exemplary anti-inflammatory agents include, for example, prednisone; methylprenisolone (Medrol ® ), triamcinolone, methotrexate (Rheumatrex ® , Trexall ® ),
• infliximab (Remicade ® ), adalimumab (Humira ® ), rituximab (Rituxan ® ), abatacept (Orencia ® ), interleukin— 1, anakinra (KineretTM), ibuprofen, ketoprofen, fenoprofen, naproxen, aspirin, acetominophen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphen
• X is selected from CH and N;
• Y is selected from -NH, -N-Ri b and oxygen
• Z is selected from N, and -CH-;
• R la and R lb are independently selected from alkyl (Ci-C 6 ), carbocycle (C 3 -C 10 ), heterocycle (C 2 - C 10 ) optionally substituted with 1 to 3 groups selected from R 4 ;
• R 2 is selected from aryl (C 5 -C 10 ) and heteroaryl (C 5 -C 10 ) optionally substituted with 1 to 5 groups selected from R 5 ;
• R 3 is selected from carbocycle (C 3 -Ci 0 ) and heterocycle (C 2 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 ;
• each R 4 is independently selected from deuterium, alkyl (Ci-C 6 ), cycloalkyl (C 3 -C 8 ), alkoxy (Ci- C 6 ), amino, -NHC(0)NH-alkyl(Ci-C 6 ), halogen, amide, -CF 3 , -CN, -N 3 , ketone, -S(O)- alkyl(Ci-C 4 ), -S0 2 -alkyl(Ci-C 6 ), thioalkyl(Ci-C 6 ), -COOH, and ester, each of which may be optionally substituted with hydrogen, F, CI, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo, and/or thio-oxo; and each R 5 is independently selected from deuterium, alkyl (Ci-C 6 ), alkoxy(Ci-C 6 ),
• Ri a is selected from alkyl (Ci-C 6 ), carbocycle (C 3 -Ci 0 ), heterocycle (C 2 -Ci 0 ) optionally
• R 2 is selected from aryl (C 5 -Ci 0 ) and heteroaryl (C 5 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 ;
• C 3 -Ci 0 is selected from carbocycle (C 3 -Ci 0 ) and heterocycle (C 2 -Ci 0 ) optionally substituted with
• each R 4 is independently selected from deuterium, alkyl (C ⁇ Q), cycloalkyi (C 3 -C 8 ), alkoxy (C C 6 ), amino, -NHC(0)NH-alkyl(C ! -C 6 ), halogen, amide, -CF 3 , -CN, -N 3 , ketone, -S(O)- alkyl(Ci-C 4 ), -S0 2 -alkyl(Ci-C 6 ), thioalkyl(Ci-C 6 ), -COOH, and ester, each of which may be optionally substituted with hydrogen, F, CI, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo, and/or thio-oxo; and
• each R 5 is independently selected from deuterium, alkyl (Ci-C 6 ), alkoxy (Ci-C 6 ),
• R l3 is selected from alkyl (Ci-Cs), carbocycle (C 3 -C 6 ), and heterocycle (C 2 -C 5 ) optionally substituted with 1 to 3 groups selected from R 4 .
• R l3 is selected from alkyl (Ci-C 6 ) and carbocycle (C 3 -C 6 ) optionally substituted with 1 to 3 groups selected from R 4 .
• R ia is selected from the following structures, which may be optionally substituted with 1 to 3 groups selected from R 4
• R ia is selected from the following structures, which may be optionally substituted with 1 to 3 groups selected from R 4
• R 2 is selected from aryl (C 5 -C 10 ) optionally substituted with 1 to 5 groups selected from R 5 .
• R 2 is selected from heteroaryl (C 5 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 .
• R 2 is selected from the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5 :
• R 2 is selected from the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5
• R 2 is selected from the following:
• R 2 is selected from the following:
• R 2 is selected from the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5
• R 2 is The compound according to any one of embodiments 1-29, wherein R 3 is selected from carbocycle (C 3 -C 10 ) optionally substituted with 1 to 5 groups selected from R 5 .
• R 3 is selected from aryl groups (C 5 -Cio) optionally substituted with 1 to 5 groups selected from R 5 .
• R 3 is selected from heterocycle (C 2 -Ci 0 ) optionally substituted with 1 to 5 groups selected from R 5 .
• R 3 is selected from the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5 :
• R 3 is selected from the following structures, which may be optionally substituted with 1 to 5 groups selected from R 5:
• R 3 is selected from phenyl groups which may be optionally substituted with 1 to 5 groups selected from R 5 .
• R 3 is an unsubstituted phenyl group.
• each R 4 is independently selected from deuterium, alkyl (C ! -C 6 ), alkoxy (C ! -C 6 ), amino, -NHCiOjNH-alky Ci-Cs), halogen, amide, -CF 3 , -CN, -N 3 , ketone, -SiOj-alkyKCrQ), -S0 2 -alkyl(C 1 -C 6 ), and thioalkyKCi-Q).
• each R 4 is independently selected from deuterium, alkyl (Ci-C 3 ), alkoxy (Ci-C 3 ), and halogen.
• each R 5 is independently selected from deuterium, alkyl (Ci-C 6 ), alkoxy (Ci-C 6 ), amino, -NHC(0)NH-alkyl(Ci-C 6 ), halogen, amide, -CF 3 , -CN, -N 3 , ketone, -S(0)-alkyl(Ci-C 4 ), -S0 2 -alkyl(Ci-C 6 ), thioalkyl(Ci-C 6 ), -COOH, and ester.
• a pharmaceutical composition comprising the compound of any one of embodiments 1-43, and a pharmaceutically acceptable carrier.
• a method of treating an autoimmune or inflammatory disorder associated with BET proteins comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating an acute or chronic non-autoimmune inflammatory disorder characterized by disregulation of IL-6 and/or IL-17 comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer associated with overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein that is sensitive to BET inhibition comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer associated with overexpression, translocation, amplification, or rearrangement of BET proteins comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer that relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer associated with upregulation of BET responsive genes CDK6, Bcl2, TY 03, MYB, and hTERT comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer associated with a gene regulated by a super enhancer comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer that is sensitive to effects of BET inhibition comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a cancer that is resistant to treatment with immunotherapy, hormone- deprivation therapy, and/or chemotherapy comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• the therapeutic 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), IFNa2
• a method of treating a benign proliferative or fibrotic disorder selected from the group consisting of benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, postoperative stricture, keloid formation, scleroderma, and cardiac fibrosis comprising
• a method of treating a disease or disorder that benefits from up-regulation or ApoAI transcription and protein expression comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of treating a metabolic disease or disorder comprising administering a
• a method of treating a cancer associated with a virus comprising administering a
• a method for treating HIV infection comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44 alone or in combination with anti-retroviral therapeutic.
• a method for treating a disease or disorder selected from Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• a method of male contraception comprising administering a therapeutically effective amount of the compound of any one of embodiments 1-43 or a pharmaceutical composition according to embodiment 44.
• autoimmune or inflammatory disorder is selected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia, Allergic Disease,
• 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
• the acute or chronic non-autoimmune inflammatory disorder is selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections.
• the acute or chronic non-autoimmune inflammatory disorder is selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections.
• COPD chronic obstructive pulmonary disease
• the acute or chronic non-autoimmune inflammatory disorder is selected from rheumatoid arthritis (RA) and multiple sclerosis (MS).
• 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, superficial spreading, Neuroblastoma, esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cell carcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lung carcinoma.
• the cancer is selected from NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer, head and neck squamous cell carcinoma, breast cancer, prostate cancer, and colon cancer.
• the cancer is selected from chronic lymphocytic leukemia and multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas and activated, anaplastic large cell lymphoma, neuroblastoma and primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer.
• chronic lymphocytic leukemia and multiple myeloma follicular lymphoma
• diffuse large B cell lymphoma with germinal center phenotype Burkitt's lymphoma
• Hodgkin's lymphoma follicular lymphomas and activated
• anaplastic large cell lymphoma neuroblastoma and primary neuroectodermal tumor
• rhabdomyosarcoma prostate cancer
• breast cancer selected from chronic lymphocytic leukemia
• the cancer is selected from pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma.
• NMV NUT-midline carcinoma
• AML acute myeloid leukemia
• B-ALL acute B lymphoblastic leukemia
• Burkitt's Lymphoma B-cell Lymphoma
• Melanoma mixed lineage leukemia, multiple myeloma, pro- myelocytic leukemia (PML), non-Hodgkin's lymphoma, Neuroblastoma, Medulloblastoma, lung carcinoma (NSCLC, SCLC), breast cancer, prostate cancer, and colon carcinoma.
• the cancer is selected from adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK- cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymph
• dysgerminoma embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer,
• hemangiopericytoma hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer , MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, medias
• neurofibroma neuroma, neuroma, nodular melanoma, NUT-midline carcinoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma,
• rhabdomyosarcoma ichter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,
• somatostatinoma soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer,
• the method of embodiment 58 wherein the disease is cardiovascular disease, dyslipidemia, atheroschlerosis, hypercholesterolemia, metabolic syndeome, and Alzheimer's disease.
• the method of embodiment 59 wherein the metabolic disorder is selected from obesity- associated inflammation, type II diabetes, and insulin resistance.
• the virus is selected from Epstein-Barr Virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma associated virus (KSHV), human papilloma virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV).
• EBV Epstein-Barr Virus
• HBV hepatitis B virus
• HCV hepatitis C virus
• KSHV Kaposi's sarcoma associated virus
• HPV human papilloma virus
• Merkel cell polyomavirus and human cytomegalovirus (CMV).
• DCM dichloromethane
• DM F dimethylformamide
• EtOAc ethyl acetate
• NBS /V-bromosuccinimide
• MeOH methanol
• PE petroleum ether
• SEM-CI (2- (chloromethoxy)ethyl)trimethylsilane
• TEA triethylamine
• TFA trifluoroacetic acid
• TH F
• Example 17 4-(Cyclopropylmethyl)-3-(5-(l-methyl-lH-indazol-6-yl)-2-phenyl-lH-imidazol-4-yl)-lH- l,2,4-triazol-5(4H)-one)
• n-BuLi (2.5 M, 1.81 m L, 1.80 eq) was added to a solution of compound 19 (1.46 g, 2.51 mmol, 1.00 eq) in TH F (33 mL) at -78 °C under a nitrogen atmosphere.
• the resulting slurry was stirred at - 78 °C for 5 min, then a solution of 1,1, 1,2,2,2-hexachloroethane (832 mg, 3.51 mmol, 1.40 eq) in THF (3 m L) was added in portions.
• the reaction mixture was stirred for 30 min at -78 °C as the color turned from brown to red.
• Example 28 Inhibition of tetra-acetylated histoneH4 binding individual BET Bromodomains
• Proteins were cloned and overexpressed with a /V-terminal 6xHis tag, then purified by nickel affinity followed by size exclusion chromatography. Briefly, E.coli BL21(DE3) cells were transformed with a recombinant expression vector encoding /V-terminally Nickel affinity tagged bromodomains from Brd2, Brd3, Brd4. Cell cultures were incubated at 37°C with shaking to the appropriate density and induced overnight with IPTG. The supernatant of lysed cells was loaded onto Ni-IDA column for purification. Eluted protein was pooled, concentrated and further purified by size exclusion chromatography. Fractions representing monomeric protein were pooled, concentrated, aliquoted, and frozen at -80°C for use in subsequent experiments.
• N-terminally His- tagged bromodomains B D4(1) at 20 nM and BRD4(2) at ⁇
• biotinylated tetra-acetylated histone H4 (10-25 nM) were incubated in the presence of nickel chelate acceptor beads and streptavidin donor beads (PerkinAlmer, 6760000K ) added to a final concentration of 2 ⁇ g/ml under green light in a white 96 well microtiter plate (Greiner).
• BikinAlmer 6760000K
• Example 29 Inhibition of cMYC expression in cancer cell lines
• MV4-11 cells (CRL-9591) were plated at a density of 2.5xl0 4 cells per well in 96 well U-bottom plates and treated with increasing concentrations of test compound or DMSO (0.1%) in IMDM media containing 10% FBS and penicillin/streptomycin, and incubated for 3 h at 37°C. Triplicate wells were used for each concentration. Cells were pelleted by centrifugation and harvested using the mRNA Catcher PLUS kit according to manufacturer's instructions.
• RNA UltraSenseTM One-Step Kit Life Technologies
• TaqMan ® primer-probes for cMYC and Cyclophilin Applied Biosystems
• Real-time PCR plates were run on a ViiATM7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for cMYC to an internal control, prior to determining the fold expression of each sample, relative to the control.
• Example 30 Inhibition of cell proliferation in cancer cell lines
• MV4-11 cells (C L-9591) were plated at a density of 5xl0 4 cells per well in 96 well flat bottom plates and treated with increasing concentrations of test compound or DMSO (0.1%) in I M DM media containing 10% FBS and penicillin/streptomycin. Triplicate wells were used for each concentration and a well containing only media was used as a control. Plates were incubated at 37°C, 5% C0 2 for 72 h before adding 20 ⁇ of the Cell Titer Aqueous One Solution (Promega) to each well and incubated at 37°C, 5% C0 2 for an additional 3-4 h.
• the absorbance was read at 490 nm in a spectrophotometer and the percentage of cell titer relative to DMSO-treated cells was calculated after correcting for background by subtracting the blank well's signal. IC 50 values were calculated using the GraphPad Prism software.
• RNA UltraSenseTM One-Step Kit Life Technologies
• TaqMan ® primer-probes for hlL-6 and Cyclophilin.
• Real-time PCR plates were run on a ViiATM7 real time PCR machine (Applied Biosystems), data was analyzed, normalizing the Ct values for hlL-6 to an internal control, prior to determining the fold expression of each sample, relative to the control.
• Examples 32 In vivo efficacy in athymic nude mouse strain of an acute myeloid leukemia xenograft model using MV4-11 cells
• MV4-11 cells (ATCC) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with 5x10 s cells/animal in 100 ⁇ PBS + 100 ⁇
• mice are randomized based on tumor volume (L x W x H)/2) of average " ⁇ 00-300 mm 3 .
• Mice are dosed orally with compound at 5 to 120 mg/kg b.i.d and/or q.d. on a continuous dosing schedule and at 2.5 to 85 mg/kg q.d. on a 5 day on 2 day off, lOOmg/kg q.d. on a 4 day on and 3 day off, 135 mg/kg q.d.

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• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2015
  • 2015-12-11 CN CN201580066758.8A patent/CN107207474B/zh active Active
  • 2015-12-11 CA CA2966449A patent/CA2966449A1/en not_active Abandoned
  • 2015-12-11 EP EP15866917.6A patent/EP3230277B1/en not_active Not-in-force
  • 2015-12-11 US US15/534,105 patent/US10292968B2/en not_active Expired - Fee Related
  • 2015-12-11 WO PCT/IB2015/002479 patent/WO2016092375A1/en not_active Ceased
  • 2015-12-11 HK HK18104394.4A patent/HK1245248B/en unknown
  • 2015-12-11 JP JP2017531764A patent/JP2017537946A/ja active Pending

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