HK40010367B - Bicyclic bromodomain inhibitors - Google Patents

Description

Bicyclic bromodomain inhibitors

This application is a divisional application of the international application with application number PCT/US2014/043423 filed on June 20, 2014, and invention name “Novel Bicyclic Bromodomain Inhibitors”, which entered the Chinese national phase on December 18, 2015, with application number 201480034817.9.

This application claims priority to U.S. Provisional Patent Application No. 61/837,841, filed June 21, 2013, which is hereby incorporated by reference in its entirety.

Technical Field

The present invention provides novel compounds, pharmaceutical compositions containing such compounds, and their use in preventing and treating diseases and conditions associated with bromodomain and extra-terminal domain (BET) proteins.

Background Art

Post-translational modifications (PTMs) of histones are involved in the regulation of gene expression and chromatin organization in eukaryotic cells. Histone acetylation at specific lysine residues is a PTM regulated by histone acetylases (HATs) and deacetylases (HDACs). Peserico, A. and C. Simone, “Physical and functional HAT/HDAC interplay regulates protein acetylation balance,” J Biomed Biotechnol, 2011: 371-832 (2011). Small molecule inhibitors of HDACs and HATs are being investigated as cancer therapies. Hoshino, I. and H. Matsubara, “Recent advances in histone deacetylase targeted cancer therapy” Surg Today 40(9):809-15(2010); Vernarecci, S., F. Tosi and P. Filetici, “Tuning acetylated chromatin with HAT inhibitors: a novel tool for therapy” Epigenetics 5(2):105-11(2010); Bandyopadhyay, K. et al., "Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo-and radiosensitization," Cell Cycle8(17):2779-88(2009); Arif, M. et al., "Protein lysine acetylation in cellular function and its role in cancer manifestation,” Biochim Biophys Acta 1799(10-12):702-16(2010). Histone acetylation controls gene expression by recruiting protein complexes that directly bind 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 (bromodomain and extra-terminal domain (BET) proteins) includes Brd2, Brd3, Brd4, and BrdT, each of which contains two tandem bromodomains that can independently bind acetylated lysine, as reviewed in Wu, S.Y. and C.M. Chiang, “The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation,” J Biol Chem 282(18):13141-5(2007).

Interference with BET protein interactions through bromodomain inhibition results in the regulation of transcriptional programs that are often associated with diseases characterized by dysregulation of cell cycle control, inflammatory cytokine expression, viral transcription, hematopoietic differentiation, insulin transcription, and adipogenesis. Belkina, A.C. and G.V. Denis, “BET domain co-regulators inobesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012). BET inhibitors are believed to be useful in treating diseases or conditions associated with systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, and in preventing and treating viral infections. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Prinjha, R.K., J. Witherington, and K. Lee, “Place your BETs: thetherapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53(2012).

Autoimmune diseases (which are often chronic and debilitating) are the result of a dysregulated immune response that causes the body to attack its own cells, tissues, and organs. Proinflammatory cytokines including IL-1β, TNF-α, IL-6, MCP-1, and IL-17 are overexpressed in autoimmune diseases. IL-17 expression defines a subset of T cells known as Th17 cells, which are differentiated in part by IL-6 and drive many of the pathogenic consequences of autoimmune diseases. Therefore, the IL-6/Th17 axis represents an important potential druggable target for the treatment of autoimmune diseases. Kimura, A. and T. Kishimoto, "IL-6: regulator of Treg/Th17 balance," Eur J Immunol 40(7):1830-5(2010). BET inhibitors are expected to have anti-inflammatory and immunomodulatory properties. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Prinjha, R.K., J. Witherington and K. Lee, “Place your BETs: the therapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012). BET inhibitors have been shown to have broad-spectrum anti-inflammatory effects in vitro, including the ability to reduce the expression of proinflammatory cytokines such as IL-1β, MCP-1, TNF-α, and IL-6 in activated immune cells. Mirguet, O., et al., “From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Nicodeme, E., et al., “Suppression of inflammation by a synthetic histone mimic,” Nature 468(7327):1119-23 (2010); Seal, J., et al., “Identification of a novel series of BET family bromodomain inhibitors: binding mode and profileof I-BET151 (GSK1210151A),” Bioorg Med Chem Lett 22(8):2968-72 (2012). The mechanism of these anti-inflammatory effects may involve BET inhibitors disrupting Brd4 coactivation of NF-κB-regulated proinflammatory 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); Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition," J Biol Chem, 287(34): 8840-51 (2012); Zhou, M., et al., "Bromodomain protein Brd4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9atthreonine 29," J Virol 83(2): 1036-44 (2009). In addition, because Brd4 is involved in T cell lineage differentiation, BET inhibitors may be applicable to inflammatory disorders characterized by specific programs of T cell differentiation. Zhang, W.S., et al., "Bromodomain-Containing-Protein 4(BRD4)Regulates RNA Polymerase II Serine 2Phosphorylation in Human CD4+T Cells," J Biol Chem (2012).

The anti-inflammatory and immunomodulatory effects of BET inhibition have also been demonstrated in vivo. BET inhibitors prevented endotoxin- or bacterial sepsis-induced death and cecal ligation and puncture-induced death in mice, demonstrating the utility of BET inhibitors in sepsis and acute inflammatory conditions. Nicodeme, E., et al., “Suppression of inflammation by asynthetic histone mimic,” Nature 468(7327):1119-23 (2010). BET inhibitors have been shown to improve inflammation and renal damage in HIV-1 transgenic mice (an animal model of HIV-associated nephropathy) in part by inhibiting the interaction of Brd4 with NF-κB. Zhang, G., et al., “Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition,” J Biol Chem, 287(34):8840-51 (2012). The utility of BET inhibition in autoimmune diseases was demonstrated in a mouse model of multiple sclerosis, where BET inhibition resulted in abolition of clinical signs of disease, in part by inhibition of IL-6 and IL-17. R. Jahagirdar, S. M. et al., “An Orally Bioavailable Small Molecule RVX-297 Significantly Decreases Disease in a Mouse Model of Multiple Sclerosis,” World Congress of Inflammation, Paris, France (2011). These results were supported in a similar mouse model, where treatment with a BET inhibitor was shown to inhibit T cell differentiation into pro-autoimmune Th1 and Th17 subsets in vitro and also abrogate disease induced by pro-inflammatory Th1 cells. Bandukwala, H. S., et al., “Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Mycinhibitors,” Proc Natl Acad Sci USA, 109(36):14532-7 (2012).

BET inhibitors can be used to treat a variety of chronic autoimmune inflammatory conditions. Accordingly, 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, conditions and syndromes that can be treated using the compounds and methods of the present invention include, but are not limited to, pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis (Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIV associated Kidney Disease by BRD4 Inhibition," J Biol Chem, 287(34):8840-51 (2012)), osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis (Prinjha, R.K., J. Witherington and K. Lee, "Place your BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci 33(3):146-53 (2012)), Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis (Bandukwala, H.S., et al., "Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors," Proc Natl Acad Sci USA, 109(36):14532-7(2012)), scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, type I diabetes (Belkina, A.C. and G.V. Denis, "BET domain co-regulators in obesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77(2012)), septic shock (Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition," J Biol Chem, 287(34):8840-51(2012)), systemic lupus erythematosus (SLE) (Prinjha, R.K., J. Witherington and K. Lee, "Place your BETs: the therapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53(2012)), rheumatoid arthritis (Denis, G.V., “Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99(2010)), psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom’s macroglobulinemia, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet’s disease, uveitis, dry eye disease, scleroderma, mycosis fungoides, and Graves’ disease.

BET inhibitors are useful in treating a wide variety of acute inflammatory conditions, and thus, one aspect of the invention provides compounds, compositions, and methods for treating inflammatory conditions, including, but not limited to, acute gout, giant cell arteritis, nephritis (including lupus nephritis), vasculitis with organ damage (such as glomerulonephritis), vasculitis (including giant cell arteritis), Wegener's granulomatosis, polyarteritis nodosa, Behcet's disease, Kawasaki disease, and Takayasu's arteritis.

BET inhibitors can be used to prevent and treat diseases or conditions involving inflammatory responses to bacteria, viruses, fungi, parasites and their toxins, such as, but not limited to, sepsis, septic 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), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, adult respiratory distress syndrome (ARDS), acute renal failure, fulminant hepatitis, burns, postoperative syndrome, sarcoidosis, Herxheimer's reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronaviruses. Belkina, A.C. and G.V. Denis, "BET domain co-regulators inobesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77 (2012). Thus, one aspect of the present invention provides compounds, compositions and methods for treating diseases or conditions that are inflammatory responses to bacteria, viruses, fungi, parasites and their toxins as described herein.

Cancer is a group of diseases caused by dysregulated cell proliferation. Treatment methods aim to reduce the number of cancer cells by inhibiting cell replication or by inducing cancer cell differentiation or death, but there is still a significant unmet medical need for more effective therapeutic agents. Cancer cells accumulate genetic and epigenetic changes that alter cell growth and metabolism, thereby 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 chromatin structure regulation, including dysregulation of histone PTMs. Watson, J.D., "Curing 'incurable' cancer," Cancer Discov1(6):477-80(2011); Morin, R.D., et al., "Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma" Nature 476(7360):298-303(2011).

One aspect of the present invention provides compounds, compositions and methods for treating human cancers, including but not limited to cancers caused by aberrant translocation or overexpression of BET proteins (e.g., NUT midline carcinoma (NMC) (French, C.A., "NUT midline carcinoma," Cancer Genet Cytogenet 203(1):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 translocation of the Brd4 or Brd3 gene to the nutlin1 gene. Filippakopoulos, P., et al., "Selective inhibition of BET bromodomains," Nature 468(7327):1067-73(2010). BET inhibition has demonstrated potent antitumor activity in a mouse xenograft model of NMC, a rare but lethal form of cancer. The present disclosure also provides methods for treating human cancers, including, but not limited to, cancers that depend on members 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). These cancers include Burkitt's lymphoma, acute myeloid 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 sensitive to BET protein inhibition; treatment of tumors with c-myc activation with BET inhibitors has been shown to result in tumor regression through inactivation of c-myc transcription. Dawson, M.A., et al., Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 2011. 478(7370): p. 529-33; Delmore, J.E., et al., “BET bromodomain inhibition as a therapeutic strategy to target c-Myc,” Cell 146(6):904-17(2010); Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA108(40):16669-74(2011); Ott, C.J., et al., “BET bromodomain inhibition targets both c-Myc and IL7R in high risk acute lymphoblastic leukemia,” Blood 120(14):2843-52(2012); Zuber, J., et al., “RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia,” Nature 478(7370):524-8(2011).

Embodiments of the present invention include methods for treating human cancers that rely on BET proteins and pTEFb (Cdk9/CyclinT) for regulation of oncogenes (Wang, S. and P.M. Fischer, "Cyclin-dependent kinase9: a key transcriptional regulator and potential drug target inoncology, virology and cardiology," Trends Pharmacol Sci 29(6):302-13 (2008)) and cancers that can be treated by inducing apoptosis or senescence through inhibition of 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 bromodomaininhibition as a therapeutic strategy to target c-Myc," Cell 146(6):904-17 (2010); Ruden, M. and N. Puri, "Novel anticancer therapeutics targeting telomerase," Cancer Treat Rev (2012).

BET inhibitors can be used to treat cancers including, but not limited to, adrenal carcinoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidrosis, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, and 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., et al., “RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia” ... myeloidleukaemia,” Nature 478(7370):524-8 (2011)), adenocarcinoma, adenoid cystic carcinoma, adenoma, odontogenic adenomatoid tumor, adenosquamous carcinoma, adipose tissue tumor, 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 lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell acute lymphoblastic leukemia (Ott, C.J., et al., “BET bromodomain inhibition targets both c-Myc and IL7R in high risk acute lymphoblastic leukemia,” Blood 120(14):2843-52(2012)), B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, 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)), basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, brown tumor, Burkitt's lymphoma (Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BETbromodomains,” Proc Natl Acad Sci USA 108(40):16669-74(2011)), breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementum tumor, medullary sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos' disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland tumor, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, parasitic fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma , giant cell tumor of bone, glioma, glioblastoma multiforme, neuroglioma, glioma, glioblastoma, glucagonoma, gonadoblastoma, granulosa cell tumor, amphotericinoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, infiltrative lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline cancer, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia (Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA 108(40):16669-74(2011)), chronic lymphocytic leukemia, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant salamander tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma (Miguel F. Segura, et al., “BRD4 is a novel therapeutic target in melanoma,” Cancer Research. 72(8): Suppl 1 (2012)), meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, Mullerian mixed tumor, mixed lineage 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)), mucinous tumors, multiple myeloma (Delmore, J.E., et al., “BET bromodomain inhibition as atherapeutic strategy to target c-Myc,” Cell 146(6):904-17 (2010)), muscle tissue tumors, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, NUT-midline carcinoma (Filippakopoulos, P., et al., “Selective inhibition of BET bromodomains,” Nature 468(7327):1067-73(2010)), eye cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancrest tumor, papillary thyroid cancer, paraganglioma, pinealocyte tumor, pinealocyte tumor, pituitary cell tumor, 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, kidney cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small round blue cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty warts, spinal tumors, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary's disease, small intestinal cancer, squamous cell carcinoma, gastric cancer, testicular cancer, theca cell tumor, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, optic pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Worthing and Wilms' tumors. Thus, one aspect of the present invention provides compounds, compositions and methods for treating such cancers.

BET inhibitors may be used to treat benign proliferative and fibrotic disorders, including benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic pilonidal disease, dermatofibromas, pilaris cysts, pyogenic granulomas, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, scleroderma, and cardiac fibrosis. See, e.g., Tang, X et al., “Assessment of Brd4 Inhibition in Idiopathic Pulmonary Fibrosis Lung Fibroblasts and in Vivo Models of Lung Fibrosis,” Am J Pathology in press (2013). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating such benign proliferative and fibrotic disorders.

Cardiovascular disease (CVD) is a 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(1):e2-e220 (2012). Atherosclerosis, a potential cause of CVD, is a multifactorial disease characterized by dyslipidemia and inflammation. BET inhibitors are expected to be effective in atherosclerosis and related conditions due to their aforementioned anti-inflammatory effects and ability to increase the transcription of ApoA-I (the main component of HDL). Mirguet, O., et al., "From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151," Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C.W., et al., "Discovery and characterization of small molecule inhibitors of the BET family bromodomains," J Med Chem 54(11):3827-38 (2011). Accordingly, one aspect of the present invention provides compounds, compositions, and methods for treating cardiovascular diseases, including but not limited to atherosclerosis.

Upregulation of ApoA-I is considered a useful strategy for treating atherosclerosis and CVD. Degoma, E.M. and D.J. Rader, “Novel HDL-directed pharmacotherapeutic strategies,” Nat Rev Cardiol 8(5):266-77 (2011). BET inhibitors have been shown to increase ApoA-I transcription and protein expression. Mirguet, O., et al., “From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C.W., et al., “Discovery and characterization of small molecule inhibitors of the BET family bromodomains,” J Med Chem 54(11):3827-38 (2011). It has also been shown that BET inhibitors directly bind to BET proteins and inhibit their binding to acetylated histones at the ApoA-1 promoter, indicating the presence of a BET protein inhibitory complex on the ApoA-1 promoter that can be functionally disrupted by BET inhibitors. It has been concluded that BET inhibitors may be useful for treating lipid metabolism disorders 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 by regulating ApoA-1 and HDL. Elliott, D.A., et al., "Apolipoproteins in the brain: implications for neurological and psychiatric disorders," Clin Lipidol 51(4):555-573 (2010). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating cardiovascular disorders by upregulating ApoA-1.

BET inhibitors can be used to prevent and treat conditions associated with ischemia-reperfusion injury, such as, but not limited to, myocardial infarction, stroke, acute coronary syndrome (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, cardiopulmonary bypass surgery, hypertension, pulmonary, renal, hepatic, gastrointestinal or limb peripheral embolism. Thus, one aspect of the present invention provides compounds, compositions, and methods for preventing and treating conditions associated with ischemia-reperfusion injury as described herein.

Obesity-associated inflammation is a hallmark of type 2 diabetes, insulin resistance, and other metabolic disorders. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G.V., “Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99 (2010). Consistent with the ability of BET inhibitors to inhibit inflammation, genetic disruption of Brd2 in mice abolished inflammation and protected animals from obesity-induced insulin resistance. Wang, F., et al., “Brd2 disruption in mice causes severe obesity without Type 2 diabetes,” Biochem J 425(1):71-83 (2010). Brd2 has been shown to interact with PPARγ and oppose its transcriptional function. Knockdown of Brd2 in vitro promotes transcription of the PPARγ regulatory network, including those that control 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 beta 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(1):71-83 (2010). In summary, the combined effects of BET inhibitors on inflammation and metabolism reduce insulin resistance and may be useful in treating individuals with prediabetes and type 2 diabetes, as well as patients with other metabolic complications. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating and preventing metabolic disorders including, but not limited to, obesity-related inflammation, type II diabetes, and insulin resistance.

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 papillomavirus (HPV) to enable E2-mediated transcription of E2-target genes. Gagnon, D., et al., “Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein4,” J Virol 83(9):4127-39 (2009). Similarly, Brd2, Brd3, and Brd4 all bind to the latent nuclear antigen 1 (LANA1) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), thereby promoting LANA1-dependent proliferation of KSHV-infected cells. You, J., et al., “Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes,” J Virol 80(18):8909-19 (2006). BET inhibitors have been shown to inhibit Brd4-mediated recruitment of the transcription elongation complex pTEFb to the Epstein-Barr virus (EBV) viral C promoter, suggesting therapeutic value against EBV-associated malignancies. Palermo, R.D., et al., “RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus,” PLoS Pathog 7(10):e1002334 (2011). In addition, BET inhibitors reactivate HIV in models of latent T cell infection and latent mononuclear cell infection, potentially allowing viral eradication by complementary antiretroviral therapy. Zhu, J., et al., "Reactivation of Latent HIV-1 by Inhibition of BRD4," Cell Rep (2012); Banerjee, C., et al., "BET bromodomain inhibition as a novel strategy for reactivation of HIV-1," J Leukoc Biol (2012); Bartholomeeusen, K., et al., "BET bromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP," J Biol Chem (2012); Li, Z., et al., "The BETbromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4inhibition of Tat-transactivation," Nucleic Acids Res (2012).

BET inhibitors can be used to prevent and treat episomal DNA viruses, including but not limited to human papillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiency virus (Belkina, A.C. and G.V. Denis, "BETdomain co-regulators in obesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77 (2012)), adenovirus, poxvirus, hepatitis B virus and hepatitis C virus. Therefore, the present invention also provides compounds, compositions and methods for treating and preventing episomal DNA virus infections as described herein.

Some central nervous system (CNS) diseases are characterized by disorders of epigenetic processes. Brd2 haploinsufficiency has been linked to neuronal insufficiency and epilepsy. Velisek, L., et al., “GABAergic neuron deficit as anidiopathic 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 psychiatric disorders, including schizophrenia and bipolar disorder. Prinjha, R.K., J. Witherington, and K. Lee, “Place your BETs: the therapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012). Furthermore, the ability of BET inhibitors to increase ApoA-I transcription may make BET inhibitors suitable for Alzheimer's disease therapy, taking into account the proposed relationship between increased ApoA-I and Alzheimer's disease and other neurological disorders. Elliott, D.A., et al., "Apolipoproteins in the brain: implications for neurological and psychiatric disorders," Clin Lipidol 51(4):555-573 (2010). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating such CNS diseases and disorders.

BRDT is a testis-specific member of the BET protein family that 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). Genetic deletion of BRDT or inhibition of BRDT interaction with acetylated histones by BET inhibitors results in a contraceptive effect in mice, which is reversible when a small molecule BET inhibitor is used. Matzuk, M.M., et al., "Small-Molecule Inhibition of BRDT for Male Contraception," Cell 150(4):673-684 (2012); Berkovits, B.D., et al., "The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTRtruncation in round spermatids," Nucleic Acids Res 40(15):7162-75 (2012). These data suggest the potential utility of BET inhibitors as novel and effective male contraceptive methods. Therefore, another aspect of the present invention provides compounds, compositions, and methods for male contraception.

Monocyte chemoattractant 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 regulates the recruitment of monocytes from the arterial lumen to the subendothelial space through its chemotactic activity, where they develop into macrophage foam cells and initiate the formation of fatty streaks that can develop into atherosclerotic plaques. Dawson, J., et al., “Targeting monocyte chemoattractant protein-1 signaling in disease,” Expert Opin Ther Targets 7(1):35-48 (2003). The important role of MCP-1 (and its cognate receptor CCR2) in the development of atherosclerosis has been examined in different transgenic and knockout mouse models in a hyperlipidemic background. Boring, L., et al., “Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis,” Nature 394(6696):894-7(1998); Gosling, J., et al., “MCP-1deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B,” J Clin Invest 103(6):773-8(1999); Gu, L., et al., "Absence of monocyte chemoattractant protein-1reduces atherosclerosis in low density lipoprotein receptor-deficient mice," Mol Cell 2(2):275-81(1998); Aiello, R.J., et al., "Monocyte chemoattractant protein-1accelerates atherosclerosis in apolipoprotein E-deficient mice,” Arterioscler Thromb VascBiol 19(6):1518-25(1999). These reports demonstrated that ablation of MCP-1 signaling resulted in reduced macrophage infiltration of the arterial wall and reduced atherosclerotic lesion development.

The association between MCP-1 and cardiovascular disease in humans is 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 receptors are overexpressed by endothelial cells, smooth muscle cells, and infiltrating monocytes/macrophages in human atherosclerotic plaques. Nelken, N.A., et al., “Monocyte chemoattractant protein-1 in human atheromatousplaques,” J Clin Invest 88(4):1121-7 (1991). In addition, elevated circulating levels of MCP-1 are positively correlated with most cardiovascular risk factors, measures of coronary atherosclerosis burden, and the incidence of coronary heart disease (CHD). Deo, R., et al., “Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinicalatherosclerosis,” J Am Coll Cardiol 44(9):1812-8 (2004). CHD patients with the highest MCP-1 levels are those with acute coronary syndrome (ACS). de Lemos, J.A., et al., “Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes,” Circulation 107(5):690-5 (2003). In addition to playing a role in the underlying inflammation associated with CHD, MCP-1 has been shown to be involved in plaque rupture, ischemia/reperfusion injury, restenosis, and cardiac transplant rejection. 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 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 joints in RA and is overexpressed in the synovial fluid of RA patients. Koch, A.E., et al., "Enhanced production of monocytechemoattractant protein-1 in rheumatoid arthritis," J Clin Invest 90(3):772-9 (1992). Blockade of MCP-1 and MCP-1 signaling in animal models of RA has also shown the importance of MCP-1 for macrophage accumulation and proinflammatory cytokine expression associated with RA. Brodmerkel, C.M., et al., "Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344," J Immunol 175(8):5370-8(2005); Bruhl, H., et al., "Dual role of CCR2 during initiation and progression of collagen-induced arthritis: evidence for regulatory activity of CCR2+T cells," J Immunol 172(2):890-8(2004); Gong, J.H., et al., "An antagonist of monocyte chemoattractant protein 1(MCP-1) inhibitsarthritis in the MRL-lpr mouse model," J Exp Med 186(1):131-7(1997); 65. Gong, J.H., et al., "Post-onset inhibition of murine arthritis using combined chemokineantagonist therapy,” Rheumatology (Oxford 43(1):39-42(2004).

Overexpression of MCP-1 in the brain, cerebrospinal fluid (CSF) and blood has also been associated with chronic and acute MS in humans. Mahad, DJ and RM Ransohoff, "The role of MCP-1 (CCL2) and CCR2 in multiplesclerosis and experimental autoimmune encephalomyelitis (EAE)," Semin Immunol 15 (1): 23-32 (2003). During disease progression, MCP-1 is overexpressed by multiple cell types in the brain and contributes to the infiltration of macrophages and lymphocytes, which mediate the tissue damage associated with MS. Genetic deletion of MCP-1 or CCR2 in the experimental autoimmune encephalomyelitis (EAE) mouse model (a model similar to human MS) leads to resistance to the disease, mainly due to reduced macrophage infiltration into the CNS. Fife, B.T., et al., "CC chemokine receptor 2iscritical for induction of experimental autoimmune encephalomyelitis," J ExpMed 192(6):899-905(2000); Huang, D.R., et al., "Absence of monocyte chemoattractantprotein 1in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1immune response in experimental autoimmuneencephalomyelitis,” J Exp Med 193(6):713-26(2001).

Preclinical data have shown that small and macromolecular inhibitors of MCP-1 and CCR2 have potential as therapeutic agents for inflammatory and autoimmune indications. Accordingly, one aspect of the present invention provides compounds, compositions and methods for treating cardiovascular, inflammatory and autoimmune conditions associated with MCP-1 and CCR2.

Summary of the Invention

Thus, the present invention provides compounds useful for inhibiting BET protein function by binding to bromodomains, pharmaceutical compositions comprising one or more of those compounds, and the use of these compounds or compositions in treating and preventing diseases and conditions, including but not limited to cancer, autoimmunity, and cardiovascular disease. The compounds of the present invention are defined by Formula Ia or Formula IIa:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof,

in:

A is selected from a 5- or 6-membered monocyclic heterocyclic ring fused to ring B;

Provided that A cannot be substituted or unsubstituted

B is a six-membered aromatic carbocyclic ring or heterocyclic ring;

Y is selected from N, C and CH;

W ₁ is selected from N and CR ₁ ;

W ₂ is selected from N and CR ₂ ;

W ₃ is selected from N and CR ₃ ;

W ₄ and W ₅ are independently selected from N, CH and C or alternatively, W ₄ and W ₅ are both C (see, e.g., Formula Ib and Formula IIb below);

W ₁ , W ₂ and W ₃ may be the same as or different from each other;

R ₁ and R ₂ are independently selected from hydrogen, deuterium, alkyl, —OH, —NH ₂ , -alkylthio, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN;

R ₃ is selected from hydrogen, -NH ₂ , -CN, -N ₃ , halogen, and deuterium; or alternatively, R ₃ is selected from -NO ₂ , -OMe, -OEt, -NHC(O)Me, NHSO ₂ Me, cyclic amino, cyclic amido, -OH, -SO ₂ Me, -SO ₂ Et, -CH ₂ NH ₂ , -C(O)NH ₂ , and -C(O)OMe;

X is selected _{from -CH2-} , _-CH2CH2- , _-CH2CH2CH2- , -CH2CH2O- _, -CH2CH2NH-, -CH2CH2S-, _-C (O _{) -} , -C( _{O) CH2-} , _-C (O _)CH2- , -C(O) _CH2CH2- , -CH2C(O)-, -CH2CH2C(O) _{- , -C} (O) _NH- , -C(O) _O- , -C(O)S-, -C(O)NHCH2-, -C(O) _OCH2- , -C(O) _SCH2- , wherein one or more hydrogens may be independently replaced by deuterium, halogen, _-CF3 , ketone, and wherein S may be oxidized to sulfoxide or sulfone; or alternatively, X may be selected from -NH-, _-CH (OH)-, -CH( _CH3 )- and hydroxymethyl, wherein one or more hydrogens may be independently replaced by deuterium, halogen, -CF ₃ , ketone, and wherein S may be oxidized to form a sulfoxide or sulfone;

R ₄ is selected from 4-7 membered carbocyclic and heterocyclic rings; or alternatively, R ₄ is a 3 membered carbocyclic or heterocyclic ring;

D ₁ is selected from 5-membered monocyclic carbocycles and heterocycles; or alternatively, D ₁ is a monocyclic heterocycle, wherein D ₁ is connected to the B ring via a carbon atom that is part of a double bond;

Provided that if R ₃ is hydrogen and A is a 5-membered ring, then D ₁ cannot be

and provided that if D ₁ is and R ₂ and R ₃ are hydrogen and R ₁ is –OMe, then the AB bicyclic ring is not

and provided that if D ₁ is and each of R ₁ , R ₂ , and R ₃ is hydrogen, then the AB bicyclic ring is not

Unless the B ring is substituted;

and provided that if each of R ₁ , R ₂ , and R ₃ is hydrogen, then the AB bicyclic ring is not

and provided that if each of R ₁ , R ₂ , and R ₃ is hydrogen, then the AB bicyclic ring is not

In certain embodiments, A is a five-membered ring. In certain embodiments, Y is N or C. In certain embodiments, R ₁ and R ₂ are independently selected from hydrogen, deuterium, alkyl, -OH, -NH ₂ , -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide, sulfonamide, and -CN. In certain embodiments, the compound of Formula Ia is a compound of Formula Ib, i.e., wherein W ₄ and W ₅ of Formula I are both C.

In some embodiments, the compound of Formula IIa is a compound of Formula IIb, ie, wherein W ₄ and W ₅ of Formula I are both C.

In another aspect of the present invention, a pharmaceutical composition comprising a compound of Formula Ia, Formula Ib, Formula IIa and/or Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers, diluents or excipients is provided.

In another aspect of the present invention, provided are compounds of Formula Ia, Formula Ib, Formula IIa and/or Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, or pharmaceutical compositions comprising such compounds, for use in treatment, particularly in the treatment of diseases or conditions for which bromodomain inhibitors are indicated.

In yet another aspect of the present invention, provided are compounds of Formula Ia, Ib, IIa, and/or IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, in the manufacture of a medicament for treating a disease or condition for which a bromodomain inhibitor is indicated.

definition

When used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, except to the extent otherwise indicated by the context in which they are used. The following abbreviations and terms have the indicated meanings throughout.

As used herein, "cardiovascular disease" refers to diseases, disorders, and conditions of the heart and circulatory system that are mediated by BET inhibition. Exemplary cardiovascular diseases (including cholesterol or lipid-related disorders) include, but are not limited to, acute coronary syndrome, angina pectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, Hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia-reperfusion injury, ischemic heart disease, myocardial ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal atherosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient ischemic attack, and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes, syndrome X, impotence, multiple sclerosis, Parkinson's disease, and inflammatory diseases.

As used herein, "inflammatory diseases" refers to diseases, disorders, and conditions mediated by BET inhibition. Exemplary inflammatory diseases include, but are not limited to, arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, late and chronic solid organ rejection after transplantation, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves' disease, gastrointestinal irritability, conjunctivitis, atherosclerosis, coronary artery disease, angina, and arteriole disease.

As used herein, "cancer" refers to diseases, disorders, and conditions 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 a germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphoma, and activated anaplastic large cell lymphoma, neuroblastoma and primary neuroectodermal tumors, rhabdomyosarcoma, prostate cancer, breast cancer, NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute B-lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, B-cell lymphoma, melanoma, mixed lineage leukemia, multiple myeloma, promyelocytic leukemia (PML), non-Hodgkin's lymphoma, neuroblastoma, medulloblastoma, lung cancer (NSCLC, SCLC), and colon cancer.

"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 can be used in both human therapy and veterinary applications. In one embodiment, the subject is a human.

As used herein, "treatment" or "treating" refers to the improvement of a disease or disorder or at least one of its perceptible symptoms. In another embodiment, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter that is not necessarily perceptible by the patient. In another embodiment, "treatment" or "treating" refers to inhibiting the progression of a disease or disorder physically (e.g., stabilization of perceptible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may comprise lowering blood cholesterol levels.

As used herein, "prevention" or "preventing" refers to reducing the risk of acquiring a given disease or condition.

A hyphen ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, _-CONH2 is attached through a carbon atom.

"Optional" or "optionally" means 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 where it does not occur. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined below. One skilled in the art will understand that, with respect to any group containing one or more substituents, the group is not intended to introduce any sterically impractical, synthetically unfeasible, and/or inherently unstable substitution or substitution pattern.

As used herein, the term "hydrate" refers to a crystal form in which a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal structure.

As used herein, the term "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 to 8 carbon atoms, referred to herein as a ( _C2 - _C8 ) alkenyl. Exemplary 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.

As used herein, the term "alkoxy" refers to an alkyl group attached to an oxygen group (-O-alkyl-). "Alkoxy" also includes an alkenyl group attached to an oxygen group ("alkenyloxy") or an alkynyl group attached to an oxygen group ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, groups of alkyl, alkenyl, or alkynyl groups having 1-8 carbon atoms, referred to herein as (C1 _{- C8} )alkoxy groups. Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy groups.

As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1 to 8 carbon atoms, referred to herein as a (Ci _- Cg) alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, ₂ -methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

As used herein, the term "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 to 8 carbon atoms, referred to herein as a (C2 _{- C8} ) alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

As used herein, the term "amide" refers to the form _-NRaC (O)( _Rb )- or _-C (O) _NRbRc , wherein _Ra , _Rb and _Rc are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. Amides can be connected to another group through carbon, nitrogen, _Rb or _Rc . Amides can also be cyclic, for example, _Rb and _Rc can be connected to form a 3 to 8-membered ring, such as a 5 or 6-membered ring. The term "amide" encompasses groups such as sulfonamide, urea, urea radicals, carbamates, carbamic acid and cyclic versions thereof. The term "amide" also encompasses amide groups connected to a carboxyl group, for example -amide-COOH or salts such as -amide-COONa; amino groups connected to a carboxyl group (for example, -amino-COOH or salts such as -amino-COONa).

As used herein, the term "amine" or "amino" refers to the form _-NRdRe or -N( _Rd ) _Re- , wherein _Rd and _Re are independently selected from alkyl, _alkenyl , alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. The amino group can be connected to the parent molecular group through nitrogen. The amino group can also be cyclic, for example, any two of _Rd and _Re can be connected together or connected to N to form a 3 to 12-membered ring (for example, 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 _Rd or _Re is an alkyl group. In some embodiments, Rd and Re can each be optionally substituted by hydroxyl, halogen, alkoxy, ester or amino.

As used herein, the term "aryl" refers to a mono-, bi- or other polycyclic, aromatic ring system. The aryl group may optionally be fused to one or more rings selected from aryl, cycloalkyl and heterocyclyl. The aryl groups of the present disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thione. 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, monocyclic aromatic ring systems wherein the ring contains 6 carbon atoms, referred to herein as "(C ₆ )aryl".

As used herein, the term "arylalkyl" refers to an alkyl group having at least one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system, wherein the ring contains 6 carbon atoms, referred to herein as "(C ₆ )arylalkyl".

As used herein, the term "carbamate" refers to a group of the form _-RgOC (O)N( _Rh )-, _-RgOC (O)N( _Rh ) _Ri- , or -OC(O) _NRhRi , wherein _Rg , _Rh , _{and Ri} are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroarylcarbamates (e.g., wherein at least one of _Rg , _Rh , and _Ri is independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).

The term "carbocycle" as used herein refers to an aryl group or a cycloalkyl group.

As used herein, the term "carboxyl" refers to -COOH or its corresponding carboxylate (e.g., -COONa). The term carboxyl also includes "carboxycarbonyl," such as a carboxyl group attached to a carbonyl, e.g., -C(O)-COOH or a salt such as -C(O)-COONa.

The term "cyano" as used herein refers to -CN.

The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon radical of 3-12 carbon atoms or 3-8 carbon atoms derived from a cycloalkane, referred to herein as a "( _C3 - _C8 )cycloalkyl". Exemplary cycloalkyl radicals include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl radicals may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione. Cycloalkyl radicals may be fused to other cycloalkyl radicals, saturated or unsaturated aryl radicals, or heterocyclyl radicals.

As used herein, term " dicarboxylic acid " refers to the 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 can be replaced by alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic radical, 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, toxilic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid and terephthalic acid. The dicarboxylic acid also includes its carboxylic acid derivatives such as anhydrides, imides, and hydrazides (eg, succinic anhydride and succinimide).

The term "ester" refers to the structure -C(O)O-, -C(O)O- _Rj- , _-RkC (O)O-Rj- _, or _-RkC (O)O-, wherein O is not bonded to a hydrogen, and Rj and _Rk can be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. _Rk can be hydrogen, but Rj cannot be hydrogen. Esters can be cyclic, for example, a carbon atom and Rj, an oxygen atom and _Rk , or Rj and _Rk can be linked to form a 3- to 12-membered ring. Exemplary esters include, but are not limited to, alkyl esters in which at least one of Rj or _Rk is an alkyl group, such as -OC(O)-alkyl, -C(O)-O-alkyl-, and -alkyl-C(O)-O-alkyl. Exemplary esters also include aryl or heteroaryl esters, for example, where at least one of Rj or Rk is a heteroaryl group, such as pyridine, pyridazine, pyrimidine, and pyrazine, such as nicotinate. Exemplary esters also include reverse esters having the structure _-RkC (O)O-, where the oxygen is bound to the parent molecule. Exemplary reverse esters include succinate, D-arginine ester, L-arginine ester, L-lysine ester, and D-lysine ester. Esters also include carboxylic anhydrides and acyl halides.

As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms."Haloalkyl" also encompasses alkenyl or alkynyl groups substituted with one or more halogen atoms.

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or other polycyclic aromatic ring system containing one or more heteroatoms, for example 1-3 heteroatoms such as nitrogen, oxygen and sulfur. Heteroaryl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryl can also be fused to a non-aromatic ring. Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, furanyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings wherein the ring contains 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C ₂ -C ₅ )heteroaryl".

As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered rings containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocycle may be aromatic (heteroaryl) or non-aromatic. The heterocycle may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles are fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuranyl, dihydroindolinyl, dihydropyranyl, dihydrothiophenyl, dithiazolyl, furanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazine 1-Hydroxy, ...

As used herein, the terms "hydroxy" and "hydroxyl" refer to -OH.

The term "hydroxyalkyl" as used herein refers to a hydroxy group attached to an alkyl group.

The term "hydroxyaryl" as used herein refers to a hydroxy group attached to an aryl group.

As used herein, the term "ketone" refers to the structure -C(O)-Rn (e.g., acetyl, -C(O) _CH3 ) or _-Rn- C(O) _-R0- . The ketone can be attached to another group through _Rn or _R0 . _Rn or _R0 can be an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl, or _Rn or _R0 can be attached to form a 3- to 12-membered ring.

As used herein, the term "monoester" refers to an analog of a dicarboxylic acid in which one carboxylic acid is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or a salt of a carboxylic acid. Examples of monoesters include, but are not limited to, monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic acid, and maleic acid.

As used herein, the term "phenyl" refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. The phenyl group may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.

The term "thioalkyl" as used herein refers to an alkyl group attached to a sulfur (-S-alkyl-).

"Alkyl," "alkenyl," "alkynyl," "alkoxy," "amino," and "amide" groups may be optionally substituted, interrupted, or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxy, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thione, urea, and N. The substituents may be branched to form substituted or unsubstituted heterocyclic or cycloalkyl groups.

As used herein, suitable substitutions on optionally substituted substituents refer to groups that do not counteract the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates used to prepare the compounds. Examples of suitable substitutions include, but are not limited to, C _1-8 alkyl, alkenyl, or alkynyl; C _1-6 aryl, C _2-5 heteroaryl; C ₃₇ cycloalkyl; C _1-8 alkoxy; C ₆ aryloxy; -CN; -OH; oxo; halo, carboxyl; amino, such as -NH(C _1-8 alkyl), -N(C _1-8 alkyl) ₂ , -NH((C ₆ ) aryl) or -N((C ₆ ) aryl) ₂ ; formyl; ketone, such as -CO(C _1-8 alkyl), -CO((C ₆ aryl) ester, such as -CO ₂ (C _1-8 alkyl) and -CO ₂ (C ₆ aryl). Those skilled in the art can readily select suitable substitutions based on the stability and pharmacological activity of the compounds of the present disclosure and the synthetic activity.

As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

As used herein, the term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds of the present disclosure, and where possible, zwitterionic forms 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. A discussion is provided in Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Roche, E.B., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can 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, malate, 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, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). In addition to the acids mentioned above, compounds included in the present compositions that contain an amino moiety can form pharmaceutically acceptable salts with a variety of amino acids. The compounds that are acidic in nature and included in the compositions of the present invention are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal salts and alkaline earth metal salts and, in particular, calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts and iron salts.

The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. As used herein, the term "stereoisomer" is comprised of all geometric isomers, enantiomers and diastereomers. These compounds may be designated by the symbols "R" or "S" depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses a variety of stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be designated as "(±)" in nomenclature, but a skilled artisan will recognize that a structure may implicitly represent a chiral center.

Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary, (2) employing an optically active resolving agent to form a salt, or (3) directly separating the mixture of optical enantiomers on a chiral liquid chromatography column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

Geometric isomers may also exist in the compounds of the present disclosure. The present disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around carbon-carbon double bonds or around carbocyclic rings. Substituents around carbon-carbon double bonds are designated as being in "Z" or "E" configurations, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both E and Z isomers.

Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond, and "trans" refers to substituents on opposite sides of the double bond. The arrangement of substituents around a carbon ring is designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the plane of the ring, while the term "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring is designated "cis/trans."

The compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the present disclosure, even though only one tautomeric structure is depicted.

Exemplary embodiments of the present invention

The present invention provides compounds and pharmaceutical compositions comprising one or more of those compounds, wherein the structure of the compound is defined by Formula Ia, Formula Ib, Formula IIa and/or Formula IIb:

or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof,

in:

A is selected from an optionally substituted 5- or 6-membered monocyclic heterocycle fused to ring B,

Provided that A cannot be substituted or unsubstituted

B is a six-membered aromatic carbocyclic ring or heterocyclic ring;

Y is selected from N and C;

W ₁ is selected from N and CR ₁ ;

W ₂ is selected from N and CR ₂ ;

W ₃ is selected from N and CR ₃ ;

_W4 and _W5 , if present, are independently selected from N, CH and C;

W ₁ , W ₂ and W ₃ may be the same as or different from each other;

X is selected from -NH-, _-CH2- , _-CH2CH2- , _{-CH2CH2CH2- ,} -CH2CH2O- _, -CH2CH2NH- _, -CH2CH2S-, _{-C (} O ₎ -, -C( _{O) CH2-} , -C(O)CH2CH2-, -CH2C(O)-, _-CH2CH2C (O ₎ -, -C(O) _{NH-, -C (} O) _O- , _-C (O)S- _, -C(O)NHCH2-, -C(O)OCH2-, -C(O) _SCH2- , -CH(OH)-, and -CH( _CH3 )-, wherein one or more hydrogens can be independently replaced _by deuterium, hydroxymethyl, halogen, _-CF3 , ketone, and wherein S can be oxidized to form a sulfoxide or sulfone _;

_R4 is selected from 3-7 membered carbocyclic and heterocyclic rings;

D ₁ is selected from a 5-membered monocyclic heterocycle, wherein D ₁ is connected to the B ring via a carbon atom that is part of the double bond within the D ₁ ring.

R ₁ and R ₂ are independently selected from hydrogen, deuterium, alkyl, —OH, —NH ₂ , -alkylthio, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide, sulfonamide, and —CN;

R ₃ is selected from hydrogen, -NH ₂ , -CN, -N ₃ , halogen, deuterium, -NO ₂ , -OMe, -OEt, -NHC(O)Me, NHSO ₂ Me, cyclic amino, cyclic amido, -OH, -SO ₂ Me, -SO ₂ Et, -CH ₂ NH ₂ , -C(O)NH ₂ , and -C(O)OMe;

Provided that if R ₃ is hydrogen and A is a 5-membered ring, then D ₁ cannot be

and provided that if D ₁ is and R ₂ and R ₃ are hydrogen and R ₁ is –OMe, then the AB bicyclic ring is not

and provided that if D ₁ is and each of R ₁ , R ₂ , and R ₃ is hydrogen, then the AB bicyclic ring is not

Unless the B ring is substituted;

and provided that if each of R ₁ , R ₂ , and R ₃ is hydrogen, then the AB bicyclic ring is not

and provided that if each of R ₁ , R ₂ , and R ₃ is hydrogen, then the AB bicyclic ring is not

In some embodiments, the A ring of the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is optionally substituted with Z, wherein Z is selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NH pyridinyl, -NH heterocycle(C ₄ -C ₆ ), -NH carbocycle(C ₄ -C ₆ )), alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ), and alkoxy(C ₁ -C ₆ ). In some embodiments, Z is selected from

-Me, -CF ₃ , -Et, CH ₃ CH ₂ O-, CF ₃ CH ₂ -, SMe, -SOMe, -SO ₂ Me, -CN,

In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

It may be optionally substituted with groups independently selected from hydrogen, deuterium, _-NH2 , amino (such as NH( _C1 - _C5 ), carbocycle( _C1 - _C5 ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle( _C4 - _C6 ), -NHcarbocycle(C4-C6)), heterocycle( _C4 - _C6 ), carbocycle( _C4 - _C6 ), halogen, -CN, -OH, _-CF3 , alkyl( _C1 - _C6 ), thioalkyl( _C1 - _C6 ), alkenyl( _C1 - _C6 ), and alkoxy( _{C1 - C6} ); wherein X, _R4 , and _D1 are _as defined for any embodiment disclosed herein.

In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

Which may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₆ ), -NHcarbocycle(C ₄ -C ₆ ), heterocycle(C ₄ -C ₆ ), carbocycle(C ₄ -C ₆ ), halogen, -CN, -OH, -CF ₃ , alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ); wherein X, R ₄ and D ₁ are as defined for any embodiment disclosed herein.

In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

It may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₆ ), -NHcarbocycle(C ₄ -C ₆ )), heterocycle(C ₄ -C ₆ ), carbocycle(C ₄ -C ₆ ), halogen, -CN, -OH, -CF ₃ , alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ); wherein X, R ₄ and D ₁ are as defined for any embodiment disclosed herein.

In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

It may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₆ ), -NHcarbocycle(C ₄ -C ₆ )), heterocycle(C ₄ -C ₆ ), carbocycle(C ₄ -C ₆ ), halogen, -CN, -OH, -CF ₃ , alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ); wherein X, R ₄ and D ₁ are as defined for any embodiment disclosed herein.

In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

wherein Z is selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₆ ), -NHcarbocycle(C ₄ -C ₆ )), alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ); carboxyl;

_D1 is

X is selected from -CH ₂ - and -CH(CH ₃ )-; and

R ₄ is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C ₁ -C ₄ ), alkoxy (C ₁ -C ₄ ), halogen, -CF ₃ , CN and -thioalkyl (C ₁ -C ₄ ), wherein each alkyl, alkoxy and thioalkyl may be optionally substituted with F, Cl or Br.

In certain embodiments, R ₄ is a phenyl ring optionally substituted with one or more alkyl (C ₁ -C _{4 ) selected from methyl, ethyl, propyl, isopropyl, and butyl; alkoxy (C 1 -C 4} ) selected from methoxy, ethoxy, and isopropoxy; halogen selected from F and Cl; and thioalkyl (C ₁ -C ₄ ) selected from —SMe, _—SEt , _—SPr , and —Sbu.

In some embodiments, the A-B bicyclic ring in the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

wherein Z is selected from hydrogen, deuterium, -NH ₂ , amino (such as —NH(C ₁ -C ₅ ), —N(C ₁ -C ₅ ) ₂ , —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C ₄ -C ₆ ), —NHcarbocycle(C ₄ -C ₆ )), alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ).

In some embodiments, the A-B bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from

In some embodiments, the A-B bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from but not limited to

It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₇ ), -NHcarbocycle(C ₄ -C ₇ )), heterocycle(C ₄ -C ₇ ), carbocycle(C ₄ -C ₇ ), halogen, -CN, -OH, -CF ₃ , sulfone, sulfoxide, alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C _{1 -C 6} ), alkoxy(C ₁ -C ₆ ), ketone(C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide(C ₁ -C ₆ ), oxo, and thio-oxo.

In some embodiments of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, the A-B bicyclic ring is selected from

It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₇ ), -NHcarbocycle(C ₄ -C ₇ )), heterocycle(C ₄ -C ₇ ), carbocycle(C ₄ -C ₇ ), halogen, -CN, -OH, -CF ₃ , sulfone, sulfoxide, alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C _{1 -C 6} ), alkoxy(C ₁ -C ₆ ), ketone(C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide(C ₁ -C ₆ ), oxo, and thio-oxo.

In some embodiments, the A-B bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from

It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₇ ), -NHcarbocycle(C ₄ -C ₇ )), heterocycle(C ₄ -C ₇ ), carbocycle(C ₄ -C ₇ ), halogen, -CN, -OH, -CF ₃ , sulfone, sulfoxide, alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C _{1 -C 6} ), alkoxy(C ₁ -C ₆ ), ketone(C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide(C ₁ -C ₆ ), oxo, and thio-oxo.

In some embodiments, the A-B bicyclic ring of the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from

It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₇ ), -NHcarbocycle(C ₄ -C ₇ )), heterocycle(C ₄ -C ₇ ), carbocycle(C ₄ -C ₇ ), halogen, -CN, -OH, -CF ₃ , sulfone, sulfoxide, sulfonamide, alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ), alkoxy(C ₁ -C ₆ ), ketone(C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide(C ₁ -C ₆ ), oxo, and thio-oxo.

In some embodiments, the AB bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from the group which may be optionally substituted with groups independently selected from hydrogen, deuterium, _-NH2 , amino (such as -NH( _C1 - _C5 ), -N( _C1 - _C5 ) ₂ , -NHPh, -NHBn, -NHpyridinyl, -NHheterocycle( _C4 - _C7 ), -NHcarbocycle( _C4 - _C7 )), heterocycle( _C4 -C7), carbocycle( _C4 - _C7 ), halogen, -CN, -OH, _-CF3 , sulfone, sulfoxide, sulfonamide, alkyl( _C1 - _C6 ), thioalkyl( _C1 - _C6 ), alkenyl( _C1 - _C6 ), alkoxy( _C1 - _{C6 )} , ketone(C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide (C ₁ -C ₆ ), oxo, and thio-oxo.

In some embodiments, the A ring in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-membered heterocyclic ring fused to the B ring.

In some embodiments, Y in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

In some embodiments, _D1 in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-membered monocyclic heterocycle, such as, but not limited to:

It is optionally replaced by hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ , ketone (C ₁ -C ₄ ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C ₁ -C ₄ ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl (C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl (C ₁ -C ₄ ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, _D1 in the compound of any of Formulas Ia, Ib, IIa or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is a monocyclic heterocycle, which is optionally substituted by hydrogen, deuterium, alkyl ( _C1 - _C4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( _C1 - _C4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as _-NH2 , -NHMe, -NHEt, -NHiPr, -NHBu- _NMe2 , NMeEt, _-NEt2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O) _NEt2 , -C(O)NiPr), _-CF3 , CN, _-N3 , ketone ( _C1 -C4), _-C (O)Pr), -S(O)alkyl(C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl(C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl(C _{1 -C 4} ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), _each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, _D1 in the compound of any of Formula Ia, Ib, IIa and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from a 5-membered monocyclic heterocycle containing one oxygen and one or two nitrogens, wherein the heterocycle is attached to the remainder of the molecule via a carbon-carbon bond and is optionally substituted by hydrogen, deuterium, alkyl ( _C1 - _C4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( _C1 - _C4 ) (such as methoxy, ethoxy, isopropoxy), amino (such as _-NH2 , -NHMe, -NHEt, -NHiPr, -NHBu- _NMe2 , NMeEt, _-NEt2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt2 _, , -C(O)NiPr), _-CF3 , CN, _-N3 , ketone ( _C1 - _C4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl ( _C1 - _C4 ) (such as -S(O)Me, -S(O)Et), _-SO2alkyl ( _C1 - _C4 ) (such as _-SO2Me , _-SO2Et , _-SO2Pr ), -thioalkyl ( _C1 - _C4 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, _-NH2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, _D1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is isoxazole optionally substituted with hydrogen, deuterium, alkyl (C1-C4) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( _C1 - _C4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH2, -NHMe, -NHEt, -NHiPr, -NHBu-NMe2, NMeEt, -NEt2, _-NEtBu , -NHC(O ₎ NHalkyl), halogen (such as _F , Cl), amide (such as -NHC( _O) Me, -NHC(O ₎ Et, -C(O)NHMe, -C(O)NEt2, -C(O)NiPr), -CF3, CN, -N3, ketone (C1-C4), or a ketone (such as -NH2, -NHMe, -NHEt, _-NHiPr , -NHBu-NMe2, NMeEt, _-NEt2 , _-NEtBu , -NHC(O)NHalkyl). _{-C 1} -C ₄ ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl(C ₁ -C ₄ ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl(C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl(C ₁ -C ₄ ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, _D1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from a 5-membered monocyclic heterocycle, which is optionally substituted with hydrogen, deuterium, alkyl (C1-C4) (such as methyl, ethyl, propyl), each of which may be optionally substituted with hydrogen, -OH, -F and _-NH2 .

In some embodiments, _D1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from a 5-membered monocyclic heterocycle containing one oxygen and one or two nitrogens, wherein the heterocycle is linked to the remainder of the molecule via a carbon-carbon bond and is optionally substituted with hydrogen, deuterium, alkyl ( _C1 - _C4 ) such as methyl, ethyl, propyl, each of which may be optionally substituted with hydrogen, -OH, -F and _-NH2 .

In some embodiments, D ₁ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is isoxazole or pyrazole, optionally substituted with hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl), each of which may be optionally substituted with hydrogen, -OH, -F, and -NH ₂ .

In some embodiments, D1 in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is In some embodiments, _D1 in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is In some embodiments, _D1 in the compound of any of Formula _Ia , Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is

In some embodiments, W ₁ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CR ₁ .

In some embodiments, W ₂ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CR ₂ .

In some embodiments, at least one of W ₁ and W ₂ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

In some embodiments, W ₁ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CH.

In some embodiments, _W2 in the compound of any of Formula Ia, Ib, IIa, and IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is _CR2 , wherein _R2 is selected from hydrogen, deuterium, -OH, _-NH2 , methyl, halogen, and -CN.

In some embodiments, W ₂ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CH.

In some embodiments, W ₄ and W ₅ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, are carbon.

In some embodiments, at least one of W ₄ and W ₅ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

In some embodiments, W ₃ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

In some embodiments, W ₃ in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CR ₃ , wherein R ₃ is selected from hydrogen, —NH ₂ , and halogen.

In some embodiments, R ₃ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from hydrogen and -NH ₂ .

In some embodiments, R ₃ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is —NH ₂ .

In some embodiments, X in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer _{, pharmaceutically} acceptable salt, or hydrate thereof _, is selected from _-CH2- , -CH2CH2-, _-CH2CH2CH2- , -CH2CH2O-, -CH2CH2NH-, _-CH2CH2S-, -C _{(O )} -, _{-C(O) NH- ,} -C(O ₎ O-, -C(O)S-, wherein one or more hydrogens can be independently replaced by deuterium, halogen, and wherein S can be oxidized to a sulfoxide or sulfone.

In some embodiments, X in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from —CH ₂ — and —C(O)—.

In some embodiments, X is selected from _-CH2- , -CH(CH3)-, -CH(OH)-, -NH-, _CH2CH2- , wherein one or more hydrogens may be independently replaced _by deuterium or halogen.

In some embodiments, X is selected from _-CH2- , CH( _CH3 )-, and -NH-, wherein one or more hydrogens may be independently replaced by deuterium or halogen.

In some embodiments, X is selected from _-CH2- , -CH( _CH3 )-, wherein one or more hydrogens may be independently replaced by deuterium or halogen.

In some embodiments, X in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is _-CH2- .

In some embodiments, R ₁ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from hydrogen, deuterium, alkyl, —OH, —NH ₂ , -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN.

In some embodiments, _R2 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from hydrogen, deuterium, alkyl, -OH, _-NH2 , -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and -CN.

In some embodiments, R ₁ and R ₂ in the compound of any of Formula I, Formula Ia, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof are independently selected from hydrogen, deuterium, alkyl, -NH ₂ , -thioalkyl, alkoxy, amino, amide, halogen, carbocycle, heterocycle, and -CN.

In some embodiments, R ₁ and R ₂ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, are independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₆ ), -NH ₂ , -thioalkyl (C ₁ -C ₆ ), alkoxy (C ₁ -C ₆ ), amino and amide.

In some embodiments, R ₁ and R ₂ are hydrogen.

In some embodiments, at least one of R ₁ , R _{2 , and R 3} in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula _IIb , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is not hydrogen.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-6 membered carbocyclic ring and a heterocyclic ring.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-6 membered heterocycle.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from a 5-6 membered heterocyclic ring containing 1 or 2 nitrogen atoms, such as unsubstituted and substituted pyrimidinyl rings, which are optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ , ketone (C ₁ -C ₄ ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C ₁ -C ₄ ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl (C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl (C ₁ -C ₄ ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from a 6-membered heterocyclic ring containing at least one nitrogen, such as unsubstituted and substituted pyridyl rings, which are optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ , ketone (C ₁ -C ₄ ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C ₁ -C ₄ ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl (C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl (C ₁ -C ₄ ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R ₄ in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is isoxazole or pyrazole, which is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ -C(O)OEt, -C(O) _{OBu )} , each _{of which} may be optionally substituted with hydrogen, _{F , Cl} , _Br , -OH _{, -NH 2 ,} -NHMe, -OMe, -SMe _{, oxo} and/or thio-oxo _.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-membered heterocyclic ring containing one or two nitrogens.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from a 5-6 membered carbocyclic ring, such as a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ -C(O) _OBu ) _, each _{of which} may _be optionally _substituted with hydrogen _{, F} , _Cl , _Br , -OH, _{-NH 2 ,} -NHMe, -OMe, -SMe, _oxo and/or _thio -oxo.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as _{-NH 2} , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O _{)Et, -C(O)NHMe, -C(O)NEt 2 ,} -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, _-NHiPr , -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), _-C (O)OEt, -C(O)OBu), _{each of which may} be optionally substituted with _hydrogen , _{F , Cl, Br, -OH, -NH 2 , -NHMe ,} -OMe, -SMe, _oxo and/or _{thio -} oxo.

In some embodiments, _R4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from aryl, which is optionally independently selected from hydrogen, deuterium, alkyl ( _C1 - _C4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( _C1 - _C4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as _-NH2 , -NHMe, -NHEt, -NHiPr, -NHBu- _NMe2 , NMeEt, -NEt2, _-NEtBu , -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O) _NEt2 , -C(O)NiPr), _-CF3 , CN, _-N3 , ketone (C1-C4), ... _-C (O)OEt, -C(O)OBu), _{each of which may} be optionally substituted with _hydrogen , _{F , Cl, Br, -OH, -NH 2 , -NHMe ,} -OMe, -SMe, _oxo and/or _{thio -} oxo.

In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, -XR ₄ is selected from -CH ₂ aryl.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from pyridinyl, which is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ -C(O)OEt, -C(O) _{OBu )} , each _{of which} may be optionally substituted with hydrogen, _{F , Cl} , _Br , -OH _{, -NH 2 ,} -NHMe, -OMe, -SMe _{, oxo} and/or thio-oxo _.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ , ketone (C ₁ -C 4 ) -C(O)OEt, -C( _O ) _OBu ) _{, each of} which may be optionally substituted with hydrogen _{, F} , _Cl , _{Br ,} -OH, -NH2, -NHMe, -OMe, -SMe, _oxo and/or thio-oxo _.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-6 membered carbocyclic ring.

In some embodiments, _R4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from lower cycloalkyl ( _C3 - _C6 ) and phenyl rings, which are optionally optionally substituted with one or more groups independently selected from deuterium, alkyl ( _C1 - _C4 ) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C1- _C4 ) (such as methoxy, ethoxy and isopropoxy), halogen (such as F and Cl), _-CF3 , CN and -thioalkyl ( _C1 - _C4 ) (such as, for example, -SMe, -SEt, -SPr and -Sbu), wherein _each of the alkyl, alkoxy and thioalkyl groups may be optionally substituted with F, Cl or Br.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, and butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, and isopropoxy), halogen (such as F and Cl), —CF ₃ , CN, and -thioalkyl (C ₁ -C ₄ ) (such as, for example, —SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl, or Br.

In some embodiments, R ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is aryl, which is optionally substituted with one or more groups independently selected from deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, and butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, and isopropoxy), halogen (such as F and Cl), —CF ₃ , CN, and -thioalkyl (C ₁ -C ₄ ) (such as, for example, —SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl, or Br.

In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclic ring is selected from

which may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₇ ), -NHcarbocycle(C ₄ -C ₇ )), heterocycle(C ₄ -C ₇ ), carbocycle(C ₄ -C ₇ ), halogen, -CN, -OH, -CF ₃ , sulfone, sulfoxide, alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C _{1 -C 6} ), alkoxy(C ₁ -C ₆ ), ketone(C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide(C ₁ -C ₆ ), oxo, and thio-oxo;

_D1 is

X is selected from -CH ₂ - and -C(O)-;

R ₄ is a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ , ketone (C ₁ -C ₄ ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C ₁ -C ₄ ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl (C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl (C ₁ -C ₄ ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, in the compound of any of Formula Ia, Ib, IIa and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, the AB bicyclic ring is selected from the group which may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C ₄ -C ₇ ), -NH carbocycle (C ₄ -C ₇ )), heterocycle (C ₄ -C ₇ ), carbocycle (C ₄ -C ₇ ), halogen, -CN, -OH, -CF ₃ , sulfone, sulfoxide, sulfonamide, alkyl (C ₁ -C ₆ ), thioalkyl (C ₁ -C ₆ ), alkenyl (C ₁ -C ₆ ), alkoxy (C ₁ -C _{6 ),} ), ketone (C ₁ -C ₆ ), ester, urea, carboxylic acid, carbamate, amide (C ₁ -C ₆ ), oxo, and thio-oxo.

_D1 is

X is selected from -CH ₂ -, -CH(CH ₃ )-, -CH(OH)-, and -NH-;

R ₄ is a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH ₂ , -NHMe, -NHEt, -NHiPr, -NHBu-NMe ₂ , NMeEt, -NEt ₂ , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt ₂ , -C(O)NiPr), -CF ₃ , CN, -N ₃ , ketone (C ₁ -C ₄ ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C ₁ -C ₄ ) (such as -S(O)Me, -S(O)Et), -SO ₂ alkyl (C ₁ -C ₄ ) (such as -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr), -thioalkyl (C ₁ -C ₄ ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, -XR ₄ in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is -CH ₂ aryl.

In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclic ring is selected from

wherein Z is selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₆ ), -NHcarbocycle(C ₄ -C ₆ )), alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ), carboxyl;

D ₁ is and

X is selected from -CH ₂ - and -CH(CH ₃ )-; and

R ₄ is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C ₁ -C ₄ ), alkoxy (C ₁ -C ₄ ), halogen, -CF ₃ , CN and -thioalkyl (C ₁ -C ₄ ), wherein each alkyl, alkoxy and thioalkyl may be optionally substituted with F, Cl or Br.

In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclic ring is selected from

wherein Z is selected from hydrogen, deuterium, -NH ₂ , amino (such as -NH(C ₁ -C ₅ ), -N(C ₁ -C ₅ ) ₂ , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C ₄ -C ₆ ), -NHcarbocycle(C ₄ -C ₆ )), alkyl(C ₁ -C ₆ ), thioalkyl(C ₁ -C ₆ ), alkenyl(C ₁ -C ₆ ) and alkoxy(C ₁ -C ₆ ); carboxyl;

_D1 is

X is selected from -CH ₂ - and -CH(CH ₃ )-; and

R ₄ is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C ₁ -C ₄ ) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C ₁ -C ₄ ) (such as methoxy, ethoxy and isopropyloxy), halogen (such as F and Cl), —CF ₃ , CN and -thioalkyl (C ₁ -C ₄ ) (such as, for example, —SMe, —SEt, —SPr and —Sbu), wherein each alkyl, alkoxy and thioalkyl may be optionally substituted with F, Cl or Br.

In certain embodiments of the present invention, the compound of Formula I, Formula Ia, or Formula II is selected from:

9-Benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine;

3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine;

N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one; and

1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one.

In certain embodiments of the present invention, the compound of Formula I, Formula Ia, or Formula II is selected from:

9-Benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine;

3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine;

N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one;

1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one;

4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

4-(1-(cyclopropylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one;

4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-amine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1H-benzo[d]imidazole-2,4-diamine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid methyl ester;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide

4-(Aminomethyl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

5-(3,5-Dimethylisoxazol-4-yl)-N-phenyl-1H-pyrrolo[3,2-b]pyridin-3-amine

6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide

6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5(4H)-one

4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,5-dimethylisoxazole

6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine

6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-benzo[d]imidazol-4-amine

6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N,N-dimethyl-1H-benzo[d]imidazol-4-amine

3,5-Dimethyl-4-(1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(1-Benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridine 5-oxide

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine

4-(1-Benzyl-3-bromo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-ylcarboxylate

4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzamide

4-(1-Benzyl-3-nitro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

3,5-Dimethyl-4-(3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)isoxazole

3,5-Dimethyl-4-(1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(3-(4-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-chlorobenzyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(3-(4-fluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

3,5-Dimethyl-4-(3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)isoxazole

3,5-Dimethyl-4-(1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(1-(4-Fluorobenzyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-Fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(5-(4-Fluorobenzyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-3,5-dimethylisoxazole

4-(1-(4-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

4-(1-(4-Fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-indazol-4-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one

3-((5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)amino)benzonitrile

4-(1-(4-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-Benzyl-2-ethoxy-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3,5-dimethylisoxazole

4-(1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(cyclopropylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)acetamide

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)ethanesulfonamide

4-(1-Benzyl-4-methoxy-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

7-amino-3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one

3,5-Dimethyl-4-(2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

3,5-Dimethyl-4-(2-methyl-1-(thien-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile

4-(1-Benzyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

3,5-Dimethyl-4-(2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

3,5-Dimethyl-4-(2-methyl-1-((5-methylthien-2-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(1-((5-chlorothien-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

5-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiophene-2-carbonitrile

6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridine 4-oxide

6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-5-yl acetate

1-Benzyl-6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-4-nitro-1H-benzo[d]imidazole

1-Benzyl-6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenol

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carbonitrile

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile

4-(1-Benzyl-3-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-Amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

1-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

4-(1-Benzyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-chlorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-4-amine

4-(1-(3,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

6-(3,5-Dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine

2-(azetidin-1-yl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine

3,5-Dimethyl-4-(1-(thien-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)isoxazole

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine

1-(3,4-Dichlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

1-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-indazol-4-amine

6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2(3H)-one

1-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

6-(3,5-dimethylisoxazol-4-yl)-1-(thien-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine

3,5-Dimethyl-4-(2-methyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-2,4-diamine

6-(3,5-Dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide

6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

4-(1-(cyclobutylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(1-(cyclopentylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(ethylamino)-1H-benzo[d]imidazol-4-yl)acetamide

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)acetamide

4-(1-Benzyl-4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-1H-benzo[d]imidazol-2(3H)-one

4-(2-(azetidin-1-yl)-1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-((5-chlorothien-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

(S)-3,5-Dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole

(R)-3,5-Dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole

6-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine

4-(1-Benzyl-2-ethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2(3H)-one

N-(2-(azetidin-1-yl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)acetamide

1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine

1-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

1-(Cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

6-(3,5-Dimethylisoxazol-4-yl)-N2-ethyl-1-(1-phenylethyl)-1H-benzo[d]imidazole-2,4-diamine

4-(1-Benzyl-4-nitro-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(1-Benzyl-2-(4-methylpiperazin-1-yl)-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxyethyl)-4-nitro-1H-benzo[d]imidazol-2-amine

4-(1-Benzyl-2-cyclopropyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-methoxyethyl)-1H-benzo[d]imidazole-2,4-diamine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-4-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-amine

1-Benzyl-N6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4,6-diamine

(S)-6-(3,5-Dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine

(R)-6-(3,5-Dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine

1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine

N,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-N-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-nitro-1H-benzo[d]imidazol-2-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-methyl-1H-benzo[d]imidazole-2,4-diamine

N2,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2,4-diamine

N,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine

1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine

N-(1-Benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol-4-amine

4-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinoxalin-2(1H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole-2,4-diamine

4-(1-Benzyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine

1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1H-benzo[d]imidazole-2,4-diamine

4-Amino-1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-Amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-fluoro-1H-benzo[d]imidazol-2(3H)-one

N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide

4-(1-Benzyl-2-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(1-Benzyl-2-methyl-4-(methylsulfonyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine

1-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

(S)-6-(3,5-Dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-ol

(R)-4-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

4-(1-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

1-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine

4-Amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione

(S)-4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

(R)-4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

4-(1-Benzyl-2,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)morpholine

1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-2-one

1-Benzyl-2-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-amine

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(4-Bromo-2-methyl-1-phenethyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(4-Bromo-2-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(7-Bromo-2-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole

4-(4-Bromo-2-methyl-1-(2-phenoxyethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(7-Bromo-2-methyl-1-(2-phenoxyethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole

4-(1-(cyclohexylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(cyclopentylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(cyclobutylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(1-Benzyl-2-(pyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

2-((1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethanol

1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-3-ol

1-Benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

4-amino-1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one

(4-Bromo-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone

1-Benzyl-2-methyl-6-(5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine

1-(Cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

1-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

N-(1-Benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-amine

1-Benzyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazo[4,5-b]pyridine

4-((1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclohexanol

4-(1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

4-(2-(azetidin-1-yl)-1-(cyclopentylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

4-(2-(azetidin-1-yl)-1-(cyclobutylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

N1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-N2,N2-dimethylethane-1,2-diamine

4-(1-Benzyl-2-(piperazin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-Benzyl-N-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

3-(((1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)methyl)benzonitrile;

(R)-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

(S)-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

4-(1-benzyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-carboxamide;

1-(Cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

N1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclohexane-1,4-diamine;

1-Benzyl-N-(cyclohexylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(oxetan-3-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine;

1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine;

1-Benzyl-N-cyclohexyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

4-(1-benzyl-2-(pyridin-3-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

1-((1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)-2-methylpropan-2-ol;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

(R)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one;

4-(1-benzyl-7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(thiazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboximidazole;

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamide;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)azetidin-3-ol;

4-(1-benzyl-2-(pyridin-4-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine; and

3-(1-Benzyl-1H-benzo[d]imidazol-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one;

or a stereoisomer, tautomer, salt or hydrate thereof.

Another aspect of the present invention provides methods for inhibiting the function of BET proteins by binding to bromodomains, and their use in treating and preventing diseases and conditions in mammals (e.g., humans), comprising administering a therapeutically effective amount of a compound of Formula I, Formula Ia, and/or Formula II.

In one embodiment, due to the potent effects of BET inhibitors on IL-6 and IL-17 transcription in vitro, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II are useful as therapeutic agents for inflammatory disorders in which IL-6 and/or IL-17 are implicated in the disease. The following autoimmune diseases are suitable for therapeutic inhibition of BET by administering a compound of Formula I, Formula Ia, and/or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate of Formula I, Formula Ia, and/or Formula II, due to the significant effects of IL-6 and/or IL-17: acute disseminated encephalomyelitis (Ishizu, T., et al., "CSF cytokine and chemokine profiles in acute disseminated encephalomyelitis," J Neuroimmunol 175(1-2):52-8 (2006)), agammaglobulinemia (Gonzalez-Serrano, M.E., et al., "Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia," J Clin Immunol 32(5):967-74(2012)), allergic diseases (McKinley, L., et al., “TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,” J Immunol 181(6):4089-97(2008)), ankylosing spondylitis (Taylan, A., et al., “Evaluation of the T helper 17 axis in ankylosing spondylitis,” Rheumatol Int 32(8):2511-5(2012)), anti-GBM/anti-TBM nephritis (Ito, Y., et al., “Pathogenic significance of interleukin-6 in a patient with antiglomerular basement membrane antibody-induced glomerulonephritis with multinucleated giant cells,” Am J Kidney Dis 26(1):72-9(1995)), antiphospholipid syndrome (Soltesz, P., et al., “Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction,” Rheumatology (Oxford) 47(11):1628-34(2008)), autoimmune aplastic anemia (Gu, Y., et al., “Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 and tumornecrosis factor-alpha in aplastic anaemia,” Br J Haematol 142(1):109-14(2008)), autoimmune hepatitis (Zhao, L., et al., “Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression,” PLoS One6(4):e18909(2011)), autoimmune inner ear diseases (Gloddek, B., et al., “Pharmacological influence on inner ear endothelial cells in relation to thepathogenesis of sensorineural hearing loss,” Adv Otorhinolaryngol 59:75-83(2002)), autoimmune myocarditis (Yamashita, T., et al., “IL-6-mediated Th17 differentiation through RORgammat is essential for the initiation ofexperimental autoimmune myocarditis,” Cardiovasc Res 91(4):640-8(2011)), autoimmune pancreatitis (Ni, J., et al., “Involvement of Interleukin-17A in Pancreatic Damage in Rat Experimental Acute Necrotizing Pancreatitis,” Inflammation(2012)), autoimmune retinopathy (Hohki, S., et al., “Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses,” Exp Eye Res 91(2):162-70(2010)), autoimmune thrombocytopenic purpura (Ma, D., et al., “Profile of Th17 cytokines (IL-17, TGF-beta, IL-6) and Th1 cytokine (IFN-gamma) in patients with immune thrombocytopenic purpura,” Ann Hematol 87(11):899-904(2008)), Behçet’s disease (Yoshimura, T., et al., “Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis,” Rheumatology (Oxford) 48(4):347-54 (2009)), bullous pemphigoid (D'Auria, L., P. et al., “Cytokines and bullous pemphigoid,” Eur Cytokine Netw 10(2):123-34 (1999)), Castleman's disease (El-Osta, H.E. and R. Kurzrock, “Castleman's disease:from basic mechanisms to molecular therapeutics,” Oncologist 16(4):497-511 (2011)), celiac disease (Lahdenpera, A.I., et al., “Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes,” Clin Exp Immunol 167(2):226-34(2012)), Churg-Strauss syndrome (Fujioka, A., 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 (Holtta, V., 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 (Shibuya, M., et al., “Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis,” Mod Rheumatol(2012)), dry eye syndrome (De Paiva, C.S., et al., “IL-17 disrupts corneal barrier following desiccating stress,” Mucosal Immunol 2(3):243-53(2009)), spontaneous mixed cryoglobulinemia (Antonelli, A., et al., “Serum levels of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia,” Arthritis Rheum 60(12):3841-7(2009)), dermatomyositis (Chevrel, G., et al., “Interleukin-17 increases the effects of IL-1beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis,” J Neuroimmunol 137(1-2):125-33(2003)), Devic's disease (Linhares, U.C., et al., “The Ex Vivo Production of IL-6and IL-21by CD4(+)T Cells is Directly Associated with Neurological Disability in Neuromyelitis Optica Patients,” J Clin Immunol (2012)), encephalitis (Kyburz, D. and M. Corr, “Th17 cells generated in the absence of TGF-beta induce experimental allergic encephalitis upon adoptive transfer,” Expert Rev Clin Immunol 7(3):283-5(2011)), eosinophilic esophagitis (Dias, P.M. and G. Banerjee, “The Role of Th17/IL-17 on Eosinophilic Inflammation,” J Autoimmun (2012)), eosinophilic fasciitis (Dias, P.M. and G. Banerjee, “The Role of Th17/IL-17 on Eosinophilic Inflammation,” J Autoimmun (2012)), erythema nodosum (Kahawita, I.P. and D.N. Lockwood, “Towards understanding the pathology of erythema nodosum leprosum,”Trans R Soc Trop Med Hyg 102(4):329-37(2008)), giant cell arteritis (Deng, J., et al., “Th17 and Th1 T-cell responses in giant cell arteritis,” Circulation 121(7):906-15(2010)), glomerulonephritis (Ooi, J.D., et al., “Review: T helper 17 cells: their role in glomerulonephritis,” Nephrology (Carlton) 15(5):513-21(2010)), Goodpasture's syndrome (Ito, Y., et al., “Pathogenic significance of interleukin-6 in a patient with antiglomerular basement membrane antibody-induced glomerulonephritis with multinucleated giant cells,” Am J Kidney Dis 26(1):72-9 (1995)), granulomatosis with polyangiitis (Wegener's) (Nakahama, H., et al., “Distinct responses of interleukin-6 and other laboratory parameters to treatment in a patient with Wegener's granulomatosis,” Intern Med 32(2):189-92 (1993)), Graves' disease (Kim, S.E., et al., “Increased serum interleukin-17 in Graves' ophthalmopathy,” Graefes Arch Clin Exp Ophthalmol 250(10):1521-6 (2012)), Guillain-Barré syndrome (Lu, M.O. and J. Zhu, “The role of cytokines in Guillain-Barré syndrome,” J Neurol 258(4):533-48(2011)), Hashimoto’s thyroiditis (Figueroa-Vega, N., et al., “Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis,” J Clin Endocrinol Metab 95(2):953-62(2009)), hemolytic anemia (Xu, L., et al., “Critical role of Th17 cells in development of autoimmune hemolytic anemia,” Exp Hematol (2012)), Henoch-Schonlein purpura (Jen, H.Y., et al., “Increased serum interleukin-17 and peripheral Th17 cells in children with acute Henoch-Schonlein purpura,” Pediatr Allergy Immunol 22(8):862-8(2011)), IgA nephropathy (Lin, F.J., et al., “Imbalance of regulatory T cells to Th17 cells in IgA nephropathy,” Scand J Clin Lab Invest 72(3):221-9(2012)), inclusion body myositis (Baron, P., et al., “Production of IL-6 by human myoblasts stimulated with Abeta: relevance in the pathogenesis of IBM,” Neurology 57(9):1561-5(2001)), type I diabetes (Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012)), interstitial cystitis (Lamale, L.M., et al., “Interleukin-6, histamine, and methylhistamine as diagnostic markers for interstitial cystitis,” Urology 68(4):702-6(2006)), Kawasaki disease (Jia, S., et al., “The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease,” Clin Exp Immunol 162(1):131-7(2010)), leukocytoclastic vasculitis (Min, C.K., et al., “Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient；association with pro-inflammatory cytokines,” Eur J Haematol 76(3):265-8(2006)), lichen planus (Rhodus, N.L., et al., “Proinflammatory cytokine levels in saliva before and after treatment of (erosive) oral lichen planus with dexamethasone,” Oral Dis 12(2):112-6(2006)), lupus erythematosus (SLE) (Mok, M.Y., et al., “The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity insystemic lupus erythematosus,” J Rheumatol 37(10):2046-52(2010)), microscopic polyangiitis (Muller Kobold, A.C., et al., “In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis,” Clin Exp Rheumatol 17(4):433-40(1999)), multiple sclerosis (Jadidi-Niaragh, F. and Mirshafiey A., “Th17 cell, the new player of neuroinflammatory process in multiple sclerosis,” Scand J Immunol 74(1):1-13(2011)), myasthenia gravis (Aricha, R., et al., “Blocking of IL-6suppresses experimental autoimmune myasthenia gravis,” J Autoimmun 36(2):135-41(2011)), myositis (Chevrel, G., et al., “Interleukin-17increases the effects of IL-1beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis,” J Neuroimmunol 137(1-2):125-33(2003)), optic neuritis (Icoz, S., et al., “Enhanced IL-6production in aquaporin-4antibody positive neuromyelitis optica patients,” Int J Neurosci 120(1):71-5(2010)), pemphigus (Lopez-Robles, E., et al., “TNFalpha and IL-6are mediators in the blistering process of pemphigus,” Int J Dermatol 40(3):185-8(2001)), POEMS syndrome (Kallen, K.J., et al., “New developments in IL-6dependent biology and therapy: where do we stand and what are the options?” Expert Opin Investig Drugs 8(9):1327-49(1999)), polyarteritis nodosa (Kawakami, T., et al., “Serum levels of interleukin-6 in patients with cutaneous polyarteritis nodosa,” Acta Derm Venereol 92(3):322-3(2012)), primary biliary cirrhosis (Harada, K., et al., “Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis,” Clin Exp Immunol 157(2):261-70(2009)), psoriasis (Fujishima, S., et al., “Involvement of IL-17F via the induction of IL-6 in psoriasis,” Arch Dermatol Res 302(7):499-505(2010)), psoriatic arthritis (Raychaudhuri, S.P., et al., IL-17 receptor and its functional significance in psoriatic arthritis,” Mol Cell Biochem 359(1-2):419-29(2012)), pyoderma gangrenosum (Kawakami, T., et al., “Reduction of interleukin-6, interleukin-8, and anti-phosphatidylserine-prothrombin complex antibody by granulocyte and monocyte adsorption apheresis in a patient with pyodermagangrenosum and ulcerative colitis,” Am J Gastroenterol 104(9):2363-4(2009)), relapsing polychondritis (Kawai, M., et al., “Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsingpolychondritis,” Rheumatology(Oxford)48(3):318-9(2009)), rheumatoid arthritis (Ash, Z. and P. Emery, “The role of tocilizumab in the management of rheumatoidarthritis,” Expert Opin Biol Ther,12(9):1277-89(2012)), sarcoidosis (Belli, F., et al., “Cytokines assay in peripheral blood and bronchoalveolar lavage in the diagnosis and staging of pulmonary granulomatous diseases,” Int J Immunopathol Pharmacol 13(2):61-67(2000)), scleroderma (Radstake, T.R., et al., “The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes,” PLoS One, 4(6):e5903(2009)), Sjögren's syndrome (Katsifis, G.E., et al., “Systemic and local interleukin-17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis,” Am J Pathol 175(3):1167-77(2009)), Takayasu's arteritis (Sun, Y., et al., “MMP-9 and IL-6 are potential biomarkers for disease activity in Takayasu's arteritis,” Int J Cardiol 156(2):236-8(2012)), transverse myelitis (Graber, J.J., et al., “Interleukin-17 in transverse myelitis and multiple sclerosis,” J Neuroimmunol 196(1-2):124-32(2008)), ulcerative colitis (Mudter, J. and M.F. Neurath, “Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance,” Inflamm Bowel Dis 13(8):1016-23(2007)), uveitis (Haruta, H., et al., “Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis,” Invest Ophthalmol Vis Sci 52(6):3264-71(2011)), and vitiligo (Bassiouny, D.A. and O. Shaker, "Role of interleukin-17 in the pathogenesis of vitiligo," Clin Exp Dermatol 36(3):292-7115.(2011)). Therefore, the present invention includes compounds of Formula I, Formula Ia and/or Formula II, 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 proinflammatory 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 (Bradley, D.T. and S.E. Kountakis, “Role of interleukins and transforming growth factor-beta in chronic rhinosinusitis and nasal polyposis,” Laryngoscope 115(4):684-6 (2005)), pneumonia (Besnard, A.G., et al., “Inflammasome-IL-1-Th17 response in allergic lung inflammation,” J Mol Cell Biol 4(1):3-10 (2012)), osteomyelitis (Yoshii, T., et al., “Local levels of interleukin-1beta, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to staphylococcus aureus,” Cytokine 19(2):59-65 (2002)), gastritis (Bayraktaroglu, T., et al., “Serum levels of tumor "Necrosis factor-alpha, interleukin-6 and interleukin-8 are not increased in dyspeptic patients with Helicobacter pylori-associated gastritis," Mediators Inflamm13(1):25-8 (2004)), "STAT3 activation via interleukin6trans-signalling contributes to ileitis in SAMP1/Yit" mice," Gut55(9):1263-9.(2006)), gingivitis (Johnson, R.B., et al., "Interleukin-11and IL-17and the pathogenesis of periodontal disease," J Periodontol75(1):37-43(2004)), appendicitis (Latifi, S.Q., et al., "Persistent elevation of seruminterleukin-6inintraabdominal sepsis identifies those with prolonged length of stay,” JPediatr Surg 39(10):1548-52(2004)), irritable bowel syndrome (Ortiz-Lucas, M., et al., “Irritable bowel syndrome immune hypothesis. Part two: the role of cytokines,” Rev Esp Enferm Dig 102(12):711-7(2010)), tissue transplant rejection (Kappel, L.W., et al., “IL-17 contributes to CD4-mediated graft-versus-host disease,” Blood 113(4):945-52(2009)), chronic obstructive pulmonary disease (COPD) (Traves, S.L. and L.E. Donnelly, “Th17 cells in airway diseases,” Curr Mol Med 8(5):416-26(2008)), septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc.) (Nicodeme, E., et al., “Suppression of inflammation by a synthetic histone mimic,” Nature 468(7327):1119-23(2010)), osteoarthritis (Chen, L., et al., “IL-17RAaptamer-mediated repression of IL-6inhibits synovium inflammation in a murine model of osteoarthritis,” Osteoarthritis Cartilage 19(6):711-8(2011)), acute gout (Urano, W., et al., “The inflammatory process in the mechanism of decreased serumuric acid concentrations during acute gouty arthritis,” J Rheumatol 29(9):1950-3(2002)), acute lung injury (Traves, S.L. and L.E.Donnelly, “Th17 cells in airway diseases,” Curr Mol Med8(5):416-26(2008)), acute renal failure (Simmons, E.M., et al., “Plasmacytokine levels predict mortality in patients with acute renal failure,” Kidney Int65(4):1357-65(2004)), burns (Paquet, P. and G.E. Pierard, “Interleukin-6 and the skin,” Int Arch Allergy Immunol 109(4):308-17(1996)), Herxheimer reaction (Kaplanski, G., et al., “Jarisch-Herxheimer reaction complicating the treatment of chronic Qfever endocarditis: elevated TNFalpha and IL-6 serum levels,” J Infect37(1):83-4(1998)), and SIRS associated with viral infection (Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012)). Therefore, the present invention includes compounds of Formula I, Formula Ia and/or Formula II, 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.

In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used to treat rheumatoid arthritis (RA) and multiple sclerosis (MS). There is strong proprietary data for the efficacy of BET inhibitors in preclinical models of RA and MS. R. Jahagirdar, S.M. et al., "An Orally Bioavailable Small Molecule RVX-297 Significantly Decreases Disease in a Mouse Model of Multiple Sclerosis," World Congress of Inflammation, Paris, France (2011). Both RA and MS are characterized by dysregulation of the IL-6 and IL-17 inflammatory pathways (Kimura, A. and T. Kishimoto, "IL-6: regulator of Treg/Th17 balance," Eur J Immunol 40(7):1830-5 (2010)) and are therefore particularly sensitive to BET ratio inhibition. In another embodiment, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II can be used to treat sepsis and related afflictions. BET ratio inhibition has been shown to inhibit the development of sepsis in preclinical models in both published (Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic," Nature 468(7327):1119-23 (2010)) and proprietary data, in part by inhibiting IL-6 expression.

In one embodiment, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds, can be used to treat cancer. Cancers that overexpress, translocate, amplify, or rearrange c-myc or other myc family oncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition. Delmore, J.E., et al., "BET bromodomain inhibition as an atherapeutic strategy to target c-Myc," Cell 146(6):904-17 (2010); Mertz, J.A., et al., "Targeting MYC dependence in cancer by inhibiting BET bromodomains," Proc Natl Acad Sci USA 108(40):16669-74 (2011). These cancers include, but are not limited to, B acute lymphoblastic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, superficial spreading melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, and small cell lung cancer. Vita, M. and M. Henriksson, "The Myc oncoprotein as a therapeutic target for human cancer," Semin Cancer Biol 16(4):318-30 (2006).

In one embodiment, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds can be used to treat cancers caused by abnormal regulation (overexpression, translocation, etc.) of BET proteins. These include, but are not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation to the nutlin1 gene) (French, C.A., “NUT midline carcinoma,” Cancer Genet Cytogenet 203(1):16-20 (2010)), B cell lymphoma (Brd2 overexpression) (Greenwald, R.J., et al., “E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia,” Blood 103(4):1475-84 (2004)), non-small cell lung cancer (BrdT overexpression) (Grunwald, C., et al., “Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer,” Int J Cancer 118(10):2522-8 (2006)), esophageal cancer and head and neck squamous cell carcinoma (BrdT overexpression) (Scanlan, M.J., et al., “Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9," Cancer Lett 150(2):55-64(2000)), and colon cancer (Brd4) (Rodriguez, R.M., et al., "Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer," JMol Med(Berl)90(5):587-95(2012)).

In one embodiment, because BET inhibitors reduce the Brd-dependent recruitment of pTEFb to genes involved in cell proliferation, BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be used to treat cancers that rely on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes. These cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma (Tong, W.G., et al., “Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2,7,and9 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 lymphoma, and activated anaplastic large cell lymphoma (Bellan, C., et al., “CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation,” J Pathol 203(4):946-52 (2004)), neuroblastoma, and primary neuroectodermal tumor (De Falco, G., et al., “Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors,” Cancer Biol Ther 4(3):277-81(2005)), rhabdomyosarcoma (Simone, C. and A. Giordano, “Abrogation of signal-dependent activation of the cdk9/cyclin T2a complex in human RD rhabdomyosarcoma cells,” Cell Death Differ 14(1):192-5(2007)), prostate cancer (Lee, D.K., et al., “Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptionalelongation,” J Biol Chem 276(13):9978-84(2001)), and breast cancer (Bartholomeeusen, K., et al., “BET bromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP,” J Biol Chem (2012)).

In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used to treat cancers in which BET-responsive genes such as CDK6, Bcl2, TYRO3, MYB, and hTERT are upregulated. 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); Delmore, J.E., et al., "BET bromodomain inhibition as a therapeutic strategy to target c-Myc," Cell 146(6):904-17 (2010). These cancers include, but are not limited to, pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, glioblastoma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barrett's adenocarcinoma, hepatoma, prostate cancer, promyelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal cancer. Ruden, M. and N. Puri, "Novel anticancer therapeutics targeting telomerase," Cancer Treat Rev (2012); Kelly, P.N. and A. Strasser, "The role of Bcl-2 and its pro-survivalrelatives in tumorigenesis and cancer therapy" Cell Death Differ 18(9):1414-24 (2011); Uchida, T., et al., "Antitumor Effect of bcl-2antisense phosphorothioateoligodeoxynucleotides on human renal-cell carcinoma cells in vitro and inmice,” Mol Urol 5(2):71-8 (2001).

Public and proprietary data have shown a direct effect of BET inhibition on cell proliferation in various cancers. In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used to treat cancers for which there is public and (for some cancers) proprietary in vivo and/or in vitro data showing a direct effect of BET inhibition on cell proliferation. These cancers include NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute B-lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, B-cell lymphoma, melanoma, mixed lineage leukemia, multiple myeloma, promyelocytic leukemia (PML), and non-Hodgkin's lymphoma. Filippakopoulos, P., et al., “Selective inhibition of BET bromodomains,” Nature 468(7327):1067-73(2010); 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); Zuber, J., et al., “RNAiscreen identifies Brd4 as a therapeutic target in acute myeloid leukaemia,” Nature 478(7370):524-8(2011); Miguel F. Segura, et al., “BRD4 is a novel therapeutic target in melanoma,” Cancer Research.72(8):Supplement 1(2012). Compounds of the present invention have demonstrated direct effects of BET inhibition on cell proliferation in vitro of the following cancers: neuroblastoma, medulloblastoma, lung cancer (NSCLC, SCLC) and colon cancer.

In one embodiment, due to potential synergistic or additive effects between BET inhibitors and other cancer therapies, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be combined with other therapies, chemotherapeutic agents, or anti-proliferative agents to treat human cancer and other proliferative disorders. The list of therapeutic agents that 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 (Mileland), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa) , Idarubicin, Ifosfamide (Mitoxana), IFNa2a (interferon A), Melphalan (Aikran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (midostaurin), PLX4032 (vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Lenalidomide (lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Resalva), SU11248 (sunitinib), SU11274, Vinblastine, Vincristine (Ancoping), Vinorelbine (Navelbine), Vorinostat (SAHA) and WP1130 (Degrasyn).

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be used to treat benign proliferative and fibrotic disorders, including, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratoses, gastric polyps, thyroid nodules, pancreatic cystic neoplasms, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic pilonidal disease, dermatofibromas, pilaris cysts, pyogenic granulomas, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, scleroderma, and myocardial fibrosis. Tang,

In one embodiment, due to the ability of the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds to upregulate ApoA-1 transcription and protein expression (Mirguet, O., et al., “From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C.W., et al., “Discovery and characterization of smallmolecule inhibitors of the BET family bromodomains,” J Med Chem 54(11):3827-38 (2011)), they are useful in treating cardiovascular diseases commonly associated with conditions including dyslipidemia, atherosclerosis, hypercholesterolemia, and metabolic syndrome. (Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G.V., “Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99 (2010)). In another embodiment, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II can be used to treat non-cardiovascular diseases characterized by defects in ApoA-1, including Alzheimer's disease. Elliott, D.A., et al., “Apolipoproteins in the brain: implications for neurological and psychiatric disorders,” Clin Lipidol 51(4):555-573 (2010).

In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used in patients with insulin resistance and type II diabetes. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G.V., “Bromodomain coactivators in cancer, obesity, type2diabetes, and inflammation,” Discov Med10(55):489-99(2010); Wang, F., et al., "Brd2disruption in mice causes severe obesity without Type2diabetes," Biochem J 425(1):71-83(2010); 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). The anti-inflammatory effects of BET inhibition would have additional value in reducing inflammation associated with diabetes and metabolic diseases. Alexandraki, K., et al., "Inflammatory process in type 2 diabetes: The role of cytokines," Ann N Y Acad Sci 1084:89-117 (2006).

In one embodiment, due to the ability of the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds to downregulate viral promoters, they can be used as therapeutic agents for cancers associated with viruses including Epstein-Barr virus (EBV), hepatitis viruses (HBV, HCV), Kaposi's sarcoma-associated virus (KSHV), human papilloma virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV). Gagnon, D., et al., “Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein4,” J Virol83(9):4127-39(2009); You, J., et al., “Kaposi’ssarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes,” J Virol80(18):8909-19(2006); Palermo, R.D., et al., "RNA polymerase II stalling promotesnucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus," PLoS Pathog 7(10):e1002334(2011); Poreba, E., et al., "Epigenetic mechanisms in virus-induced mechanisms" tumorigenesis,” Clin Epigenetics 2(2):233-47. 2011. In another embodiment, BET inhibitors can be used in combination with antiretroviral therapeutics to treat HIV due to their ability to reactivate HIV-1 in models of latent T cell infection and latent monocyte infection. Zhu, J., et al., "Reactivation of Latent HIV-1 by Inhibition of BRD4," Cell Rep (2012); Banerjee, C., et al., "BET bromodomain inhibition as a novel strategy for reactivation of HIV-1," J Leukoc Biol (2012); Bartholomeeusen, K., et al., "BET bromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP," J Biol Chem (2012); Li, Z., et al., "The BET bromodomaininhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition ofTat-transactivation," Nucleic Acids Res (2012.)

In one embodiment, due to the role of epigenetic processes and bromodomain-containing proteins in neurological disorders, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be used to treat diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy. Prinjha, R.K., J. Witherington, and K. Lee, "Place your BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci 33(3):146-53 (2012); Muller, S., et al., "Bromodomains as therapeutic targets," Expert Rev Mol Med 13:e29 (2011).

In one embodiment, due to the effects of BRDT deletion or inhibition on spermatocyte development, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds can be used as reversible male contraceptives. Matzuk, M.M., et al., "Small-Molecule Inhibition of BRDT for Male Contraception," Cell 150(4): 673-684 (2012); Berkovits, B.D., et al., "The 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 spermatid," Nucleic Acids Res 40(15): 7162-75 (2012).

Pharmaceutical composition

The pharmaceutical composition of the present disclosure comprises a compound of at least one Formula I-II or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate prepared together with one or more pharmaceutically acceptable carriers. These preparations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. In any given case, the most suitable form of administration will depend on the degree and severity of the condition being treated and on the properties of the specific compound used.

Formulations suitable for oral administration can be presented as discrete units such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water liquid emulsions or water-in-oil emulsions. As indicated, such formulations can be prepared by any suitable pharmaceutical method comprising the steps of bringing into association at least one compound of the present disclosure as the active compound with a carrier or excipient (which may constitute one or more auxiliary ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must be innocuous to the recipient. The carrier can be a solid or liquid, or both, and can be formulated with at least one compound described herein as the active compound in a unit dose formulation (e.g., a tablet) containing from about 0.05% to about 95% by weight of at least one active compound. Other pharmacologically active substances may also be present, including other compounds. The formulations of the present disclosure can be prepared by any well-known pharmaceutical technique consisting essentially of mixing the components.

For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient (e.g., such as water, saline, aqueous glucose solution, glycerol, ethanol, etc.) to thereby form a solution or suspension. In general, suitable formulations can be prepared by uniformly and intimately mixing 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. For example, tablets can be prepared by pressing or molding a powder or granules of at least one compound of the present disclosure optionally in combination with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing at least one compound of the present disclosure in a free-flowing form (e.g., powder or granules) optionally mixed with a binder, lubricant, inert diluent, and/or surfactant/dispersant in a suitable machine. Molded tablets may be made by molding in a suitable machine wherein the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.

Suitable formulations for buccal (sublingual) 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 at least one compound of the present disclosure in an inert base such as gelatin and glycerin or sucrose and acacia.

The formulations of the present disclosure suitable for parenteral administration comprise a sterile aqueous formulation of at least one compound of Formula I-II or its tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates, which is approximately isotonic with the blood of the intended recipient. These formulations are administered intravenously, but administration can also be achieved by subcutaneous, intramuscular or intradermal injection. Such formulations can be conveniently prepared by mixing at least one compound described herein with water and making the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from about 0.1% w/w to about 5% w/w of active compound.

Formulations suitable for rectal administration are presented as unit dose suppositories. These can be prepared by mixing at least one compound as described herein with one or more conventional solid carriers (eg, cocoa butter) and then shaping the resulting mixture.

Preparations suitable for topical application to the skin can take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Operable carriers and excipients include vaseline, lanolin, polyethylene glycol, alcohol and two or more combinations thereof. The active compound (i.e., at least one compound of Formulas I-IV or its tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates thereof) is typically present in a concentration of about 0.1% w/w to about 15% w/w (e.g., about 0.5% to about 2%) of the composition.

The amount of the active compound administered may depend on the subject being treated, the subject's weight, the mode of administration, and the judgment of the prescribing physician. For example, a dosing schedule may involve administering the encapsulated compound daily or half a day at a perceived dose of about 1 μg to about 1000 mg. In another embodiment, intermittent administration (such as on a monthly or annual basis) of the encapsulated compound may be employed. Encapsulation helps to achieve accessible sites of action and allows the active ingredient to be administered simultaneously, thereby theoretically producing a synergistic effect. According to the standard dosing regimen, the physician will easily determine the optimal dose and will be able to easily modify administration to achieve such doses.

The therapeutically effective amount of the compound or composition disclosed herein can be measured by the therapeutic efficacy of the compound. However, the dosage can vary according to the needs of the patient, the severity of the condition being treated, and the compound used. In one embodiment, the therapeutically effective amount of the disclosed compound is sufficient to produce a maximum plasma concentration. The scaling of the preliminary dose (such as, for example, determined according to animal testing) and the dosage for human administration is carried out according to recognized practices in the art.

Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the _LD50 (the dose lethal to 50% of the population) and the _ED50 (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 preferred.

Data obtained from cell culture assays or animal studies can be used in formulating a dosage range for use in humans. A therapeutically effective dose achieved in one animal model can be converted for use in another animal (including humans) using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 1 of equivalent surface area dose factors).

Table I: Equivalent surface area dose factors:

The dosage of the compound is preferably within a circulating concentration range that includes the _ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. In general, the therapeutically effective amount may vary with the age, condition, and sex of the subject, as well as the severity of the subject's medical condition. The dosage may be determined by the physician and adjusted as needed to suit the observed therapeutic effect.

In one embodiment, the compound of Formula I-II or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate is administered in combination with another therapeutic agent. Other therapeutic agents can provide cumulative or synergistic value relative to the separate administration of the disclosed compounds. The therapeutic agent can be, for example, a statin; a PPAR agonist, such as a thiazolidinedione or fibrate; nicotinic acid, RVX, FXR or LXR agonist; a bile acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; a cholesterol ester transfer protein (CETP), an ion exchange resin; an antioxidant; an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrosine phosphokinase inhibitor (tyrophostine); a sulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; an HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein; an LDL-lowering drug; an HDL-raising drug; an HDL enhancer; a regulator of apolipoprotein A-IV and/or apolipoprotein genes; or any cardiovascular drug.

In another embodiment, the compound of Formula I and/or Formula II, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered in combination with one or more anti-inflammatory agents. Anti-inflammatory agents may include immunosuppressants, TNF inhibitors, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDS), and the like. Exemplary anti-inflammatory agents include, for example, prednisone, methylprednisolone, triamcinolone, methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, infliximab, adalimumab, rituximab, abatacept, interleukin-1, anakinra (Kineret ^™ ), ibuprofen, ketoprofen, fenoprofen, naproxen, aspirin, acetaminophen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, azapropazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, hydroxybutazone, diflunisal, salsalate, olsalazine, or sulfasalazine.

Example

General method. Unless otherwise stated, reagents and solvents are used as received from commercial suppliers. Proton nuclear magnetic resonance spectra are obtained on a Bruker AVANCE 300 spectrometer at 300 MHz or in a Bruker AVANCE 500 spectrometer at 500 MHz or on a Bruker AVANCE 300 spectrometer at 300 MHz. Spectra are given in ppm (δ) units and coupling constants and J values are reported in Hertz (Hz). Tetramethylsilane is used as an internal standard for ¹ H nuclear magnetic resonance. Mass spectrometry is performed on a Waters Aquity UPLC mass spectrometer in ESI or APCI mode (when appropriate), on an Agilent 6130A mass spectrometer in ESI, APCI or MultiMode mode (when appropriate), or on an Applied Biosystems API-150EX spectrometer in ESI or APCI mode (when appropriate). Silica gel chromatography is typically performed on a Teledyne Isco Rf 200 system or a Teledyne Isco Companion system.

Abbreviations: CDI: 1,1'-carbonyldiimidazole; DMAP: N,N-dimethylaminopropylamine; EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; m-CPBA: 3-chloroperoxybenzoic acid; NBS: N-bromosuccinimide.

General Procedure A:

Preparation of 9-benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine (Example Compound 1)

Step 1: To a slurry of 1 (1.50 g, 8.84 mmol) in DMF (50 mL) was added potassium carbonate (3.64 g, 26.4 mmol) and benzyl chloride (1.01 mL, 8.84 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was poured into water (100 mL) and stirred for 5 min. The solid was harvested and dried to give 2 (1.60 g, 70%) as a yellow solid: ^1z H NMR (300 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 7.80 (br s, 2H), 7.38–7.26 (m, 5H), 5.34 (s, 2H); ESI m/z 260 [M+H] ⁺ .

Step 2: To a solution of 2 (260 mg, 1.0 mmol) in 1,4-dioxane (10 mL) and DMF (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (335 mg, 1.5 mmol), sodium carbonate (2.0 M in H ₂ O, 1.0 mL, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 h. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-5% dichloromethane/methanol) followed by trituration with EtOAc/hexanes to provide 9-benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine (Example Compound 1) (110 mg, 34%) as a white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 7.36-7.28 (m, 7H), 5.38 (s, 2H), 2.73 (s, 3H), 2.51 (s, 3H); ESI m/z 321 [M+H] ⁺ .

Preparation of 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 2)

Step 1: To a solution of 4 (500 mg, 2.66 mmol) in 1,4-dioxane (15 mL) was added CDI (517 mg, 3.19 mmol). The reaction was heated at 60° C. for 16 hours. The solid was harvested and dried to afford 5 (340 mg, 60%) as a light purple solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.58 (br s, 1H), 11.02 (br s, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H).

Step 2: To a solution of 5 (170 mg, 0.79 mmol) in 1,4-dioxane (12 mL) and DMF (6 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (352 mg, 1.58 mmol), sodium carbonate (2.0 M in H ₂ O, 1.19 mL, 2.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-5% dichloromethane/methanol) to provide 6 (130 mg, 71%) as a white solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.38 (br s, 1H), 10.90 (br s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 2.49 (s, 3H), 2.33 (s, 3H).

Step 3: To a solution of 6 (100 mg, 0.43 mmol) in DMF (10 mL) was added potassium carbonate (72 mg, 0.52 mmol) and di-tert-butyl dicarbonate (104 mg, 0.48 mmol). The reaction was stirred at room temperature for 16 hours. Potassium carbonate (72 mg, 0.52 mmol) and benzyl chloride (0.14 mL, 0.48 mmol) were added to the reaction mixture. The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate/hexanes) gave 6 (130 mg, 71%) as a colorless gum: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (d, J=8.1 Hz, 1H), 7.38-7.27 (m, 6H), 5.05 (s, 2H), 2.49 (s, 3H), 2.29 (s, 3H), 1.61 (s, 9H).

Step 4: A solution of 7 (130 mg, 0.31 mmol) in dichloromethane (4 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO ₃ (50 mL×2) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to provide 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 2) (81 mg, 81%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.15 (d, J=7.8 Hz, 1H), 5.03 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H); ESI m/z 321 [M+H] ⁺ .

Preparation of 1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 3)

Step 1: To a solution of 4 (500 mg, 2.66 mmol) and benzaldehyde (282 mg, 2.66 mmol) in dichloromethane (15 mL) was added acetic acid (319 mg, 5.32 mmol). The reaction was stirred at room temperature for 30 minutes, and then NaBH (OAc) ₃ (1.69 g, 7.98 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (100 mL) and saturated NaHCO ₃ aqueous solution (50 mL) was slowly added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/EtOAc to give 8 (401 mg, 54%) as a light brown solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.34-7.22 (m, 5H), 6.48 (d, J=7.8 Hz, 1H), 6.40 (d, J=7.8 Hz, 1H), 6.02 (br s, 2H), 5.54 (t, J=5.7 Hz, 1H), 4.27 (d, J=5.4 Hz, 2H).

Step 2: To a solution of 8 (400 mg, 1.44 mmol) in 1,4-dioxane (10 mL) was added CDI (514 mg, 3.17 mmol). The reaction was heated at 110° C. for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0–40% ethyl acetate/hexanes) afforded 9 (310 mg, 71%) as a white solid: ¹ H NMR (300 MHz, DMSO–d ₆ ) δ 11.96 (s, 1H), 7.35–7.27 (m, 6H), 7.19 (d, J=7.8 Hz, 1H), 5.02 (s, 2H).

Step 3: To a solution of 9 (310 mg, 1.02 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (341 mg, 1.53 mmol), sodium carbonate (2.0 M in H ₂ O, 1.02 mL, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica gel, 0-80% EtOAc/hexanes) and triturated with EtOAc to provide 1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 3) (202 mg, 62%) as a white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 11.76 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.36-7.28 (m, 5H), 7.11 (d, J=7.8 Hz, 1H), 5.05 (s, 2H), 2.49 (s, 3H), 2.32 (s, 3H); ESI m/z 321 [M+H] ⁺ .

General Procedure B

Preparation of 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 4) and 4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 5).

Step 1: To a solution of 10 (400 mg, 2.0 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (669 mg, 1.5 mmol), sodium carbonate (2.0 M in H ₂ O, 2.0 mL, 4.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-8% dichloromethane/methanol) followed by trituration with EtOAc/hexanes to provide 11 (228 mg, 53%) as a light yellow solid: ESI m/z 215 [M+H] ⁺ .

Step 2: To a solution of 11 (220 mg, 1.03 mmol) in CH ₃ CN (10 mL) were added potassium carbonate (426 mg, 3.09 mmol) and benzyl chloride (0.12 mL, 1.03 mmol).The reaction was stirred at room temperature for 16 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 4) (34 mg, 11%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J=1.8 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.40-7.31 (m, 5H), 5.52 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H); ESI m/z 305 [M+H] ⁺ 4-(1-Benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 5) (39 mg, 12%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 7.40–7.37 (m, 3H), 7.34 (d, J=2.1 Hz, 1H), 7.24–7.21 (m, 2H), 5.41 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 305 [M+H] ⁺ .

Preparation of 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (Example Compound 6)

Step 1: To a solution of 13 (5.00 g, 22.9 mmol) in acetic acid (50 mL), ethanol (100 mL) and water (5 mL) was added iron powder (6.42 g, 115 mmol). The reaction was heated at 80° C. under nitrogen for 2 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% hexanes/ethyl acetate) to afford 14 (3.27 g, 76%) as a brown solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.88 (d, J=2.2 Hz, 1H), 6.77 (dd, J=8.3, 2.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 6.00–5.20 (br s, 3H).

Step 2: To a solution of 14 (1.50 g, 7.98 mmol) in 1,4-dioxane (100 mL) was added 1,1'-carbonyldiimidazole (1.55 g, 9.58 mmol). The reaction was heated at 80 °C under nitrogen for 17 hours. The mixture was cooled to room temperature and 2N aqueous HCl (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexane) gave 15 (1.08 g, 63%) as an orange solid: ^1H NMR (500 MHz, DMSO- _d6 ) δ 11.81 (s, 1H), 7.27-7.25 (m, 3H).

Step 3: To a solution of 15 (150 mg, 0.701 mmol) in acetonitrile (10 mL) was added benzyl bromide (180 mg, 1.05 mmol) and potassium carbonate (193 mg, 1.40 mmol). The reaction was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0–50% ethyl acetate/hexanes) to afford 16 (195 mg, 92%) as an off-white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.41–7.30 (m, 5H), 7.22 (dd, J=8.5, 1.7 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 4.97 (s, 2H).

Step 4: To a solution of 16 (195 mg, 0.641 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (172 mg, 0.769 mmol), potassium carbonate (177 mg, 1.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol). The reaction mixture was purged with nitrogen and heated at 100 ° C for 4 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexane). This was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O to give 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (Example Compound 6) (115 mg, 56%) as an off-white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.47-7.42 (m, 3H), 7.40-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.12 (dd, J=8.2 Hz, 7.7 Hz, 1H), 5.07 (s, 2H), 2.33 (s, 3H), 2.15 (s, 3H); ESI m/z 321 [M+H] ⁺ .

General Procedure C:

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 7), 1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine (Example Compound 8), and N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 9)

To a solution of 6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine 17 (290 mg, 1.27 mmol) in CH ₃ CN (15 mL) was added potassium carbonate (350 mg, 2.54 mmol) and benzyl chloride (200 mg, 1.59 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered through a pad of celite. The filtrate was concentrated and purified by chromatography (silica gel, 0-10% _CH3OH / _CH2Cl2 ) to provide ₁ -benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 7) (109 mg, 27%) as an off-white solid: ^1H NMR (300 MHz, _CDCl3 ) δ 7.95 (s, 1H), 7.37-7.34 (m, 3H), 7.23-7.20 (m, 2H), 6.46 (d, J = 1.2 Hz, 1H), 6.40 (d, J = 1.2 Hz, 1H), 5.34 (s, 2H), 2.31 (s, 3H), 2.16 (s, 3H); ESIMS m/z 319 [M+H] ⁺ 1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine (Example Compound 8) (19 mg, 4.7%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 7.43–7.40 (m, 3H), 7.23 (d, J=1.2 Hz, 1H), 7.20–7.17 (m, 2H), 6.39 (d, J=1.2 Hz, 1H), 5.69 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H); ESIMS m/z 319 [M+H] ⁺ N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 9) (40 mg, 8%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 7.40–7.18 (m, 10H), 6.62 (d, J=1.2 Hz, 1H), 6.57 (t, J=6.0 Hz, 1H), 5.97 (d, J=1.2 Hz, 1H), 5.41 (s, 2H), 4.48 (d, J=6.0 Hz, 2H), 2.12 (s, 3H), 1.94 (s, 3H); ESIMS m/z 409 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 10)

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 10) was prepared by following the method used to prepare Example 3 to give the product as a white solid (158 mg, 47%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.81 (s, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.44-7.25 (m, 6H), 5.05 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); MM m/z 321 [M+H] ⁺ .

Preparation of 1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one (Example Compound 11)

Step 1: A solution of 18 (500 mg, 2.3 mmol), benzylamine (1.2 g, 11.4 mmmol) and pyridine (5.0 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo and the product was purified by chromatography (silica gel, 0-10% ethyl acetate/hexanes) to afford 19 (630 mg, 91%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.38 (s, 1 H), 8.05 (d, J=9.1 Hz, 1 H), 7.40-7.32 (m, 5 H), 7.01 (d, J=1.9 Hz, 1 H), 6.79 (dd, J=9.1, 1.9 Hz, 1 H), 4.51 (d, J=5.5 Hz, 2 H).

Step 2: A mixture of 19 (100 mg, 0.33 mmol), iron powder (127 mg, 2.28 mmol), ammonium chloride (27 mg, 0.5 mmol), water (0.5 mL), and ethanol (3 mL) was heated at reflux for 0.5 h. The reaction mixture was cooled and filtered. The solvent was removed to afford 20 (90 mg, 100%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40–7.29 (m, 5H), 6.81–6.77 (m, 2H), 6.61–6.58 (m, 1H), 4.27 (s, 2H), 3.41 (s, 1H); ESI m/z 278 [M+H] ⁺ .

Step 3: To a mixture of 20 (100 mg, 0.36 mmol), triethylamine (48 mg, 0.47 mmol), _CH2Cl2 (0.5 _mL ) and THF (1.0 mL) was added a solution of ethyl bromoacetate (78 mg, 0.47 mmol) in THF (1.0 mL) at room temperature. The reaction mixture was stirred for 18 h and then heated to 75 °C for 1 h. The reaction mixture was concentrated and the product was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 21 (44 mg, 39%) as a tan solid: ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.38-7.29 (m, 4H), 7.24-7.22 (m, 2H), 6.98-6.93 (m, 2H), 6.55 (d, J=8.3 Hz, 1H), 5.13 (s, 2H), 4.05 (s, 2H); ESI m/z 318 [M+H] ⁺ .

Step 4: A mixture _of 21 (44 mg, 0.14 mmol), 3 (47 mg, 0.21 mmol), _K2CO3 (39 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.01 mmol), 1,4-dioxane (3 mL) and water (0.5 mL) was heated at 90 °C for 16 h. The reaction mixture was concentrated onto silica gel and the product was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide 1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one (Example Compound 11) (16 mg, 34%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.35-7.32 (m, 2H), 7.29-7.27 (m, 1H), 7.21-7.18 (m, 3H), 7.04 (s, 1H), 5.51 (s, 1H), 2.16 (s, 3H), 2.02 (s, 3H); ESI m/z 332 [M+H] ⁺ .

Preparation of 1-benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Example Compound 12)

Step 1: To a solution of 22 (1.19 g, 5.53 mmol) and benzaldehyde (594 mg, 5.60 mmol) in CH ₂ Cl ₂ (50 mL) and CH ₃ CN (50 mL) was added acetic acid (0.2 mL). The mixture was stirred at room temperature for 1 hour. NaBH(OAc) ₃ (3.52 g, 16.59 mmol) was added. The mixture was stirred at room temperature for 8 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (50 mL) and concentrated. The residue was suspended in EtOAc (300 mL) and washed with brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50% EtOAc/heptane) to afford 23 (201 mg, 12%) as an off-white solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (d, J=5.7 Hz, 1H), 7.93 (br. s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.38-7.31 (m, 6H), 6.76 (d, J=1.8 Hz, 1H), 6.69 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (d, J=6.0 Hz, 2H).

Step 2: To a solution of 23 (518 mg, 1.70 mmol) in THF (20 mL) was added BH ₃ ·THF (1.0 M in THF, 8.50 mL, 8.50 mmol). The mixture was heated to reflux for 16 h. MeOH (40 mL) was slowly added, followed by 2N HCl (40 mL). The mixture was heated to reflux for 3 h. NH ₄ OH (60 mL) was added, and the mixture was extracted with EtOAc (200 mL x 3). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/dichloromethane) to afford 24 (372 mg, 75%) as a colorless gum: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.32-7.21 (m, 5H), 6.98 (d, J=7.8 Hz, 1H), 6.87 (t, J=6.0 Hz, 1H), 6.65 (dd, J=8.1, 2.1 Hz, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.33 (d, J=5.7 Hz, 2H), 3.71 (s, 2H), 1.92 (br. s, 2H).

Step 3: Using the procedure used for Example 3, Step 2, starting with compound 24 (362 mg, 1.24 mmol), 25 (325 mg, 85%) was obtained as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.33-7.31 (m, 3H), 7.25-7.23 (m, 3H), 7.09 (d, J=1.8 Hz, 2H), 6.86 (s, 1H), 5.05 (s, 2H), 4.35 (d, J=1.5 Hz, 2H).

Step 4: Using the procedure used for Example Compound 3, Step 3, starting with Compound 25 (317 mg, 1.00 mmol), Example Compound 12 (199 mg, 60%) was obtained as a white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.34-7.21 (m, 7H), 6.90 (dd, J=7.5, 1.0 Hz, 1H), 6.58 (d, J=1.0 Hz, 1H), 5.09 (s, 2H), 4.43 (s, 2H), 2.06 (s, 3H), 1.89 (s, 3H); MM m/z 334 [M+H] ⁺ .

General Procedure D:

Preparation of 4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 13)

Step 1: To a mixture of 26 (1.00 g, 5.32 mmol) and 3 (1.78 g, 7.98 mmol) in 1,4-dioxane (35 mL) and water (7.5 mL) was added potassium carbonate (1.47 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (307 mg, 0.27 mmol). The reaction was stirred and heated at 90 ° C for 16 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The slurry was concentrated to dryness and the resulting powder was loaded on silica gel and eluted with 0-90% ethyl acetate in hexane. The clean product was concentrated to give 27 (939 mg, 70%) as a yellow-green solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.45 (t, J=2.0 Hz, 1H), 6.78 (t, J=2.0 Hz, 1H), 2.37 (s, 3H), 2.22 (s, 3H).

Step 2: To a solution of 27 (300 mg, 1.47 mmol) in 1,2-dichloroethane (15 mL) was added benzaldehyde (156 mg, 1.47 mmol) and glacial acetic acid (200 μL) at room temperature. After stirring for 17 hours, CH ₂ Cl ₂ (20 mL) was added, followed by a saturated aqueous NaHCO ₃ solution (20 mL, slowly). The organic layer was separated and dried over Na ₂ SO _4. The suspension was filtered and concentrated. The material was purified by chromatography (silica gel, 0–60% ethyl acetate in hexane) to provide a yellow solid, which was dissolved in methanol (10 mL) and sodium borohydride (52 mg, 1.35 mmol) was added at room temperature. After stirring for 1 hour, additional sodium borohydride (156 mg, 3.40 mmol) was added and the reaction was stirred for 1 hour. A 2N aqueous HCl solution was added to the mixture until pH 4 (2 mL), and then a saturated NaHCO ₃ solution was added to alkalize to pH 8 (2 mL). Water (10 mL) was added and the solution was extracted with ethyl acetate (3×100 mL). The ethyl acetate extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated to afford 28 (401 mg, 93%) as a white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.48 (s, 1H), 7.37–7.26 (m, 5H), 6.58 (s, 1H), 4.38 (s, 2H), 4.33 (br s, 2H), 3.77 (br s, 1H), 2.24 (s, 3H), 2.08 (s, 3H).

Step 3: To 28 (350 mg, 1.19 mmol) was added triethyl orthoacetate (3.0 mL, 16.4 mmol) and sulfamic acid (1 mg). The mixture was heated to 100° C. for 1 hour. The mixture was diluted with methanol (20 mL) and adsorbed onto silica gel (10 g). The material was purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes, then 0-5% methanol in _CH2Cl2 ) to provide _4- (1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 13, 169 mg, 45%) as a white solid: ^1H NMR (500 MHz, _CD3OD ) δ 8.32 (d, J=1.0 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.36-7.29 (m, 3H), 7.20-7.17 (m, 2H), 5.56 (s, 2H), 2.69 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H); ESI m/z 319 [M+H] ⁺ .

General Procedure E:

Preparation of 1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 91) and 4-amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 90)

Step 1: To a solution of 29 (1.00 g, 4.61 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.23 g, 5.53 mmol), potassium carbonate (1.27 g, 9.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.231 mmol). The reaction mixture was purged with nitrogen and heated at 90 ° C overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexane) to give a yellow solid, which was dissolved in acetic acid (15 mL) and N-bromosuccinimide (753 mg, 4.23 mmol) was added at 0 ° C. The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. The residue was suspended in hot MeOH, cooled to room temperature and basified with 10% aqueous NaHCO ₃ solution. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to afford 30 (1.10 g, 87%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.04 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 6.69 (bs, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 312 [M+H] ⁺ .

Step 2: To a solution of 30 (500 mg, 1.60 mmol) in toluene (50 mL) was added 4-chlorobenzylamine (1.36 g, 9.62 mmol), cesium carbonate (1.04 g, 3.02 mmol), 2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (114 mg, 0.240 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 90° C. overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 31 (290 mg, 49%) as a red solid: ESI m/z 373 [M+H] ⁺ .

Step 3: To a mixture of 31 (290 mg, 0.779 mmol) in 1,4-dioxane (10 mL) was added 1,1'-carbonyldiimidazole (630 mg, 3.89 mmol) and DMAP (crystals). The reaction was heated in a sealed tube at 130°C for 4 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford Example Compound 91 (144 mg, 46%) as an orange solid: ^1H NMR (500 MHz, _CD3OD ) δ 7.80 (d, J = 1.4 Hz, 1H), 7.40-7.35 (m, 4H), 7.24 (d, J = 1.4 Hz, 1H), 5.15 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 399 [M+H] ⁺ .

Step 4: To a solution of Example Compound 91 (70 mg, 0.18 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (183 mg, 1.05 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. 2N HCl was added to the residue and heated to reflux, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in MeOH and basified with concentrated _NH4OH , concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to give Example Compound 90 (34 mg, 51%) as an off-white solid: ^1H NMR (500 MHz, _CD3OD ) δ 7.36-7.28 (m, 4H), 6.40 (d, J=1.4 Hz, 1H), 6.25 (d, J=1.4 Hz, 1H), 5.03 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); ESI m/z 369 [M+H] ⁺ .

General Procedure F:

Preparation of 4-(1-(cyclopropylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 14) and 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine (Example Compound 75)

Step 1: A solution of 32 (488 mg, 2.10 mmol) and 2,4-pentanedione (421 mg, 4.21 mmol) in anhydrous ethanol (28 mL) and 5N aqueous HCl (7.8 mL) was heated to reflux for 3 h. The mixture was concentrated to dryness and ethyl acetate (200 mL) was added. The solution was washed with saturated aqueous NaHCO ₃ solution (250 mL) and saturated aqueous NaCl solution (250 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-40% hexane/ethyl acetate) to provide 33 (495 mg, 92%) as an orange solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.38 (br s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 1.0 Hz, 1H), 2.73 (s, 3H).

Step 2: To a mixture of 33 (200 mg, 0.78 mmol) and 3 (262 mg, 1.17 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was added potassium carbonate (216 mg, 1.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol). The reaction was stirred and heated at 90° C. for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The suspension was concentrated to dryness and the resulting powder was purified by chromatography (silica gel, 0-90% hexane/ethyl acetate) to give 34 (187 mg, 88%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.00 (d, J=1.5 Hz, 1H), 7.89 (s, 1H), 2.76 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H).

Step 3: To a solution of 34 (217 mg, 0.797 mmol), potassium carbonate (220 mg, 1.59 mmol), acetonitrile (5 mL) and DMF (1 mL) was added bromomethylcyclopropane (129 mg, 0.956 mmol) and the reaction was heated at 60°C for 17 hours. The material was cooled to room temperature and poured into saturated aqueous NaCl solution (30 mL). Ethyl acetate (100 mL) was added and the layers were separated. The ethyl acetate layer was washed with saturated aqueous NaCl solution (2 x 20 _mL ), dried over _Na2SO4 , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-90% hexanes/ethyl acetate) to give Example 14 (178 mg, 68%) as a yellow solid: ^1H NMR (500 MHz, CD ₃ OD) δ 8.03 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 4.27 (d, J = 7.0 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H), 1.38-1.28 (m, 1H), 0.65-0.60 (m, 2H), 0.51-0.46 (m, 2H). ESI m/z 327 [M+H] ⁺

Step 4: To a solution of embodiment compound 14 (160 mg, 0.51 mmol) in THF (10 mL) was added dropwise a solution of sodium dithionite (446 mg, 2.56 mmol) in water (10 mL) within 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. 2N HCl aqueous solution (10 mL) was added to the residue and heated to reflux for 5 minutes. After being concentrated to dryness, methanol (20 mL) was added and the solution was adjusted to pH 8 using saturated NaHCO ₃ aqueous solution (10 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) and the product was then purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to give Example Compound 75 (131 mg, 99%) as a white solid: ^1H NMR (500 MHz, _CD3OD ) δ 6.70 (s, 1H), 6.44 (d, J=1.0 Hz, 1H), 4.08 (d, J=6.5 Hz, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 1.30-1.19 (m, 1H), 0.62-0.53 (m, 2H), 0.45-0.40 (m, 2H). ESI m/z 297 [M+H] ⁺ .

General Procedure G:

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 15) and 4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 16)

Step 1: To a solution of 32 (232 mg, 1.0 mmol) in 1,4-dioxane (5 mL) was added CDI (194 mg, 1.2 mmol). The reaction was heated at 60° C. for 16 h. The solid was harvested and dried to afford 35 (202 mg, 78%) as a tan solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.83 (br s, 1H), 11.53 (br s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H).

Step 2: To a solution of 35 (200 mg, 0.78 mmol) in DMF (7 mL) was added potassium carbonate (118 mg, 0.85 mmol) and benzyl chloride (98 mg, 0.78 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexane) gave 36 (101 mg, 37%) as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.15 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.36-7.28 (m, 5H), 5.10 (s, 2H).

Step 3: To a solution of 36 (100 mg, 0.29 mmol) in 1,4-dioxane (7 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (128 mg, 0.57 mmol), sodium carbonate (2.0 M in H ₂ O, 0.43 mL, 0.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 h. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 10-50% ethyl acetate/hexanes) followed by trituration with ethyl acetate to provide Example Compound 15 (70 mg, 66%) as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.42-7.28 (m, 5H), 5.13 (s, 2H), 2.35 (s, 3H), 2.15 (s, 3H); ESI m/z 365 [M+H] ⁺ .

Step 4: To a solution of Example Compound 15 (52 mg, 0.14 mmol) in THF (5 mL) and water (4 mL) was added Na ₂ S ₂ O ₄ (149 mg, 0.86 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na ₂ CO ₃ was slowly added to adjust the pH to 9. The mixture was extracted with _CH2Cl2 (100 _mL ), and the organic layer was washed with brine (50 mL), filtered, concentrated, and purified by chromatography (silica gel, 70-100% ethyl acetate/hexanes) to provide Example Compound 16 (30 mg, 63%) as an off-white solid: ^1H NMR (500 MHz, DMSO- _d6 ) δ 10.44 (s, 1H), 7.36-7.25 (m, 5H), 6.28 (s, 2H), 5.04 (s, 2H), 4.95 (s, 2H), 2.28 (s, 3H), 2.10 (s, 3H); ESI m/z 335 [M+H] ⁺ .

General Procedure H:

Preparation of 4-(1-benzyl-4-bromo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 121)

Step 1: To a solution of 30 (1.09 g, 3.49 mmol) in tetrahydrofuran (30 mL) was added sodium dithionite (4.86 g, 28.0 mmol) in water (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was dissolved in MeOH/water (1:1, 150 mL) and a solid was precipitated by removing some of the MeOH under vacuum. The solid was filtered, washed with water and dried under vacuum to afford 37 (440 mg, 34%) as a yellow solid: ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.85 (d, J=1.8 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 4.00-3.60 (bs, 2H), 3.60-3.30 (bs, 2H), 2.36 (s, 3H), 2.23 (s, 3H); ESI m/z 282 [M+H] ⁺ .

Step 2: To a solution of 37 (4.01 g, 14.2 mmol) in methanol (87 mL) was added triethyl orthoacetate (3.45 g, 21.3 mmol) and sulfamic acid (69 mg, 0.71 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (50 mL), basified with NaHCO ₃ and filtered. The solid was dried to provide 38 (4.2 g, 96%) as a brown solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.82 (br. s, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H).

Step 3: A mixture of 38 (300 mg, 0.980 mmol), benzyl bromide (503 mg, 2.94 mmol) and potassium carbonate (676 mg, 4.90 mmol) in acetonitrile (50 mL) was heated in a sealed tube at 75° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 121 (276 mg, 71%) as an off-white solid: ^1H NMR (500 MHz, CD ₃ OD) δ 7.40-7.25 (m, 5H), 7.15 (d, J=7.7 Hz, 2H), 5.51 (s, 2H), 2.64 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 396 [M+H] ⁺ .

Preparation of 4-(1-benzyl-4-methoxy-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 66)

A mixture of Example 121 (80 mg, 0.20 mmol), NaOCH ₃ (108 mg, 2.0 mmol) and CuI (57 mg, 0.30 mmol) in MeOH (1 mL) and DMF (3 mL) was purged with nitrogen and heated at 100° C. for 6 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 40-100% EtOAc/hexanes) to provide Example Compound 66 (386 mg, 55%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.30 (m, 3H), 7.09-7.06 (m, 2H), 6.64 (d, J=1.2 Hz, 1H), 6.53 (s, 1H), 5.32 (s, 2H), 4.03 (s, 3H), 2.66 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H); ESI m/z 348 [M+H] ⁺ .

General Procedure I:

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine (Example Compound 18) and 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N ² -ethyl-1H-benzo[d]imidazol-2,4-diamine (Example Compound 19)

Step 1: A mixture of Example Compound 15 (73 mg, 0.668 mmol) in _POCl₃ (3 mL) was heated at 110°C for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in _CH₂Cl₂ (100 _mL ) and washed with saturated _NaHCO₃ (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in a solution of ethylamine in THF (2.0 M, 10 mL) and the mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica gel, 20-60% EtOAc/hexanes) to provide Example Compound 18 (113 mg, 43%) as an orange solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84 (d, J=1.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.16-7.13 (m, 2H), 7.03 (d, J=1.5 Hz, 1H), 5.15 (s, 2H), 4.29 (t, J=5.4 Hz, 1H), 3.78-3.69 (m, 2H), 2.36 (s, 3H), 2.21 (s, 3H), 1.27 (t, J=7.5 Hz, 3H); ESI m/z 392 [M+H] ⁺ .

Step 2: To a solution of Example Compound 18 (90 mg, 0.23 mmol) in THF (5 mL) and water (4 mL) was added Na ₂ S ₂ O ₄ (240 mg, 1.38 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na ₂ CO ₃ was slowly added to adjust the pH to 9. The mixture was extracted with _CH2Cl2 (100 _mL ), and the organic layer was washed with brine (50 mL), dried over _Na2SO4 , filtered, concentrated, and purified by chromatography (silica _gel , 0-10% methanol/ethyl acetate) to provide Example Compound 19 (60 mg, 72%) as an off-white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.34-7.20 (m, 5H), 6.62 (t, J=5.4 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.19 (s, 2H), 4.83 (s, 2H), 3.47-3.38 (m, 2H), 2.28 (s, 3H), 2.11 (s, 3H), 1.22 (t, J=7.2 Hz, 3H); ESI m/z 362[M+H] ⁺ .

General Procedure J:

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid methyl ester (Example Compound 20), 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide (Example Compound 21), and 4-(aminomethyl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-one (Example Compound 22)

Step 1: To a solution of 39 (2.00 g, 8.70 mmol) in 1,4-dioxane (80 mL) and water (8 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.13 g, 9.57 mmol), potassium carbonate (2.40 g, 17.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (502 mg, 0.435 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to provide 40 (1.43 g, 63%) as an off-white solid: ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.74 (d, J=2.1 Hz, 1 H), 7.15 (dd, J=2.1, 8.4 Hz, 1 H), 6.73 (d, J=8.4 Hz, 1 H), 5.81 (s, 2H), 3.88 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H); ESI m/z 247 [M+H] ⁺ .

Step 2: To a mixture of 40 (1.34 g, 5.45 mmol) in acetic acid (40 mL) was added N-bromosuccinimide (1.07 g, 5.99 mmol). The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in MeOH and neutralized to pH 7 with 10% sodium bicarbonate. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to provide 41 (1.65 g, 93%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.74 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 6.43 (bs, 2H), 3.90 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H).

Step 3: To a solution of 41 (500 mg, 1.54 mmol) in toluene (40 mL) under nitrogen atmosphere were added benzylamine (823 mg, 7.69 mmol), cesium carbonate (1.00 g, 2.08 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (110 mg, 0.231 mmol) and tris(dibenzylideneacetone)dipalladium(0) (141 mg, 0.154 mmol). The reaction mixture was heated at 90° C. overnight, cooled to room temperature and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to provide 42 (310 mg, 57%) as a light brown solid: ^1H NMR (500 MHz, CDCI ₃ ) δ 7.40-7.25 (m, 6H), 6.56 (d, J=1.8 Hz, 1H), 5.68 (s, 2H), 4.36 (d, J=4.4 Hz, 2H), 3.88 (s, 3H), 3.68 (s, 1H), 2.22 (s, 3H), 2.09 (s, 3H); ESI m/z 352 [M+H] ⁺ .

Step 4: To a mixture of 42 (310 mg, 0.883 mmol) in 1,4-dioxane (10 mL) was added 1,1'-carbonyldiimidazole (244 mg, 2.12 mmol) and DMAP (a crystal).The reaction was heated at 80°C in a sealed tube for 5 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 20 (160 mg, 48%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.54 (d, J=1.5 Hz, 1 H), 7.37-7.24 (m, 5 H), 7.07 (d, J=1.5 Hz, 1 H), 5.14 (s, 2 H), 3.97 (s, 3 H), 2.27 (s, 3 H), 2.09 (s, 3 H); HPLC >99%, t _R =15.0 min; ESI m/z 378 [M+H] ⁺ .

Step 5: To a mixture of Example Compound 20 (50 mg, 0.13 mmol) in formamide (4 mL) was added potassium tert-butoxide (30 mg, 0.26 mmol). The mixture was heated in a microwave at 100° C. for 3 h, concentrated, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford Example Compound 21 (13 mg, 26%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.41 (d, J=1.3 Hz, 1H), 7.37-7.24 (m, 5H), 7.00 (d, J=1.4 Hz, 1H), 5.13 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H); HPLC 98.3%, t _R =12.3 min; ESI m/z 363 [M+H] ⁺ .

Step 6: To a solution of Example Compound 21 (40 mg, 0.11 mmol) in THF (10 mL) was added sodium borohydride (38 mg, 0.99 mmol) under a nitrogen atmosphere. The mixture was heated to 65 ° C and boron trifluoride diethyl etherate (0.2 mL) was added. The mixture was heated at 65 ° C for 2 hours. After cooling to room temperature, hydrochloric acid (2N, 5 mL) was added and the mixture was stirred for 2 hours. The mixture was basified with NaOH (2N, 5 mL), concentrated, and purified by chromatography (silica gel, 0-100% CMA in dichloromethane) (CMA = chloroform: methanol: concentrated ammonium hydroxide = 80: 18: 2). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O to give Example Compound 22 (16 mg, 42%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.37-7.23 (m, 5H), 6.99 (d, J=1.4 Hz, 1H), 6.77 (d, J=1.4 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H); ESI m/z 340 [M+H] ⁺ .

General Procedure K:

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine (Example Compound 55)

A mixture of Example 121 (250 mg, 0.63 mmol), BocNH ₂ (221 mg, 1.89 mmol), Xantphos (73 mg, 0.126 mmol), Pd ₂ (dba) ₃ (58 mg, 0.063 mmol) and Cs ₂ CO ₃ (720 mg, 2.21 mmol) in 1,4-dioxane (13 mL) was purged with nitrogen and heated at 100 ° C for 18 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-50% EtOAc/hexane) to provide a light brown foam, which was dissolved in CH ₂ Cl ₂ (4 mL) and TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO ₃ (50 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-10% MeOH/EtOAc) gave Example Compound 55 (146 mg, 88%) as an off-white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.34-7.28 (m, 3H), 7.09-7.08 (m, 2H), 6.42 (d, J=1.5 Hz, 1H), 6.36 (d, J=1.5 Hz, 1H), 5.28 (s, 2H), 4.42 (br. s, 2H), 2.60 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H); ESI m/z 333 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (Example Compound 88) and 4-(1-benzyl-3-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 89)

Step 1: To a suspension of 43 (200 mg, 1.0 mmol) in _CH₃CN (6 mL) was added _ClSO₂NCO (360 mg, 2.5 mmol). The reaction mixture was stirred at 60°C for 4 h. After the mixture was cooled to room temperature, DMF (1 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with 30% i-PrOH in _CHCl₃ (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was dissolved in _CH₃CN (4 mL), and potassium carbonate (280 mg, 2.0 mmol) and benzyl chloride (128 mg, 1.0 mmol) were added. The reaction was stirred at 70°C for 16 h. The reaction mixture was filtered through a pad of celite and concentrated. The residue was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 44 (16 mg, 5%) as a yellow oil and 45 (12 mg, 4%) as an off-white solid; 44: ESIMS m/z 312 [M+H] ⁺ ; 45: ESI MS m/z 321 [M+H] ⁺ .

Step 2: Compound 44 (16 mg, 0.051 mmol) was subjected to a procedure analogous to that used for General Procedure C, Step 1 to afford Example Compound 88 (6 mg, 36%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 7.41-7.40 (m, 3H), 7.20-7.15 (m, 2H), 5.42 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); ESI MS m/z 329 [M+H] ⁺ .

Compound 45 (12 mg, 0.037 mmol) was subjected to a procedure analogous to that used for General Procedure C, Step 1 to afford Example Compound 89 (8 mg, 64%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.38-7.36 (m, 3H), 7.18-7.16 (m, 2H), 5.36 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); ESIMS m/z 338 [M+H] ⁺ .

General Procedure M:

Preparation of 5-(3,5-dimethylisoxazol-4-yl)-N-phenyl-1H-pyrrolo[3,2-b]pyridin-3-amine (Example Compound 23)

Step 1: To a solution of 46 (500 mg, 2.54 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (792 mg, 3.56 mmol), sodium carbonate (538 mg in 2 mL H ₂ O, 5.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (294 mg, 0.25 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded 47 (700 mg, >100%) as a yellow oil: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.4 (s, 1H), 7.85 (dd, J=8.1, 0.9 Hz, 1H), 7.68 (t, J=3.0 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 2.49 (s, 3H), 2.37 (s, 3H).

Step 2: To a solution of 47 (700 mg, 2.54 mmol) in DMF (8 mL) was added NBS (497 mg, 2.79 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours. The mixture was diluted with dichloromethane (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) gave 48 (660 mg, 89%) as a brown solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.8 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.90 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 2.49 (s, 3H), 2.37 (s, 3H); ESI m/z 292 [M+H] ⁺ .

Step 3: To a solution of 48 (250 mg, 0.86 mmol) in CH ₂ Cl ₂ (5 mL) was added NEt ₃ (130 mg, 1.28 mmol), DMAP (12 mg, 0.1 mmol), and di-tert-butyl dicarbonate (224 mg, 1.03 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate/hexanes) gave 49 (210 mg, 70%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (d, J=5.4 Hz, 1H), 7.93 (s, 1H), 7.34 (d, J=5.1 Hz, 1H), 2.64 (s, 3H), 2.50 (s, 3H), 1.69 (s, 9H).

Step 4: To a solution of 49 (100 mg, 0.26 mmol) in 1,4-dioxane (5 mL) was added aniline (71 mg, 0.76 mmol), cesium carbonate (250 mg, 0.76 mmol), X-phos (24 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.03 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 90°C for 16 hours. The mixture was diluted with dichloromethane (10 mL) and filtered through a pad of celite. The filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexane) gave a red oil, which was dissolved in dichloromethane (5 mL). TFA (2 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was dissolved in dichloromethane (100 mL) and washed with saturated NaHCO ₃ (50 mL×2) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 23 (47 mg, 64%) as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.1 (d, J=1.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.85 (d, J=7.5 Hz, 2H), 6.60 (t, J=7.2 Hz, 1H), 2.48 (s, 3H), 2.29 (s, 3H); ESIMS m/z 305 [M+H] ⁺ .

General Procedure N:

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide (Example Compound 24) and 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5(4H)-one (Example Compound 25)

Step 1: To a solution of Example Compound 53 (85 mg, 0.25 mmol) in CH ₂ Cl ₂ (3 mL) was added m-CPBA (160 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 7 hours. The mixture was diluted with dichloromethane (50 mL) and washed with 10% Na ₂ S ₂ O ₃ solution (10 mL), 2N NaOH solution (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-70% ethyl acetate/dichloromethane) provided Example Compound 24 (60 mg, 67%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (d, J=0.9 Hz, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.40-7.35 (m, 2H), 7.20-7.14 (m, 2H), 5.59 (s, 2H), 2.69 (s, 3H), 2.45 (s, 3H), 2.27 (s, 3H); ESIMS m/z 353 [M+H] ⁺ .

Step 2: A solution of Example Compound 24 (32 mg, 0.091 mmol) in Ac ₂ O (3 mL) was heated at 130 ° C for 2 hours. The mixture was concentrated. The residue was diluted with 1:1 CH ₃ OH/H ₂ O (10 mL) and stirred at 80 ° C for 10 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) gave Example Compound 25 (20 mg, 63%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.0 (s, 1H), 8.07 (s, 1H), 7.36-7.31 (m, 2H), 7.19-7.13 (m, 2H), 5.45 (s, 2H), 2.30 (s, 6H), 2.14 (s, 3H); ESIMS m/z 353 [M+H] ⁺ .

Preparation of 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,5-dimethylisoxazole (Example Compound 26)

[0114] Step 1: To a solution of 50 (560 mg, 2.57 mmol) in _CH3CN (15 mL) was added _{K2CO3 (} 887 mg, 6.43 mmol) and benzyl chloride (484 mg, 2.83 mmol). The reaction was heated at 60°C for 16 hours. The mixture was diluted with ethyl acetate (100 mL), filtered, and concentrated to afford 51 (790 mg, 100%) as a yellow solid: ^1H NMR (300 MHz, _CDCl3 ) δ 8.58 (br s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.46-7.35 (m, 5H), 6.82 (d, J = 8.7 Hz, 1H), 4.82 (d, J = 5.7 Hz, 2H).

Step 2: To a solution of 51 (790 mg, 2.56 mmol) in 1,4-dioxane (25 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.14 g, 5.12 mmol), sodium carbonate (2.0 M in H ₂ O, 3.84 mL, 7.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 8 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-20% EtOAc/hexanes) to give 52 (500 mg, 60%) as a yellow oil: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.09 (t, J=6.0 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H), 7.32-7.20 (m, 5H), 6.96 (d, J=8.7 Hz, 1H), 4.85 (d, J=6.3 Hz, 2H), 2.47 (s, 3H), 2.25 (s, 3H); ESI m/z 325 [M+H] ⁺ .

Step 3: To a solution of 52 (500 mg, 1.54 mmol) in THF (15 mL) and water (12 mL) was added Na ₂ S ₂ O ₄ (1.61 g, 9.24 mmol). The mixture was stirred at room temperature for 5 hours; 2N HCl (10 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na ₂ CO ₃ was slowly added to adjust to pH 9. The mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (50 mL), filtered, and concentrated to give 53 (460 mg, 100%) as a brown oil: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.33-7.18 (m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.52 (d, J=7.5 Hz, 1H), 6.29 (t, J=5.7 Hz, 1H), 4.94 (s, 2H), 4.60 (d, J=5.7 Hz, 2H), 2.36 (s, 3H), 2.17 (s, 3H); ESI m/z 295 [M+H] ⁺ .

Step 4: A solution of 53 (150 mg, 0.51 mmol), trimethyl orthoformate (81 mg, 0.765 mmol) and sulfamic acid (3 mg) in MeOH (5 mL) was heated to reflux for 4 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 30-100% ethyl acetate/hexanes) to afford Example Compound 26 (100 mg, 65%) as an off-white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.67 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.36-7.27 (m, 5H), 5.52 (s, 2H), 2.54 (s, 3H), 2.34 (s, 3H); ESI m/z 305 [M+H] ⁺ .

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine (Example Compound 27), 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-benzo[d]imidazol-4-amine (Example Compound 28), and 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N,N-dimethyl-1H-benzo[d]imidazol-4-amine (Example Compound 29)

Example Compound 27 was prepared by a procedure analogous to that described for Example 7: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.23 (s, 1H), 7.42 (dd, J=8.0, 6.0 Hz, 2H), 7.17 (dd, J=9.0, 9.0 Hz, 2H), 6.62 (s, 1H), 6.32 (s, 1H), 5.40 (s, 4H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 337 [M+H] ⁺ .

To a solution of Example Compound 27 (35 mg, 0.10 mmol) in dichloromethane (5 mL) was added a solution of 37% formaldehyde in water (8.5 μL) and acetic acid (1 drop). The solution was stirred for 45 minutes, sodium triacetoxyborohydride (66 mg, 0.31 mmol) was added and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane (20 mL) and neutralized with saturated sodium bicarbonate (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0–75% ethyl acetate/dichloromethane) to provide Example Compound 28 (8 mg, 22%) as a white solid and Example Compound 29 (7 mg, 18%) as a transparent solid. Example Compound 28: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.43 (dd, J = 8.8, 5.5 Hz, 2H), 7.16 (dd, J = 8.8, 5.5 Hz, 2H), 6.65 (d, J = 1.0 Hz, 1H), 6.09 (d, J = 1.0 Hz, 1H), 5.85 (q, J = 5.0 Hz, 1H), 5.41 (s, 2H), 2.83 (d, J = 5.5 Hz, 3H), 2.35 (s, 3H), 2.17 (s, 3H); ESI m/z 351 [M+H] ⁺ ; Example 29: ¹ H NMR (500 MHz, DMSO-d ₆ )δ8.28(s,1H),7.41(dd,J＝8.5,5.5Hz,2H),7.17(dd,J＝9.0,9.0Hz,2H),6.85(d,J＝1.0 Hz,1H),6.25(d,J＝1.0Hz,1H),5.43(s,2H),3.18(s,6H),2.35(s,3H),2.18(s,3H); ESI m/z 365[M+H] ⁺ .

Preparation of 4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 30)

Step 1: To a suspension of 3-amino-5-bromo-2-nitropyridine (54, 780 mg, 3.58 mmol) and potassium carbonate (2.28 g, 16.5 mmol) in dry acetonitrile (50 mL) was added 1-(bromoethyl)benzene (1.22 g, 6.60 mmol). The mixture was heated to 80 ° C for 48 hours, then water (20 mL) and ethyl acetate (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate fractions were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes) to provide 55 (219 mg, 19%) as a yellow solid: ^1H NMR (500 MHz, CDCI ₃ ) δ 8.14 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.40-7.29 (m, 6H), 4.64 (quint, J=6.5 Hz, 1H), 1.67 (d, J=7.0 Hz, 3H).

Step 2: To a mixture of 55 (261 mg, 0.81 mmol) and 3 (217 mg, 0.97 mmol) in 1,4-dioxane (7 mL) and water (1.5 mL) was added potassium carbonate (224 mg, 1.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.04 mmol). The reaction was stirred and heated at 90 ° C for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded on silica gel and eluted with 0-50% ethyl acetate in hexane. The clean product was concentrated to give 56 (226 mg, 82%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.19 (d, J=4.5 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.40-7.28 (m, 5H), 6.89 (d, J=2.0 Hz, 1H), 4.66 (quint, J=5.0 Hz, 1H), 2.10 (s, 3H), 1.94 (s, 3H), 1.71 (d, J=7.0 Hz, 3H).

Step 3: To a solution of 56 (226 mg, 0.67 mmol) in THF (20 ml) was added dropwise a solution of sodium dithionite (698 mg, 4.01 mmol) in water (20 mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. A 2N HCl aqueous solution was added to the residue and heated to reflux for 5 minutes. After being concentrated to dryness, methanol (10 mL) was added and the solution was adjusted to pH 8 using a saturated NaHCO ₃ aqueous solution (20 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was loaded on silica gel and eluted with 0–70% ethyl acetate in hexane. The clean product was concentrated to give 57 (96 mg, 47%) as a beige solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.42 (d, J = 2.0 Hz, 1H), 7.33-7.30 (m, 4H), 7.25-7.22 (m, 1H), 6.34 (d, J = 1.5 Hz, 1H), 4.44 (quint, J = 5.0 Hz, 1H), 4.36 (br s, 2H), 3.70 (br s, 1H), 2.07 (s, 3H), 1.89 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H).

Step 4: A mixture of 57 (47 mg, 0.15 mmol), trimethyl orthoformate (2 mL, 18.3 mmol) and sulfamic acid (1 mg) was heated in a sealed tube at 100° C. for 30 min. The mixture was cooled, concentrated and loaded onto silica gel and eluted with 0-20% ethyl acetate in hexanes. The resulting material was purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O to provide (Example Compound 30) (19 mg, 39%) as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.76 (s, 1 H), 8.36 (d, J=2.0 Hz, 1 H), 7.65 (d, J=2.5 Hz, 1 H), 7.40-7.30 (m, 5 H), 4.44 (q, J=7.0 Hz, 1 H), 2.29 (s, 3 H), 2.10 (s, 3 H), 2.06 (d, J=7.0 Hz, 3 H). ESI m/z 319 [M+H] ⁺ .

Preparation of 4-(1-benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 31), 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridine 5-oxide (Example 32), and 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (Example Compound 33)

Step 1: To a solution of 58 (1.00 g, 5.76 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.93 g, 8.64 mmol), potassium carbonate (1.59 g, 11.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (333 mg, 0.288 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to provide 59 (1.42 g, >99%) as a yellow solid: ¹ H NMR (300 MHz, CDCI ₃ ) δ 9.26 (s, 1H), 6.67 (s, 1H), 6.90-6.00 (bs, 2H), 2.61 (s, 3H), 2.44 (s, 3H); ESI m/z 235 [M+H] ⁺ .

[0114] Step 2: A mixture of 59 (710 mg, 3.03 mmol), benzyl bromide (778 mg, 4.55 mmol) and potassium carbonate (836 mg, 6.06 mmol) in acetonitrile (30 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford 60 (303 mg, 30%) as a brown solid: ^1H NMR (500 MHz, CDCl ₃ ) δ 9.26 (s, 1H), 8.68 (s, 1H), 7.50-7.10 (m, 5H), 6.50 (s, 1H), 4.65 (d, J=4.1 Hz, 2H), 2.39 (s, 3H), 2.19 (s, 3H); ESI m/z 325 [M+H] ⁺ .

Step 3: To a solution of 60 (300 mg, 0.926 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (967 mg, 5.56 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was suspended in MeOH and the solid was filtered, washed with MeOH, and the filtrate was concentrated under vacuum. 2N HCl was added to the residue and heated to just boiling, cooled to room temperature and concentrated under vacuum. The residue was dissolved in MeOH and basified with 10% NaHCO ₃ , concentrated and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to provide 61 (150 mg, 55%) as a grey solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.40-7.28 (m, 5H), 6.39 (s, 1H), 4.64 (s, 1H), 4.43 (d, J=5.4 Hz, 2H), 3.15 (s, 2H), 2.33 (s, 3H), 2.21 (s, 3H); ESI m/z 295 [M+H] ⁺ .

Step 4: To a solution of 61 (150 mg, 0.51 mmol) in ethanol (5 mL) was added trimethyl orthoformate (81 mg, 0.77 mmol) and sulfamic acid (1 mg, 0.01 mmol). The reaction was heated in a sealed tube at 90 ° C. overnight. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 31 (143 mg, 92%) as a yellow solid: ^1H NMR (500 MHz, CD ₃ OD) δ 9.00 (d, J = 1.0 Hz, 1H), 8.05 (s, 1H), 7.48 (d, J = 1.0 Hz, 1H), 7.40-7.30 (m, 5H), 5.58 (s, 2H), 2.40 (s, 3H), 2.25 (s, 3H); ESI m / z 305 [M + H] ⁺ .

Step 5: To a mixture of Example Compound 31 (100 mg, 0.329 mmol) in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (264 mg, 77% aqueous solution, 1.18 mmol). The mixture was stirred at room temperature overnight, concentrated, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford Example Compound 32 (127 mg, >99%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.92 (s, 1H), 8.61 (s, 1H), 7.67 (s, 1H), 7.45-7.25 (m, 5H), 6.57 (s, 2H), 2.28 (s, 3H), 2.17 (s, 3H); ESI m/z 321 [M+H] ⁺ .

Step 6: To a mixture of phosphorus oxybromide (268 mg, 0.938 mmol) in DMF (2 mL) was added Example 32 (100 mg, 0.313 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 10 minutes and heated at 100°C for 1 hour. After cooling to room temperature, water and MeOH were added. The mixture was neutralized to pH 7 by adding 10% sodium bicarbonate and concentrated. The residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to provide 62 (30 mg, 25%) as an off-white solid: ¹ H NMR (500 MHz, CDCI ₃ ) δ 8.09 (s, 1H), 7.43-7.35 (m, 3H), 7.23-7.19 (m, 2H), 7.03 (s, 1H), 5.38 (s, 2H), 2.47 (s, 3H), 2.31 (s, 3H); ESI m/z 383 [M+H] ⁺ .

Step 7: To a solution of 62 (30 mg, 0.078 mmol) in toluene (10 mL) was added tert-butyl carbamate (27 mg, 0.23 mmol), cesium carbonate (51 mg, 0.16 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (6 mg, 0.01 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7 mg, 0.008 mmol) under nitrogen atmosphere. The reaction mixture was heated at 90 ° C. overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O to give Example Compound 33 (10 mg, 40%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.21 (s, 1H), 7.42-7.25 (m, 5H), 6.70 (s, 1H), 5.46 (s, 2H), 2.39 (s, 3H), 2.24 (s, 3H); HPLC 96.9%, t _R =10.1 min; ESI m/z 320 [M+H] ⁺ .

Preparation of 4-(1-benzyl-3-bromo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole. (Example Compound 34)

Step 1: To a solution of 46 (1.0 g, 5.08 mmol) in 1,4-dioxane (50 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.47 g, 6.6 mmol), sodium carbonate (1.10 g in 8 mL H ₂ O, 10.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (587 mg, 0.51 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded 63 (850 mg, 79%) as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.4 (s, 1H), 8.30 (t, J=2.1 Hz, 1H), 7.75 (dd, J=1.8, 0.9 Hz, 1H), 7.70 (t, J=3.0 Hz, 1H), 6.61-6.59 (m, 1H), 2.42 (s, 3H), 2.24 (s, 3H).

Step 2/3: To a solution of 63 (500 mg, 2.35 mmol) in DMF (10 mL) at 0°C was added NBS (500 mg, 2.82 mmol). The reaction mixture was stirred at 0°C for 2 hours. The mixture was diluted with dichloromethane (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product 64 was used further in the reaction. To a solution of 64 (300 mg, 1.03 mmol) in DMF (1 mL) and CH ₃ CN (10 mL) were added potassium carbonate (283 mg, 2.06 mmol) and benzyl chloride (130 mg, 1.03 mmol). The reaction was stirred at 70°C for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated. Purification by chromatography on silica gel, 0-50% ethyl acetate/dichloromethane (500 MHz, CD ₃ OD) afforded Example Compound 34 (200 mg, 51%) as an off-white solid: ¹ H NMR (500 MHz, CD 3 OD) δ 8.33 (d, J=1.5 Hz, 1H), 7.86 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.34-7.24 (m, 5H), 5.48 (s, 2H), 2.35 (s, 3H), 2.17 (s, 3H); ESI MS m/z 382 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (Example Compound 35)

Step 1: To a mixture of 46 (300 mg, 1.5 mmol) and hexamethylenetetramine (0.32 g, 2.25 mmol) was added AcOH (2 mL). The reaction mixture was stirred at 120 ° C for 6 hours and quenched with H ₂ O (5 mL). The precipitate was harvested by filtration to afford 65 (190 mg, 56%) as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.4 (s, 1H), 10.1 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.47 (s, 1H), 8.18 (d, J = 2.1 Hz, 1H).

Step 2: To a solution of 65 (190 mg, 0.84 mmol) in 1,4-dioxane (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (245 mg, 1.09 mmol), sodium carbonate (178 mg in 1 mL H ₂ O, 1.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.08 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded 66 (135 mg, 67%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.5 (s, 1H), 10.2 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 2.44 (s, 3H), 2.26 (s, 3H); ESIMS m/z 242 [M+H] ⁺ .

Step 3: To a solution of 66 (92 mg, 0.38 mmol) in DMF (0.5 mL) and CH ₃ CN (5 mL) were added potassium carbonate (105 mg, 0.76 mmol) and benzyl chloride (58 mg, 0.46 mmol). The reaction was stirred at 70° C. for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 35 (72 mg, 57%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.2 (s, 1H), 8.73 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.44-7.30 (m, 5H), 5.59 (s, 2H), 2.40 (s, 3H), 2.21 (s, 3H); ESI MS m/z 332 [M+H] ⁺ .

Preparation of 1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine (Example Compound 72)

A solution of Example Compound 35 (54 mg, 0.16 mmol), dimethylamine (0.25 mL, 2 M in THF, 0.49 mmol) and NaBH(OAc) ₃ (104 mg, 0.49 mmol) in CH ₂ Cl ₂ (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 72 (42 mg, 71%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 7.36-7.32 (m, 4H), 7.21-7.18 (m, 2H), 5.39 (s, 2H), 4.50 (s, 2H), 2.86 (s, 6H), 2.32 (s, 3H), 2.16 (s, 3H); ESIMS m/z 361 [M+H] ⁺ .

Preparation of 1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (Example Compound 36)

Step 1: To a suspension of AlCl ₃ (313 mg, 2.35 mmol) in CH ₂ Cl ₂ (20 mL) was added 63 (100 mg, 0.47 mmol) and AcCl (184 mg, 2.35 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction was carefully quenched with methanol (10 mL) and the pH was adjusted to neutralize with solid Na ₂ CO _3. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-10% methanol/dichloromethane) provided 67 (82 mg, 68%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.8 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 2.71 (s, 3H), 2.45 (s, 3H), 2.26 (s, 3H); ESIMS m/z 256 [M+H] ⁺ .

Step 2: To a solution of 67 (62 mg, 0.24 mmol) in DMF (0.5 mL) and CH ₃ CN (5 mL) were added potassium carbonate (67 mg, 0.48 mmol) and benzyl chloride (37 mg, 0.29 mmol). The reaction was stirred at 70° C. for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 36 (30 mg, 36%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59 (d, J=1.5 Hz, 1H), 8.22 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.40-7.36 (m, 3H), 7.21-7.18 (m, 2H), 5.40 (s, 2H), 2.89 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); ESI MS m/z 346 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl formate (Example Compound 37)

Step 1: A solution of Example Compound 56 (165 mg, 0.52 mmol) in DMF (2 mL) was added to POCl ₃ (159 mg, 1.03 mmol). The reaction mixture was heated at 100° C. for 2 hours and concentrated. The residue was dissolved in CH ₂ Cl ₂ (100 mL) and washed with saturated NaHCO ₃ (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 37 (81 mg, 45%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.90 (s, 1H), 7.62 (s, 1H), 7.43-7.41 (m, 3H), 7.28 (s, 1H), 7.22-7.18 (m, 3H), 5.31 (s, 2H), 2.22 (s, 3H), 2.10 (s, 3H); ESIMS m/z 348 [M+H] ⁺ .

Preparation of 4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzamide (Example Compound 38)

To a solution of Example Compound 70 (100 mg, 0.29 mmol) in ethanol (3 mL) was added 2N sodium hydroxide in water (1.46 mL, 2.9 mmol). The mixture was heated to 85°C for 20 minutes, then cooled to room temperature and neutralized with 2 mL of acetic acid. The mixture was basified (pH 8) with solid sodium carbonate, diluted in dichloromethane (100 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo and purified by chromatography (silica gel, 0-20% methanol/dichloromethane) to provide Example Compound 38 (71 mg, 68%) as a white solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.35 (d, J=1.8 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.94 (br s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.37 (br s, 1H), 7.27 (d, J=8.4 Hz, 2H), 5.61 (s, 2H), 2.60 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H); ESI m/z 362 [M+H] ⁺ .

Preparation of 4-(1-benzyl-3-nitro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 39)

Step 1: To a solution of 63 (100 mg, 0.47 mmol) in _H2SO4 (0.5 _mL ) was added _HNO3 (35 mg, 0.47 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with _H2O (10 mL) and adjusted with 6N NaOH solution to neutralize the pH. The solution was extracted with _CH2Cl2 (30 mL). The organic layer was dried, _filtered and concentrated. Purification by chromatography (silica gel, 0-10% methanol/dichloromethane) afforded 68 (82 mg, 68%) as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.9 (s, 1H), 8.85 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 2.45 (s, 3H), 2.26 (s, 3H); ESIMS m/z 259 [M+H] ⁺ .

Step 2: To a solution of 68 (82 mg, 0.32 mmol) in DMF (0.5 mL) and CH ₃ CN (5 mL) were added potassium carbonate (88 mg, 0.64 mmol) and benzyl chloride (44 mg, 0.35 mmol). The reaction was stirred at 70° C. for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 39 (68 mg, 61%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.56 (s, 1H), 7.45-7.42 (m, 3H), 7.27-7.26 (m, 2H), 5.47 (s, 2H), 2.35 (s, 3H), 2.17 (s, 3H); ESIMS m/z 349 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-amine (Example Compound 17)

Step 1: A mixture of 37 (200 mg, 0.709 mmol) in tetraethoxymethane (340 mg, 1.77 mmol) was heated at 100° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 69 (177 mg, 74%) as a yellow solid: ^1H NMR (500 MHz, CD ₃ OD) δ 7.30-7.15 (m, 2H), 4.57 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.23 (s, 3H), 1.47 (t, J=7.0 Hz, 3H); ESI m/z 336 [M+H] ⁺ .

Step 2: To a solution of 69 (250 mg, 0.74 mmol) in CH ₃ CN (8 mL) and DMF (2 mL) was added K ₂ CO ₃ (155 mg, 0.82 mmol) and benzyl chloride (104 mg, 0.82 mmol). The reaction was heated at 60° C. for 16 h. The mixture was diluted with ethyl acetate (100 mL), filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to afford 70 (200 mg, 63%) as an off-white solid and 71 (87 mg, 27%) as a colorless oil: 70: ^1H NMR (300 MHz, CDCl ₃ ) δ 7.34-7.29 (m, 3H), 7.21-7.18 (m, 3H), 6.77 (d, J=1.5 Hz, 1H), 5.16 (s, 2H), 4.75 (q, J=7.5 Hz, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 1.50 (t, J=7.0 Hz, 3H); 71: ^1H NMR (300 MHz, CDCl 3 ) δ 7.34-7.29 (m, 3H), 7.21-7.18 (m, 3H), 6.77 (d, J=1.5 Hz, 1H), 5.16 (s, 2H), 4.75 (q, J=7.5 Hz, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 1.50 (t, J=7.0 Hz, _3H ); )δ7.37(d,J＝1.5Hz,1H),7.34–7.28(m,3H),7.18(d,J＝7.5Hz,2H),7.12(d,J＝1.5Hz,1H ), 5.60 (s, 2H), 4.63 (q, J = 7.0Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.45 (t, J = 7.0Hz, 3H).

Step 3: A mixture of 70 (100 mg, 0.235 mmol), _BocNH2 (82 mg, 0.705 mmol), Xantphos (28 mg, 0.048 mmol), _Pd2 (dba) ₃ (22 mg, 0.024 mmol) and _Cs2CO3 (268 mg, 0.823 mmol) in 1,4- _dioxane (8 mL) was purged with nitrogen and heated at 100°C for 18 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to afford 72 (90 mg, 83%) as an off-white solid: ^1H NMR (300 MHz, CDCI ₃ ) δ 7.74 (br s, 1H), 7.41 (s, 1H), 7.32-7.29 (m, 3H), 7.22-7.19 (m, 2H), 6.51 (d, J=1.5 Hz, 1H), 5.14 (s, 2H), 4.64 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 2.17 (s, 3H), 1.49 (t, J=7.2 Hz, 3H), 1.46 (s, 9H).

Step 4: A solution of 72 (90 mg, 0.195 mmol) in TFA (1 mL) and CH ₂ Cl ₂ (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO ₃ (50 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 40-100% EtOAc/hexanes) provided Example Compound 17 (51 mg, 72%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.20 (m, 5H), 6.33 (d, J=1.5 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 5.13 (s, 2H), 4.68 (q, J=6.9 Hz, 2H), 4.30 (br s, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.49 (t, J=7.2 Hz, 3H); ESI m/z 363 [M+H] ⁺ .

Preparation of 4-(1-benzyl-2-ethoxy-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 59)

To a mixture of 28 (50 mg, 0.17 mmol) and tetraethyl orthocarbonate (131 mg, 0.68 mmol) was added sulfamic acid (3 mg, 0.034 mmol). The mixture was then heated to 100 °C for 8 hours, then diluted with ethyl acetate (30 mL), washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 59 (24 mg, 41%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.75 (d, J=1.2 Hz, 1 H), 7.38-7.22 (m, 5 H), 7.18 (d, J=1.5 Hz, 1 H), 4.99 (s, 2 H), 4.34 (q, J=7.2 Hz, 2 H), 2.37 (s, 3 H), 2.18 (s, 3 H), 1.42 (t, J=7.2 Hz, 3 H); ESI m/z 349 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carbonitrile (Example Compound 85)

Compound 73 was prepared by following the method of General Procedure J, Steps 1 to 3, starting with 2-amino-5-bromobenzonitrile. Compound 73 (30 mg, 0.09 mmol) was subjected to the procedure of General Procedure D, Step 3 to afford Example Compound 85 (10 mg, 31%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.63 (d, J=1.5 Hz, 1 H), 7.60 (d, J=1.5 Hz, 1 H), 7.38-7.27 (m, 3 H), 7.19-7.14 (m, 2 H), 5.57 (s, 2 H), 2.69 (s, 3 H), 2.32 (s, 3 H), 2.16 (s, 3 H); ESI m/z 343 [M+H] ⁺ .

General Procedure O:

Preparation of N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide (Example Compound 111)

A solution of Example Compound 16 (34 mg, 0.10 mmol), acetic anhydride (12 mg, 0.12 mmol) and i-Pr ₂ NEt (26 mg, 0.20 mmol) in THF (3 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/EtOAc) to provide Example Compound 111 (28 mg, 74%) as a white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 9.85 (s, 1H), 7.60-7.46 (m, 5H), 7.28 (d, J=1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 5.22 (s, 2H), 2.51 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ESI m/z 377 [M+H] ⁺ .

General Procedure P:

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 110) and 4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 115)

Step 1: To a solution of 30 (1.00 g, 3.21 mmol) in toluene (70 mL) under nitrogen atmosphere were added benzylamine (1.94 g, 16.0 mmol), potassium tert-butoxide (539 mg, 4.82 mmol), 2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (229 mg, 0.482 mmol) and tris(dibenzylideneacetone)dipalladium(0) (293 mg, 0.321 mmol). The reaction mixture was heated at 90° C. overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to provide 74 (700 mg, 62%) as a reddish-brown solid: ^1H NMR (500 MHz, CDCI ₃ ) δ 7.50 (d, J=1.8 Hz, 1H), 7.70-7.22 (m, 5H), 6.41 (d, J=1.6 Hz, 1H), 6.07 (s, 2H), 4.48 (q, J=3.5 Hz, 1H), 3.65 (s, 1H), 2.05 (s, 3H), 1.90 (s, 3H), 1.62 (d, J=6.6 Hz, 3H); ESI m/z 353 [M+H] ⁺ .

Step 2: To a mixture of 74 (600 mg, 1.70 mmol) in 1,4-dioxane (40 mL) was added 1,1'-carbonyldiimidazole (2.76 mg, 17.0 mmol) and DMAP (crystals).The reaction was heated in a sealed tube at 120°C for 2 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 110 (420 mg, 65%) as an orange solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.75 (d, J=1.3 Hz, 1 H), 7.44 (d, J=7.7 Hz, 2H), 7.38 (t, J=7.7 Hz, 2H), 7.31 (t, J=7.7 Hz, 1 H), 6.88 (d, J=1.3 Hz, 1 H), 5.88 (q, J=7.1 Hz, 1 H), 2.20 (s, 3H), 2.02 (s, 3H), 1.91 (d, J=7.2 Hz, 3H); ESI m/z 377 [M-H] ⁺ .

Step 3: To a solution of Example Compound 110 (100 mg, 0.265 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (276 mg, 1.59 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was added 2N HCl and heated to just boiling, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in MeOH and basified with concentrated _NH4OH , concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to give Example Compound 115 (49 mg, 53%) as an off-white solid: ^1H NMR (500 MHz, _CD3OD ) δ 7.42-7.32 (m, 4H), 7.26 (t, J=6.9 Hz, 1H), 6.35 (s, 1H), 5.94 (s, 1H), 5.78 (q, J=7.2 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 1.86 (d, J=7.2 Hz, 3H); ESI m/z 349 [M+H] ⁺ .

General Procedure Q:

Preparation of 4-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine (Example Compound 114)

A mixture of Example Compound 10 (90 mg, 0.28 mmol) and phosphorus (V) oxychloride (1 mL) was heated to 110 ° C for 5 hours and then cooled to room temperature. The mixture was concentrated, dissolved in dichloromethane (75 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in a solution of 2.0 M morpholine in tetrahydrofuran (5.6 mL, 11.2 mmol) and the mixture was heated to 75 ° C for 3 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with ethyl acetate/hexanes to provide Example Compound 114 (62 mg, 57%) as a white solid: ¹ H NMR (500 MHz, CDCI ₃ ) δ 8.24 (d, J=2.0 Hz, 1 H), 7.41-7.34 (m, 3 H), 7.15 (d, J=6.5 Hz, 2 H), 7.06 (d, J=1.0 Hz, 1 H), 5.26 (s, 2 H), 3.83 (t, J=4.5 Hz, 4 H), 3.50 (t, J=4.5 Hz, 4 H), 2.29 (s, 3 H), 2.11 (s, 3 H); ESI m/z 390 [M+H] ⁺ .

General procedure R:

Preparation of 1-(3,4-dichlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 101)

Compound 75 was prepared according to general procedure D, steps 1-2.

To a solution of 75 (218 mg, 0.60 mmol) in 1,4-dioxane (5 mL) was added 1,1'-carbonyldiimidazole (117 mg, 0.72 mmol) and the mixture was heated to 100°C for 16 hours. The mixture was diluted with dichloromethane (70 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 101 (155 mg, 66%) as a white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.5, 2.0 Hz, 1H), 5.05 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 389 [M+H] ⁺ .

General Procedures:

Preparation of (S)-3,5-dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 125) and (S)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine (Example Compound 143)

Compound 76 was prepared by following the method of General Procedure P, Step 1, starting from (S)-1-phenylethylamine.

Step 1: Using the procedure used in step 1 of General Procedure F, starting from compound 76 (140 mg, 0.40 mmol), Example Compound 125 (108 mg, 72%) was obtained as a yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 1.5 Hz, 1H), 7.42-7.30 (m, 6H), 6.11 (q, J = 7.2 Hz, 1H), 2.74 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H), 1.94 (d, J = 6.9 Hz, 3H); ESIMS m/z 377 [M+H] ⁺ .

Step 2: Using the procedure used in General Procedure P, step 3, starting with Example Compound 125 (80 mg, 0.21 mmol), Example Compound 143 (53 mg, 72%) was obtained as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.39-7.26 (m, 5H), 6.23 (d, J=1.5 Hz, 1H), 6.14 (d, J=1.2 Hz, 1H), 5.86 (q, J=7.2 Hz, 1H), 5.26 (s, 2H), 2.58 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.86 (d, J=6.9 Hz, 3H); ESIMS m/z 347 [M+H] ⁺ .

General Procedure T:

Preparation of 4-(1-benzyl-2-(pyridin-3-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 236)

A mixture of Example Compound 10 (100 mg, 0.31 mmol) and phosphorus (V) oxychloride (1 mL) was heated to 110 ° C for 5 hours and then cooled to room temperature. The mixture was concentrated, dissolved with dichloromethane (75 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in N, N-dimethylformamide (2.5 mL), and 3-hydroxypyridine (109 mg, 1.15 mmol) and potassium carbonate (175 mg, 1.27 mmol) were added. The mixture was heated to 100 ° C for 16 hours, then diluted with ethyl acetate (75 mL), washed with brine (2×25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 236 (58 mg, 47%) as a light brown solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.74 (d, J=2.7 Hz, 1H), 8.57 (dd, J=4.5, 0.9 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.59 (dd, J=8.4, 4.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.42-7.30 (m, 3H), 5.53 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 398 [M+H] ⁺ .

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine (Example Compound 127) and 6-(3,5-dimethylisoxazol-4-yl)-N ² -ethyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-2,4-diamine (Example Compound 134)

Step 1: To Example Compound 110 (200 mg, 0.529 mmol) was added phosphorus(V) oxychloride (2 mL, 21.5 mmol) and N,N-dimethylformamide (one drop). The reaction was heated at 90°C overnight. The mixture was concentrated, and the residue was dissolved in tetrahydrofuran (5 mL). Ethylamine (10 mL, 1 M in tetrahydrofuran) was added. The reaction mixture was heated at 70°C in a sealed tube for 2 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 127 (40 mg, 19%) as a yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.70 (d, J=1.5 Hz, 1 H), 7.45-7.30 (m, 5 H), 6.72 (d, J=1.5 Hz, 1 H), 5.86 (q, J=7.0 Hz, 1 H), 3.72 (q, J=7.2 Hz, 2 H), 2.17 (s, 3 H), 1.98 (s, 3 H), 1.90 (d, J=7.0 Hz, 3 H), 1.36 (t, J=7.2 Hz, 3 H); ESI m/z 406 [M-H] ⁺ .

Step 2: To a solution of Example Compound 127 (35 mg, 0.086 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (90 mg, 0.52 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was added with 2N HCl and heated to just boiling, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in MeOH and basified with concentrated _NH4OH , concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to give Example Compound 134 (15 mg, 47%) as an off-white solid: ^1H NMR (500 MHz, _CD3OD ) δ 7.40-7.25 (m, 5H), 6.31 (d, J=1.5 Hz, 1H), 5.92 (d, J=1.5 Hz, 1H), 5.72 (q, J=6.9 Hz, 1H), 3.53 (q, J=7.2 Hz, 2H), 2.15 (s, 3H), 1.99 (s, 3H), 1.86 (d, J=7.0 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H); ESI m/z 376 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 150) and 4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (Example Compound 162)

Step 1: A mixture of Example Compound 15 (73 mg, 0.20 mmol), CH ₃ I (85 mg, 0.60 mmol) and K ₂ CO ₃ (110 mg, 0.8 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated with EtOAc/hexanes to provide Example Compound 150 (65 mg, 86%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48 (d, J=1.5 Hz, 1H), 7.35-7.30 (m, 5H), 6.84 (d, J=1.5 Hz, 1H), 5.15 (s, 2H), 3.65 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H); ESI m/z 379 [M+H] ⁺ .

Step 2: To a solution of Example Compound 150 (57 mg, 0.15 mmol) in THF (5 mL) and water (4 mL) was added _{Na₂S₂O₄ (} 153 _mg , 0.90 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes. After cooling to room temperature, _Na₂CO₃ was slowly _added to adjust the pH to 9. The mixture was extracted with _CH2Cl2 (100 _mL ), and the organic layer was washed with brine (50 mL), filtered, concentrated, and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to provide Example Compound 162 (60 mg, 72%) as a white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.36-7.24 (m, 5H), 6.40 (d, J=1.5 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 5.08 (s, 2H), 4.99 (s, 2H), 3.62 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H); ESI m/z 349 [M+H] ⁺ . HPLC>99%

Preparation of 4-(1-benzyl-2-methyl-4-(methylsulfonyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 168)

A mixture of Example Compound 121 (100 mg, 0.25 mmol), sodium methanesulfinate (39 mg, 0.38 mmol), CuI (5 mg, 0.025 mmol), L-proline (6 mg, 0.05 mmol), and NaOH (2 mg, 0.05 mmol) in DMSO (3 mL) was heated in a microwave reactor at 150° C. for 2 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by chromatography (silica gel, 50-100% EtOAc/hexanes) to provide Example Compound 168 (13 mg, 13%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.75 (d, J=1.5 Hz, 1H), 7.37-7.33 (m, 3H), 7.24 (d, J=1.5 Hz, 1H), 7.11-7.08 (m, 2H), 5.39 (s, 2H), 3.54 (s, 3H), 2.73 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H); ESI m/z 396 [M+H] ⁺ . HPLC 92.3%.

Preparation of 4-(1-benzyl-2,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 181)

Step 1: To a solution of 77 (4.4 g, 16.5 mmol) in 1,4-dioxane (100 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (4.4 g, 19.8 mmol), Na ₂ CO ₃ (2.0 M in H ₂ O, 25 mL, 50.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (959 mg, 0.83 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and then purified by chromatography (silica gel, 0-60% ethyl acetate/hexanes) to afford 78 (2.64 g, 57%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (s, 1H), 6.32 (s, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H).

Step 2: A mixture of 78 (1.3 g, 4.61 mmol), benzylamine (2.51 mL, 23.05 mmol), X-phos (658 mg, 1.38 mmol), Pd ₂ (dba) ₃ (632 mg, 0.69 mmol) and t-BuOK (774 mg, 6.92 mmol) in toluene (50 mL) was purged with nitrogen for 10 minutes and then heated at 90° C. for 18 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-100% EtOAc/hexanes) to afford 79 (125 mg, 9%) as a brown gum: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.38 (s, 1H), 7.31-7.22 (m, 5H), 5.68 (s, 2H), 4.28 (t, J=7.5 Hz, 1H), 4.01 (d, J=7.0 Hz, 2H), 2.14 (s, 3H), 1.93 (s, 3H), 1.74 (s, 3H).

Step 3: To a solution of 79 (80 mg, 0.26 mmol) in triethyl orthoacetate (2 mL) was added AcOH (0.2 mL). The mixture was heated to 120 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in EtOAc (100 mL) and washed with saturated _NaHCO₃ (50 mL x 2). The organic layer was dried over _Na₂SO₄ , _filtered , and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/ethyl acetate) to provide Example Compound 181 (39 mg, 45%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.37-7.31 (m, 3H), 6.95-6.92 (m, 2H), 5.58 (s, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H); ESI m/z 333 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 180)

A mixture of 79 (31 mg, 0.10 mmol) and CDI (33 mg, 0.2 mmol) in dioxane (3 mL) was heated to 120° C. for 16 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 50-100% ethyl acetate/hexanes) to afford Example Compound 180 (10 mg, 30%) as an off-white solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 7.74 (s, 1H), 7.38-7.24 (m, 3H), 7.17-7.14 (m, 2H), 5.26 (s, 2H), 2.16 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H); ESI m/z 335 [M+H] ⁺ .

Preparation of 3,5-dimethyl-4-(2-methyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole (Example Compound 108)

Step 1: To a suspension of 27 (660 mg, 3.23 mmol) in acetonitrile (33 mL) was added (1-bromoethyl)benzene (658 mg, 3.55 mmol) and potassium carbonate (893 mg, 6.46 mmol). The mixture was heated to 60 ° C for 16 hours, then cooled, diluted with dichloromethane (120 mL) and washed with brine (40 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford 57 (256 mg, 26%) as a white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.36 (d, J=1.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.20-7.17 (m, 2H), 6.15 (d, J=2.0 Hz, 1H), 5.82 (s, 2H), 5.40 (d, J=5.5 Hz, 1H), 4.51-4.45 (m, 1H), 2.05 (s, 3H), 1.84 (s, 3H), 1.48 (d, J=7.0 Hz, 3H).

Step 2: To a solution of 57 (41 mg, 0.13 mmol) in triethyl orthoacetate (0.24 mL, 1.33 mmol) was added acetic acid (20 μL, 0.36 mmol). The mixture was heated to 100 ° C for 1 hour, and then one drop of concentrated HCl was added. The mixture was heated to 100 ° C for 10 minutes. The mixture was basified with saturated sodium bicarbonate, diluted with dichloromethane (45 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-3% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 108 (11 mg, 28%) as a white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.40-7.36 (m, 4H), 7.33-7.30 (m, 1H), 6.01 (q, J=7.0 Hz, 1H), 2.70 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H), 1.93 (d, J=7.0 Hz, 3H); ESI m/z 333 [M+H] ⁺ .

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 112) and 6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-amine (Example Compound 113)

Step 1: To a suspension of 57 (250 mg, 0.81 mmol) in 1,4-dioxane (6 mL) was added 1,1'-carbonyldiimidazole (158 mg, 0.97 mmol). The mixture was purged with nitrogen for 5 minutes and then heated to 100°C for 16 hours. The mixture was diluted with dichloromethane (100 mL), filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 112 (258 mg, 95%) as an off-white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.0 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.0 Hz, 3H); ESI m/z 335 [M+H] ⁺ .

Step 2: A mixture of Example Compound 112 (100 mg, 0.30 mmol) and phosphorus (V) oxychloride (1 mL) was heated to 110 ° C for 5 hours and cooled to room temperature. The reaction mixture was concentrated, diluted with dichloromethane (75 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in a solution of 2.0 M ethylamine in tetrahydrofuran (6.0 mL, 12.0 mmol) and the mixture was heated to 75 ° C for 7 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with ethyl acetate/hexanes to provide Example Compound 113 (52 mg, 49%) as a white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.90 (d, J=2.0 Hz, 1H), 7.40-7.28 (m, 6H), 6.81 (d, J=2.0 Hz, 1H), 5.84 (q, J=7.0 Hz, 1H), 3.54-3.48 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.83 (d, J=7.0 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H); ESI m/z 362 [M+H] ⁺ .

Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Enantiomer A) (Example Compound 218) and 6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Enantiomer B) (Example Compound 219)

Example compound 112 (87 mg) was separated by SFC chiral HPLC (Chiralpak AS-H, 30 mm×250 mm, mobile phase 30% EtOH (0.2% Et ₂ NH) in CO ₂ , 120 bar, flow rate 80 mL/min) to provide Example compound 218 (enantiomer A) (41 mg, 46%) and Example compound 219 (enantiomer B) (41 mg, 46%) as off-white solids.

Example Compound 218 (Enantiomer A): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.5 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.5 Hz, 3H); ESI m/z 335 [M+H] ⁺ ; HPLC (Chiralcel OD, 4.6 mm×250 mm, 10% EtOH in heptane, 1 mL/min) >99%, t _R =9.4 minutes.

Example Compound 219 (Enantiomer B): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.5 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.5 Hz, 3H); ESI m/z 335 [M+H] ⁺ ; HPLC (Chiralcel OD, 4.6 mm×250 mm, 10% EtOH in heptane, 1 mL/min) >99%, t _R =10.9 minutes.

Preparation of 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-1H-benzo[d]imidazol-2(3H)-one (Example Compound 122)

Step 1: To a solution of 20 (214 mg, 0.77 mmol) in 1,4-dioxane (5 mL) was added 1,1'-carbonyldiimidazole (150 mg, 0.93 mmol) and the mixture was heated to 100°C for 15 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate/hexanes) to afford 80 (142 mg, 61%) as a white solid; ^1H NMR (500 MHz, DMSO- _d6 ) δ 11.13 (s, 1H), 7.35-7.25 (m, 6H), 7.12 (dd, J = 8.5, 2.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H).

Step 2: To a solution of 80 (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (110 mg, 0.49 mmol), potassium carbonate (91 mg, 0.66 mmol) and water (1 mL). The mixture was purged with nitrogen for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) was added, and the mixture was heated to 90 ° C for 16 hours. The mixture was diluted with dichloromethane (100 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with ethyl acetate/hexanes to afford 81 (55 mg, 52%) as a white solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 7.40-7.23 (m, 5H), 7.06 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.95 (dd, J=7.8, 1.5 Hz, 1H), 5.03 (s, 2H), 2.30 (s, 3H), 2.13 (s, 3H); ESI m/z 320 [M+H] ⁺ .

Step 3: To a solution of 81 (36 mg, 0.11 mmol) in acetonitrile (3 mL) was added potassium carbonate (109 mg, 0.79 mmol) and iodoethane (80 mg, 0.56 mmol), and the mixture was heated to 40 ° C for 48 hours. The mixture was diluted with dichloromethane (75 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-20% ethyl acetate/dichloromethane) followed by trituration with ethyl acetate/hexanes to provide Example Compound 122 (14 mg, 37%) as an off-white solid: ^1H NMR (500 MHz, DMSO- _d6 ) δ 7.37 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.03 (dd, J = 8.0, 1.5 Hz, 1H), 5.08 (s, 2H), 3.94 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); ESI m/z 348[M+H] ⁺ .

Preparation of 1-benzyl-N ⁶ -(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4,6-diamine (Example Compound 142)

Step 1: To a suspension of 33 (790 mg, 3.09 mmol) in acetonitrile (15 mL) was added benzyl chloride (703 mg, 5.55 mmol) and potassium carbonate (1.07 g, 7.71 mmol). The reaction mixture was heated to 60° C. for 16 h, then concentrated, and the residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 82 (813 mg, 76%) as a yellow solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.33 (d, J=1.8 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.39-7.27 (m, 3H), 7.13 (d, J=6.6 Hz, 2H), 5.62 (s, 2H), 2.60 (s, 3H).

Step 2: To a solution of 82 (150 mg, 0.43 mmol) in toluene (5 mL) was added 83 (73 mg, 0.65 mmol), cesium carbonate (282 mg, 0.87 mmol) and XPhos (41 mg, 0.087 mmol). The solution was purged with nitrogen for 5 minutes, then tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.043 mmol) was added and heated to 110° C. for 16 hours. The mixture was filtered through celite and concentrated, and the residue was purified by chromatography (silica gel, 0-7% methanol/dichloromethane) to afford 84 (80 mg, 49%) as a brown oil: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.59 (s, 1H), 7.34-7.28 (m, 4H), 7.06 (d, J=7.0 Hz, 2H), 6.76 (d, J=2.5 Hz, 1H), 5.44 (s, 2H), 2.54 (s, 3H), 2.13 (s, 3H), 1.91 (s, 3H).

Step 3: To a solution of 84 (78 mg, 0.21 mmol) in tetrahydrofuran (5 mL) was added a solution of sodium dithionite (215 mg, 1.24 mmol) in water (4 mL). The mixture was stirred at room temperature for 2 hours, then 2N HCl (1 mL) was added and the mixture was heated to reflux for 15 minutes. The mixture was basified with sodium carbonate and extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 142 (38 mg, 53%) as a reddish-brown solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.31 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.04 (d, J=7.5 Hz, 2H), 6.69 (s, 1H), 5.73 (d, J=2.0 Hz, 1H), 5.60 (d, J=2.0 Hz, 1H), 5.18 (s, 2H), 5.05 (s, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 1.92 (s, 3H); ESI m/z 348 [M+H] ⁺ .

General Procedure:

Preparation of 1-benzyl-2-methyl-6-(5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 201)

To a solution of 82 (100 mg, 0.29 mmol) in 1,4-dioxane (5 mL) was added 5-methylisoxazole-4-boronic acid pinacol ester (91 mg, 0.43 mmol), sodium carbonate (80 mg, 0.58 mmol), water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.01 mmol). The reaction mixture was purged with nitrogen and heated at 90 ° C for 5 hours. The mixture was diluted with dichloromethane (70 mL), washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% ethyl acetate/dichloromethane) to a yellow solid, which was dissolved in THF (4 mL), a solution of sodium dithionite (159 mg, 0.91 mmol) in water (2 mL) was added and the mixture was stirred at room temperature for 2 hours. 2N HCl (1 mL) was added to the mixture, and the mixture was heated to reflux for 15 minutes. The mixture was basified by saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (40 mL x 2).The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) and triturated with ethyl acetate/hexanes to provide Example Compound 201 (12 mg, 25%) as an off-white solid: ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (d, J=0.6 Hz, 1H), 7.36-7.26 (m, 3H), 7.15 (d, J=6.9 Hz, 2H), 6.78 (d, J=1.5 Hz, 1H), 6.47 (d, J=1.5 Hz, 1H), 5.40 (s, 2H), 5.33 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H); ESI m/z 319 [M+H] ⁺ .

Preparation of N-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol-4-amine (Example Compound 155)

Step 1: To a suspension of 2,3-diamino-5-bromopyridine 26 (1.5 g, 7.98 mmol) in dichloromethane (80 mL) was added benzaldehyde (931 mg, 8.78 mmol) and acetic acid (40 drops). The mixture was stirred at room temperature for 16 hours and then washed with saturated sodium bicarbonate solution (40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (50 mL) and sodium borohydride (815 mg, 21.5 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate (40 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford 85 (1.12 g, 51%) as an off-white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.35-7.34 (m, 4H), 7.28-7.23 (m, 2H), 6.54 (d, J=2.0 Hz, 1H), 5.78 (s, 2H), 5.73 (t, J=5.5 Hz, 1H), 4.30 (d, J=5.5 Hz, 2H).

Step 2: To a suspension of 85 (970 mg, 3.49 mmol) in triethyl orthoacetate (5.66 g, 37.9 mmol) was added acetic acid (539 μL, 9.42 mmol). The mixture was heated to 100 ° C for 40 minutes. The reaction mixture was basified with saturated sodium bicarbonate (8 mL), diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) to afford 86 (305 mg, 30%) as a light brown solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.41 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.30 (t, J=7.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 2H), 5.52 (s, 2H), 2.55 (s, 3H).

Step 3: To a solution of 86 (80 mg, 0.26 mmol) in toluene (5 mL) was added 83 (44 mg, 0.40 mmol), cesium carbonate (173 mg, 0.53 mmol) and XPhos (25 mg, 0.053 mmol). The solution was purged with nitrogen for 5 minutes, and then tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) was added. The mixture was heated to 110 ° C for 16 hours. The reaction mixture was diluted with dichloromethane (20 mL), filtered through celite, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 155 (40 mg, 45%) as a light brown solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.88 (d, J=2.5 Hz, 1H), 7.34-7.30 (m, 3H), 7.27 (t, J=7.0 Hz, 1H), 7.05 (d, J=7.0 Hz, 2H), 6.71 (d, J=2.5 Hz, 1H), 5.38 (s, 2H), 2.47 (s, 3H), 2.14 (s, 3H), 1.92 (s, 3H); ESI m/z 334 [M+H] ⁺ .

Preparation of 1-benzyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazo[4,5-b]pyridine (Example Compound 206)

To a solution of 86 (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (138 mg, 0.66 mmol), K ₂ CO ₃ (137 mg, 0.99 mmol), water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was diluted with ethyl acetate (70 mL), washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 206 (14 mg, 14%) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.54 (d, J=2.5 Hz, 1 H), 8.27 (d, J=2.0 Hz, 1 H), 7.96 (s, 1 H), 7.35 (t, J=7.0 Hz, 2 H), 7.29 (t, J=7.0 Hz, 1 H), 7.21 (d, J=7.0 Hz, 2 H), 5.58 (s, 2 H), 4.07 (s, 3 H), 2.60 (s, 3 H); ESI m/z 305 [M+H] ⁺ .

Preparation of 1-benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine (Example Compound 154)

1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine (Example Compound 154) was prepared by following a procedure analogous to that used for Example Compound 206 as an off-white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.48 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.29 (t, J=7.0 Hz, 1H), 7.21 (d, J=7.0 Hz, 2H), 6.46 (d, J=2.0 Hz, 1H), 5.57 (s, 2H), 3.83 (s, 3H), 2.60 (s, 3H); ESI m/z 304[M+H] ⁺ .

Preparation of 4-(1-benzyl-2-cyclopropyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 138)

To a solution of diamine 28 (100 mg, 0.340 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxaldehyde (29 mg, 0.408 mmol) and acetic acid (0.67 mL). The mixture was heated at 110 ° C for 24 hours. The mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) to provide Example Compound 138 (68 mg, 58%) as an off-white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.29 (d, J=2.1 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.37-7.33 (m, 2H), 7.30-7.28 (m, 3H), 5.67 (s, 2H), 2.38 (s, 3H), 2.37-2.35 (m, 1H), 2.20 (s, 3H), 1.13-1.11 (m, 4H); ESI m/z 345 [M+H] ⁺ . HPLC >99%. Preparation of 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 145), 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine (Example Compound 159), 4-amino-1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 161), and 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N ₂ -ethyl-1H-benzo[d]imidazol-2,4-diamine (Example Compound 160)

Step 1: To a mixture of 32 (1.50 g, 6.46 mmol) and 3 (2.16 g, 9.70 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added potassium carbonate (1.79 g, 12.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (373 mg, 0.32 mmol). The reaction was stirred and heated at 90 ° C for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (20 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded on silica gel and eluted with 0-50% ethyl acetate in hexane. The clean product was concentrated to give 87 (585 mg, 36%) as a brown solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.62 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.01 (br s, 2H), 3.52 (br s, 2H), 2.39 (s, 3H), 2.25 (s, 3H).

Step 2: To a solution of 87 (250 mg, 1.01 mmol), a catalytic amount of DMAP, and 1,4-dioxane (4 mL) in a pressure tube was added 1,1'-carbonyldiimidazole (327 mg, 2.01 mmol). The tube was sealed and heated to 80°C for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded onto silica gel (40 g) and eluted with 0-70% ethyl acetate in hexanes. The clean product was concentrated to give 88 (167 mg, 60%) as an orange solid: ^1H NMR (500 MHz, CDCl ₃ ) δ 7.74 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H).

Step 3: To a solution of 88 (309 mg, 1.13 mmol), potassium carbonate (312 mg, 2.25 mmol), acetonitrile (5 mL) and DMF (2 mL) in a pressure tube was added (bromomethyl)cyclopropane (183 mg, 1.35 mmol) and the reaction was sealed and heated at 80 ° C for 17 hours. The material was cooled to room temperature and poured into saturated aqueous NaCl solution (30 mL). Ethyl acetate (100 mL) was added and the layers were separated. The ethyl acetate layer was washed with saturated aqueous NaCl solution (2×100 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The resulting oil in CH ₂ Cl ₂ (10 mL) was loaded onto silica gel (80 g) and eluted with 0-40% ethyl acetate in hexanes. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example Compound 145 (88 mg, 35%) as a yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.82 (d, J = 1.5 Hz, 1 H), 7.52 (d, J = 1.0 Hz, 1 H), 3.87 (d, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 1.30-1.18 (m, 1H), 0.60-0.52 (m, 2H), 0.47-0.43 (m, 2H). ESI m/z 329 [M+H] ⁺ . HPLC >99%.

Step 4: A solution of Example Compound 145 (171 mg, 0.521 mmol) in phosphorus (V) oxychloride (4 mL) was placed in a sealed tube and heated at 110 ° C for 8 hours. The solvent was removed in vacuo and saturated aqueous NaHCO ₃ solution (5 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined extracts were dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated. THF (5 mL) and a 2.0 M solution of ethylamine in THF were then added, and the reaction was heated at 70 ° C for 12 hours. The reaction was concentrated to dryness and the residue was diluted with CH ₂ Cl ₂ (5 mL). The resulting solution was loaded on silica gel (40 g) and eluted with 0-80% ethyl acetate in hexane. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example Compound 159 (105 mg, 57%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.78 (d, J=1.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 4.03 (d, J=6.5 Hz, 2H), 3.67 (q, J=7.0 Hz, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.30-1.18 (m, 1H), 0.60-0.52 (m, 2H), 0.47-0.41 (m, 2H). ESI m/z 356 [M+H] ⁺ .HPLC>99%.

Step 5: A solution of Example Compound 145 (59 mg, 0.215 mmol) in THF (10 ml) was added dropwise to a solution of sodium dithionite (225 mg, 1.29 mmol) in water (10 mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. 2N HCl aqueous solution (10 mL) was added to the residue and heated to reflux for 5 minutes. After being concentrated to dryness, methanol (10 mL) was added and the solution was adjusted to pH 8 using saturated NaHCO ₃ aqueous solution (15 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was loaded on silica gel and eluted with 0–4% methanol in dichloromethane. The clean product was then purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O and the clean fractions were frozen and lyophilized to give Example Compound 161 (32 mg, 50%) as a white solid: ^1H NMR (500 MHz, _CD3OD ) δ 6.49 (d, J = 1.5 Hz, 1H), 6.42 (d, J = 1.5 Hz, 1H), 3.75 (d, J = 6.5 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.28-1.18 (m, 1H), 0.56-0.48 (m, 2H), 0.44-0.39 (m, 2H). ESI m/z 299 [M+H] ⁺ . HPLC 97.4%.

Step 6: A solution of Example Compound 159 (90 mg, 0.253 mmol) in THF (10 ml) was added dropwise to a solution of sodium dithionite (265 mg, 1.52 mmol) in water (10 mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. 2N HCl aqueous solution (10 mL) was added to the residue and heated to reflux for 5 minutes. After concentration to dryness, methanol (10 mL) was added and the solution was adjusted to pH 8 using saturated NaHCO ₃ aqueous solution (15 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was loaded on silica gel and eluted with 0–4% methanol in dichloromethane. The clean product was then purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O and the clean fractions were frozen and lyophilized to give Example Compound 160 (61 mg, 74%) as a white solid: ^1H NMR (500 MHz, _CD3OD ) δ 6.49 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 3.88 (d, J = 6.5 Hz, 2H), 3.48 (q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.28-1.18 (m, 1H), 0.53-0.48 (m, 2H), 0.40-0.35 (m, 2H). ESI m/z 326 [M+H] ⁺ . HPLC >99%.

Preparation of 4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 129).

To a solution of Example Compound 104 (54 mg, 0.15 mmol) in dichloromethane (5 mL) was added boron tribromide (0.45 mL, 1 M in dichloromethane, 0.45 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, treated with methanol, and concentrated in vacuo. The residue was dissolved in methanol, basified with ammonium hydroxide, concentrated in vacuo, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It was further purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to give Example Compound 129 (31 mg, 59%) as an off-white solid: ^1H NMR (500 MHz, _CD3OD ) δ 7.17 (d, J=8.6 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 6.39 (d, J=1.3 Hz, 1H), 6.26 (d, J=1.3 Hz, 1H), 4.94 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); HPLC >99%, _tR = 11.0 min; ESI m/z 351 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-ol (Example Compound 173)

Step 1: To a solution of 89 (5.00 g, 32.5 mmol) and triethylamine (9.04 mL, 65.0 mmol) in N,N-dimethylformamide (150 mL) was added tert-butylchlorodimethylsilane (5.86 g, 39.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate. The mixture was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to afford 90 (8.59 g, 98%) as a brown oil: ^1H NMR (300 MHz, CDCl ₃ ) δ 7.75 (dd, J = 1.3, 8.9 Hz, 1H), 6.89 (dd, J = 1.2, 7.6 Hz, 1H), 6.53 (dd, J = 8.8, 7.6 Hz, 1H), 6.45–6.15 (bs, 2H), 1.03 (s, 9H), 0.28 (s, 6H).

Step 2: To a solution of 90 (8.59 g, 32.1 mmol) in acetic acid (120 mL) was added N-bromosuccinimide (6.28 g, 35.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in methanol and basified with 5% aqueous sodium bicarbonate solution. The resulting precipitate was filtered, washed with water, and dried under vacuum to afford 91 (8.56 g, 76%) as an orange solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.91 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.50–6.12 (bs, 2H), 1.03 (s, 9H), 0.30 (s, 6H).

Step 3: To a solution of 91 (5.00 g, 14.4 mmol) in tetrahydrofuran (60 mL) was added platinum on carbon (1.00 g, 5% Pt on carbon). The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere. The mixture was filtered, washed with MeOH, and the filtrate was concentrated to afford 92 (5.65 g, >99%) as a dark brown oil: ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.51 (d, J = 2.0 Hz, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 3.50-2.50 (bs, 4 H), 1.01 (s, 9 H), 0.24 (s, 6 H); ESI m/z 317 [M+H] ⁺ .

Step 4: To a solution of 92 (2.00 g, 6.31 mmol) in ethanol (50 mL) was added triethyl orthoacetate (3.07 g, 18.9 mmol) and sulfamic acid (1 mg, 0.01 mmol). The reaction was heated in a sealed tube at 80° C. overnight. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford 93 (2.07 g, 96%) as a light red solid: ^1H NMR (500 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.45 (s, 1H), 6.78 (s, 1H), 3.61 (s, 3H), 1.03 (s, 9H), 0.28 (s, 6H); ESI m/z 341 [M+H] ⁺ .

Step 5: A mixture of 93 (200 mg, 0.587 mmol), benzyl bromide (150 mg, 0.880 mmol) and potassium bicarbonate (113 mg, 0.822 mmol) in acetonitrile (20 mL) was heated at 45 °C for 2 days. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to provide 94 (303 mg, 30%) as a brown solid: ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.36-7.26 (m, 3H), 7.01 (d, J=8.2 Hz, 2H), 6.97 (d, J=1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 5.22 (s, 2H), 2.50 (s, 3H), 1.05 (s, 9H), 0.30 (s, 6H); ESI m/z 431 [M+H] ⁺ .

Step 6: To a solution of 94 (75 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (58 mg, 0.26 mmol), potassium bicarbonate (70 mg, 0.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0087 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give 95 (53 mg, 70%) as an off-white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.33 (t, J = 6.3 Hz, 2H), 7.27 (t, J = 5.1 Hz, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.89 (d, J = 1.3 Hz, 1H), 6.58 (d, J = 1.3 Hz, 1H), 5.45 (s, 2H), 2.59 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.05 (s, 9H), 0.30 (s, 6H); HPLC > 99%, t _R = 16.4 min; ESI m/z 448 [M+H] ⁺ .

Step 7: A mixture of 95 (48 mg, 0.11 mmol) and potassium carbonate (30 mg, 0.22 mmol) in acetonitrile (10 mL) was heated in a sealed tube at 80° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It was further purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to give Example Compound 173 (32 mg, 87%) as an off-white solid: ^1H NMR (500 MHz, DMSO- _d6 ) δ 9.84 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.1 Hz, 2H), 6.86 (d, J = 1.3 Hz, 1H), 6.47 (d, J = 1.3 Hz, 1H), 5.42 (s, 2H), 2.52 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H); ESI m/z 334 [M+H] ⁺ .

Preparation of 4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione (Example Compound 177).

A mixture of Example Compound 16 (34 mg, 0.10 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) was heated to 180° C. in a microwave reactor for 2 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-40% EtOAc/hexanes) followed by chromatography ( _Ci8 , 10-70% _CH3CN /water) to afford Example Compound 177 (13 mg, 37%) as an off-white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 12.56 (s, 1H), 7.45-7.42 (m, 2H), 7.34-7.25 (m, 3H), 6.44 (d, J=1.2 Hz, 1H), 6.39 (d, J=1.5 Hz, 1H), 5.44 (s, 4H), 2.29 (s, 3H), 2.11 (s, 3H); ESI m/z 351 [M+H] ⁺ . HPLC 98.6%

Prepare 1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 198) and 4-amino-1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 199).

Compound 96 was prepared by following a procedure similar to that used to prepare Example Compound 15 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Step 1: A mixture of 96 (70 mg, 0.20 mmol), CH ₃ I (85 mg, 0.60 mmol) and K ₂ CO ₃ (110 mg, 0.8 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 20-70% ethyl acetate/hexanes) to provide Example Compound 198 (50 mg, 68%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.36-7.30 (m, 5H), 7.02 (d, J=1.5 Hz, 1H), 6.27 (d, J=1.2 Hz, 1H), 5.16 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H); ESI m/z 364 [M+H] ⁺ .

Step 2: To a solution of Example Compound 198 (45 mg, 0.12 mmol) in THF (5 mL) and water (4 mL) was added Na ₂ S ₂ O ₄ (129 mg, 0.74 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na ₂ CO ₃ was slowly added to adjust the pH to 9. The mixture was extracted with _CH2Cl2 (100 _mL ), and the organic layer was washed with brine (50 mL), filtered, concentrated, and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to provide Example Compound 199 (37 mg, 90%) as a white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.39 (d, J=1.8 Hz, 1H), 7.35-7.24 (m, 5H), 6.56 (d, J=1.5 Hz, 1H), 6.54 (d, J=1.5 Hz, 1H), 6.20 (d, J=1.8 Hz, 1H), 5.15 (s, 2H), 5.01 (s, 2H), 3.72 (s, 3H), 3.63 (s, 3H); ESI m/z 334 [M+H] ⁺ .

Preparation of 4-(1-benzyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 220)

To a solution of 28 (100 mg, 0.34 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (65 mg, 0.51 mmol) in CH ₂ Cl ₂ was added EDC (131 mg, 0.68 mmol), i-Pr ₂ NEt (132 mg, 1.02 mmol) and DMAP (10 mg). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL) and saturated NaHCO ₃ (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in AcOH (2 mL) and heated to reflux for 5 hours. The mixture was concentrated, and the residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO ₃ (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/EtOAc) to give Example Compound 220 (47 mg, 36%) as a light brown solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.41 (d, J=1.8 Hz, 1H), 7.38-7.32 (m, 3H), 7.24 (d, J=2.1 Hz, 1H), 7.08-7.05 (m, 2H), 5.42 (s, 2H), 4.12 (dd, J=11.7, 1.8 Hz, 2H), 3.52 (td, J=11.7, 1.8 Hz, 2H), 3.20-3.12 (m, 1H), 2.36-2.23 (m, 5H), 2.14 (s, 3H), 1.83-1.78 (m, 2H); ESI m/z 389[M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-carboxamide (Example Compound 221)

A mixture of 28 (300 mg, 1.02 mmol) and methyl 2,2,2-trimethoxyacetate (1.5 mL) was heated to 120° C. for 16 hours. The mixture was purified by chromatography (silica gel, 20-80% EtOAc/hexanes) to give a brown solid. The solid was dissolved in CH ₃ NH ₂ /THF (2M) (3 mL) and heated at 80° C. for 16 hours. The mixture was concentrated and the residue was purified by chromatography ( _Ci8 , 10-70% _CH3CN /water) to give Example Compound 221 (45 mg, 12%) as an off-white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.31 (q, J = 4.5 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.36-7.24 (m, 5H), 5.54 (s, 2H), 3.00 (d, J = 4.8 Hz, 3H), 2.21 (s, 3H), 2.00 (s, 3H); ESI m/z 362 [M+H] ⁺ .

Preparation of 1-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 171)

Step 1: To a solution of 85 (1.14 g, 4.09 mmol) in 1,4-dioxane (41 mL) was added 1,1'-carbonyldiimidazole (796 mg, 4.91 mmol). The reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) gave 97 (1.03 g, 83%) as a white solid: ^1H NMR (500 MHz, DMSO- _d6 ) δ 11.89 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.37-7.32 (m, 4H), 7.30-7.26 (m, 1H), 5.02 (s, 2H).

Step 2: To a solution of 97 (334 mg, 1.09 mmol) in 1,4-dioxane (11 mL) was added 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (457 mg, 2.20 mmol), sodium carbonate (1.0 M in H ₂ O, 3.29 mL, 3.29 mmol) and tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.1 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 32 hours. The mixture was diluted with dichloromethane (80 mL), washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with EtOAc to provide Example Compound 171 (173 mg, 52%) as a white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.87 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.38 (d, J=7.5 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.27 (t, J=7.0 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 5.06 (s, 2H), 3.77 (s, 3H); ESI m/z 306 [M+H] ⁺ .

Preparation of N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide (Example Compound 99)

To a solution of Example Compound 39 (100 mg, 0.29 mmol) in EtOH (3 mL) and AcOH (1 mL) was added iron powder (162 mg, 2.9 mmol). The reaction mixture was heated at 80° C. for 1 hour, filtered through a pad of Celite, and the filtrate was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) provided Example Compound 99 (28 mg, 27%) as a red solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.2 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.32-7.25 (m, 5H), 5.45 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H); ESI MS m/z 361 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine (Example Compound 100)

To a solution of Example Compound 39 (100 mg, 0.29 mmol) in EtOH (3 mL) and H ₂ SO ₄ (0.5 mL) was added iron powder (162 mg, 2.9 mmol). The reaction mixture was heated at 80° C. for 1 hour. It was diluted with EtOH (20 mL) and adjusted to pH 7 with 6N aqueous NaOH. The mixture was filtered through a pad of Celite, and the filtrate was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) provided Example Compound 100 (12 mg, 13%) as a red solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (d, J=1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.33-7.21 (m, 5H), 7.06 (s, 1H), 5.30 (s, 2H), 4.26 (s, 2H), 2.37 (s, 3H), 2.21 (s, 3H); ESI MS m/z 319 [M+H] ⁺ .

Preparation of 4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (Example Compound 156)

Step 1: A solution of 4-bromo-2-fluoro-1-nitrobenzene (1.00 g, 4.54 mmol), ethyl 2-(benzylamino)acetate (0.87 g, 4.5 mmol) and potassium carbonate (0.78 g, 5.7 mmol) in ethanol (15 mL) and water (11 mL) was heated at 85° C. for 10 hours and then stirred at room temperature for 8 hours. The reaction mixture was diluted with water and brine, then washed with dichloromethane. The resulting aqueous layer was filtered to provide 99 (1.28 g, 72%) as an orange solid: ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.57 (d, J=8.6 Hz, 1H), 7.37–7.21 (m, 6H), 6.97 (dd, J=8.7, 2.0 Hz, 1H), 4.52 (s, 2H), 3.40 (s, 2H).

Step 2: To a solution of 99 (1.28 g, 3.51 mmol) in acetic acid (14 mL) was added iron (470 mg, 8.4 mmol) at room temperature and the resulting slurry was heated to 90 ° C for 2.25 hours. The mixture was cooled to room temperature and filtered through celite, rinsing with dichloromethane. The filtrate was concentrated in vacuo and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (silica gel, 0-100% ethyl acetate/dichloromethane) to afford 100 (430 mg, 39% yield) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.74 (br s, 1H), 7.39-7.26 (m, 5H), 6.89-6.85 (m, 2H), 6.62 (d, J=8.0 Hz, 2H), 4.39 (s, 2H), 3.80 (s, 2H).

Step 3: Compound 100 was subjected to a procedure analogous to that used in Step 1 of Example 7 to give Example 156 as a white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 7.38-7.34 (m, 4H), 7.30-7.23 (m, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.51 (s, 1H), 4.46 (s, 2H), 3.86 (s, 2H), 2.15 (s, 3H), 1.97 (s, 3H); ESI m/z 334 [M+H] ⁺ .

Preparation of 4-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one (Example Compound 166)

Using a procedure analogous to that used for Example 7, Step 1, on Compound 100, Example 166 was obtained as a white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 7.37-7.33 (m, 5H), 7.29-7.25 (m, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.80 (dd, J=7.9, 1.8 Hz, 1H), 6.70 (d, J=1.6 Hz, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.58 (s, 3H); ESI m/z 319 [M+H] ⁺ .

Preparation of (R)-4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Example Compound 174)

Step 1: A solution of 4-bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.3 mmol), (R)-methyl 2-(benzylamino)propanoate (0.55 g, 2.3 mmol) and potassium carbonate (0.47 g, 3.4 mmol) in ethanol (8 mL) and water (6 mL) was heated at 85 ° C for 10 hours and then stirred at room temperature for 8 hours. The reaction mixture was diluted with water and filtered. The pH of the filtrate was adjusted to ~4 with 6N aqueous HCl and the resulting slurry was re-filtered to provide 101 as a sticky orange solid (not weighed; used directly in the next step).

Step 2: Compound 101 was subjected to a procedure analogous to that used in Step 2 of Example 156 to give compound 102 (430 mg, 39% yield) as a white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.57 (br s, 1H), 7.39–7.25 (m, 5H), 6.87–6.66 (m, 3H), 4.60 (d, J=15.5 Hz, 1H), 4.29 (d, J=15.2 Hz, 1H), 3.85 (q, J=6.9 Hz, 1H), 1.08 (d, J=6.7 Hz, 3H).

Step 3: Compound 102 was subjected to a procedure analogous to that used in Step 3 of Example 156 to provide Example 174 as an off-white solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 7.37–7.32 (m, 4H), 7.26–7.23 (m, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.66 (dd, J=7.9, 1.7 Hz, 1H), 6.42 (d, J=1.5 Hz, 1H), 4.54 (d, J=15.6 Hz, 1H), 4.37 (d, J=15.7 Hz, 1H), 3.98 (q, J=6.7 Hz, 1H), 2.11 (s, 3H), 1.93 (s, 3H), 1.12 (d, J=6.7 Hz, 3H); ESI m/z 348[M+H] ⁺ .

Preparation of 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 118) and 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine (Example Compound 131)

Step 1: To a stirred solution _of 26 (2.00 g, 10.6 mmol) in dry _CH2Cl2 (50 mL) was added glacial acetic acid (0.61 mL, 10.8 mmol) and cyclopropanecarboxaldehyde (0.81 mL, 12.3 mmol). The solution was stirred at room temperature for 1 hour and cooled to 0°C. Sodium borohydride (1.21 g, 31.8 mmol) was carefully added and the reaction was warmed to room temperature. After stirring at room temperature for 15 hours, saturated aqueous _NaHCO3 (20 mL) was added to basify the mixture, and then the mixture was extracted with _CH2Cl2 ( ₂ x 100 _mL ). The combined dichloromethane layers were dried over _Na2SO4 , filtered, and the filtrate was concentrated to a brown residue. The residue was diluted with _CH2Cl2 (20 _mL ), the solution was loaded onto silica gel (120 g) and eluted with 0-70% ethyl acetate in hexanes to provide 103 (330 mg, 13%) as a yellow solid: ^1H NMR (500 MHz, _CDCl3 ) δ 7.62 (d, J = 2.0 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 4.17 (br s, 2H), 3.39 (br s, 1H), 2.90 (d, J = 5.0 Hz, 1H), 2.89 (d, J = 5.0 Hz, 1H), 1.19-1.07 (m, 1H), 0.63-0.56 (m, 2H), 0.27-0.22 (m, 2H).

Step 2: To a mixture of 103 (300 mg, 1.24 mmol) and 3 (415 mg, 1.86 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was added potassium carbonate (343 mg, 2.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.062 mmol). The reaction was stirred and heated at 90 ° C for 17 hours. The mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded on silica gel (80 g) and eluted with 0-80% ethyl acetate in hexane. The clean product was concentrated to give 104 (312 mg, 97%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.48 (d, J=1.5 Hz, 1H), 6.61 (d, J=1.5 Hz, 1H), 4.27 (br s, 2H), 3.39 (br s, 1H), 2.92 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.18-1.09 (m, 1H), 0.63-0.56 (m, 2H), 0.28-0.22 (m, 2H).

Step 3: To a solution of 104 (310 mg, 1.20 mmol), a catalytic amount of DMAP, and 1,4-dioxane (4 mL) in a pressure tube was added 1,1'-carbonyldiimidazole (390 mg, 2.40 mmol). The tube was sealed and heated to 80°C for 2 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded onto silica gel (40 g) and eluted with 0-80% ethyl acetate in hexanes. The clean product was concentrated to give 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (275 mg, 81%) as a yellow solid. A 50 mg sample was then purified by reverse phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O , and the clean fractions were frozen and lyophilized to give Example Compound 118 (37 mg) as a white solid: ^1H NMR (500 MHz, _CD3OD ) δ 7.90 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 3.81 (d, J=7.0 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.31-1.20 (m, 1H), 0.60-0.53 (m, 2H), 0.44-0.38 (m, 2H); ESI m/z 285 [M+H] ⁺ .

Step 4: A solution of Example Compound 118 (220 mg, 0.774 mmol) in phosphorus (V) oxychloride (3 mL) was placed in a sealed tube and heated at 110 ° C for 6 hours. The solvent was removed in vacuo and saturated aqueous NaHCO ₃ solution (5 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined extracts were dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated. THF (5 mL) and a 2.0 M solution of ethylamine in THF (6 mL, 12.0 mmol) were then added and the reaction was heated at 70 ° C for 17 hours. The reaction was concentrated to dryness and the residue was diluted with CH ₂ Cl ₂ (5 mL). The resulting solution was loaded onto silica gel (40 g) and eluted with 0-80% ethyl acetate in hexane. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example Compound 131 (91 mg, 38%) as a white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.93 (d, J=2.0 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 3.98 (d, J=6.5 Hz, 2H), 3.57 (q, J=7.0 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.29-1.19 (m, 1H), 0.59-0.52 (m, 2H), 0.45-0.39 (m, 2H); ESI m/z 312 [M+H] ⁺ .

Preparation of 4-(1-(cyclohexylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 191), 4-(1-(cyclopentylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 192), and 4-(1-(cyclobutylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 193)

Step 1: A mixture of 2,3-diamino-5-bromopyridine (10.0 g, 0.053 mol), cyclohexanecarboxaldehyde (6.08 g, 0.054 mol), and glacial acetic acid (3.05 mL) in _{dry CH₂Cl₂} (250 mL) was stirred at room temperature for 1.5 hours. Sodium borohydride (6.06 g, 0.159 mol) was added portionwise over 20 minutes, and the mixture was stirred at room temperature for 17 hours. Saturated aqueous _NaHCO₃ was added until the mixture reached pH 8 (70 mL), and the aqueous layer was extracted with _CH₂Cl₂ (100 _mL ). _The combined _CH₂Cl₂ layers were combined, washed with water (500 _mL ), dried over _Na₂SO₄ , filtered, and concentrated. The brown solid was dissolved in methanol (100 mL) and silica gel (40 g) was added. The suspension was concentrated to dryness and the material was purified by chromatography (silica gel, 0-50% EtOAc/hexanes, then 0-10% EtOAc/ _CH2Cl2 ) to afford 105a (1.30 g, 9%) as _a brown-grey solid: ^1H NMR (500 MHz, _CDCl3 ) δ 7.60 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 4.11 (br s, 2H), 3.28 (br s, 1H), 2.88 (d, J=5.0 Hz, 2H), 1.88-1.64 (m, 4H), 1.70-1.52 (m, 1H), 1.38-1.15 (m, 4H), 1.10-0.96 (m, 2H).

Starting from cyclopentanecarboxaldehyde, 105b was prepared (14% yield; brown-grey solid): ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.60 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 4.14 (br s, 2H), 3.28 (br s, 1H), 2.99-2.93 (m, 2H), 2.23-2.11 (m, 1H), 1.88-1.71 (m, 2H), 1.70-1.53 (m, 4H), 1.32-1.23 (m, 2H).

Starting from cyclobutanecarbaldehyde, 105c was prepared (15% yield; brown-grey solid): ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.61 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 4.12 (br s, 2H), 3.14 (br s, 1H), 3.09-3.02 (m, 2H), 2.67-2.52 (m, 1H), 2.18-2.11 (m, 2H), 2.07-1.86 (m, 2H), 1.80-1.71 (m, 2H).

Step 2: To a mixture of 105a (500 mg, 1.76 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (589 mg, 2.64 mmol), potassium carbonate (487 mg, 3.52 mmol), water (4 mL) and 1,4-dioxane (16 mL) was added tetrakis(triphenylphosphine)palladium(0) and the mixture was heated to 90° C. for 17 hours. The biphasic mixture was diluted with methanol (20 mL) and silica gel was added. After concentration to dryness, the material was purified by chromatography (silica gel, 0-80% EtOAc/hexanes) to afford 106a (551 mg, 99%) as a brown solid: ^1H NMR (500 MHz, CDCl ₃ ) δ 7.47 (d, J=2.0 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 4.25 (br s, 2H), 3.34 (br s, 1H), 2.92 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.88-1.67 (m, 4H), 1.67-1.56 (m, 1H), 1.33-1.19 (m, 4H), 1.10-0.96 (m, 2H).

Starting from 105b, 106b was prepared (96% yield; brown-grey solid): ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.47 (d, J=1.5 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H), 4.25 (br s, 2H), 3.28 (br s, 1H), 2.99 (t, J=6.0 Hz, 1H), 2.38 (s, 3H), 2.24 (s, 3H), 2.24-2.17 (m, 1H), 1.90-1.81 (m, 2H), 1.72-1.55 (m, 4H), 1.38-1.22 (m, 2H).

Starting from 105c, 106c was prepared (95% yield; brown-grey solid): ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.65 (d, J=1.5 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 4.26 (br s, 2H), 3.18 (br s, 1H), 3.09 (t, J=6.0 Hz, 1H), 2.67-2.58 (m, 1H), 2.20-2.12 (m, 2H), 2.02-1.86 (m, 2H), 1.82-1.72 (m, 2H).

Step 3: A solution of 106a (100 mg, 0.33 mmol), triethyl orthoacetate (5 mL), and glacial acetic acid (0.10 mL) was heated in a sealed tube at 80°C for 24 h. The mixture was evaporated to dryness and methanol (10 mL), saturated aqueous _NaHCO₃ (5 mL), and silica gel (10 g) were added. After concentration to dryness, the resulting powder was loaded onto silica gel and eluted with 0–5% methanol in dichloromethane. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example Compound 191 (56 mg, 52%) as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.30 (d, J=1.5 Hz, 1 H), 7.96 (d, J=2.0 Hz, 1 H), 4.14 (d, J=7.5 Hz, 2 H), 2.69 (s, 3 H), 2.44 (s, 3 H), 2.28 (s, 3 H), 1.95-1.82 (m, 1 H), 1.76-1.50 (m, 5 H), 1.29-1.07 (m, 5 H); ESI m/z 325 [M+H] ⁺ .

Starting from 106b, Example Compound 192 (31 mg, 29%) was prepared as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.30 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 4.26 (d, J = 8.0 Hz, 2H), 2.71 (s, 3H), 2.49-2.38 (m, 1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.80-1.68 (m, 4H), 1.66-1.57 (m, 2H), 1.40-1.27 (m, 2H); ESI m/z 311 [M+H] ⁺ .

Starting from 106c, Example Compound 193 (33 mg, 30%) was prepared as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.30 (d, J=1.5 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 4.33 (d, J=7.0 Hz, 2H), 2.92-2.80 (m, 1H), 2.70 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H), 2.10-1.98 (m, 2H), 1.96-1.81 (m, 4H); ESI m/z 297 [M+H] ⁺ .

Preparation of 1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 202) and 1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 203)

A solution of 106b (1.30 g, 4.54 mmol), 1,1'-carbonyldiimidazole (1.47 g) and N,N-dimethylaminopyridine (5 mg) in 1,4-dioxane (16 mL) was heated at 80°C for 2 hours and cooled to room temperature. Silica gel (10 g) and methanol (20 mL) were added to the mixture and the suspension was concentrated to dryness. The material was loaded onto silica gel (80 g) and eluted with 0-90% ethyl acetate in hexanes to give 1.08 g (76%) of Example Compound 202 as a yellow solid. A 100 mg sample of the product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example Compound 202 as a white solid: ¹ H NMR (500 MHz, CD ₃ OD)δ7.90(d,J＝1.5Hz,1H),7.47(d,J＝2.0Hz,1H),3.86(d,J＝7.5Hz,2H),2.52–2.38(m,1H ),2.41(s,3H),2.25(s,3H),1.78–1.68(m,4H),1.60–1.52(m,2H),1.41–1.30(m,2H); ESI m/z 313[M+H] ⁺ .

Starting from 106c, Example Compound 203 (76% yield, white solid) was synthesized by a procedure similar to Example Compound 202: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.89 (d, J=1.5 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 3.94 (d, J=7.0 Hz, 2H), 2.86-2.77 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.08-1.98 (m, 2H), 1.94-1.80 (m, 4H); ESI m/z 299 [M+H] ⁺ .

Preparation of 4-(1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine (Example Compound 208) and 4-(2-(azetidin-1-yl)-1-(cyclopentylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 209)

A solution of Example Compound 202 (175 mg, 0.56 mmol) and phosphorus (V) oxychloride (4 mL) was heated to 110 ° C for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO ₃ aqueous solution (5 mL) and ethyl acetate (20 mL) were added. The ethyl acetate layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to a dark yellow solid. The solid was dissolved in THF (5 mL) and morpholine (732 mg, 8.40 mmol) was added. The stirred solution was heated to 70 ° C for 17 hours. Silica gel (5 g) and methanol (20 mL) were added to the cooled mixture and the suspension was concentrated to a dry powder. The material was loaded on silica gel (40 g) and eluted with 0-3% methanol in dichloromethane to obtain 143 mg (67%) of the product as an off-white solid. A sample of the product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example Compound 208 as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.17 (d, J=1.5 Hz, 1 H), 7.81 (d, J=2.0 Hz, 1 H), 4.14 (d, J=7.5 Hz, 2H), 3.87 (t, J=5.0 Hz, 4H), 3.41 (t, J=5.0 Hz, 4H), 2.58-2.49 (m, 1 H), 2.43 (s, 3H), 2.27 (s, 3H), 1.75-1.66 (m, 2H), 1.62-1.50 (m, 4H), 1.30-1.19 (m, 2H). ESI m/z 382[M+H] ⁺ .

Example compound 209 was synthesized using a procedure similar to that used for Example 208; Example compound 209 (166 mg, 84%) was obtained as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.00 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 4.42-4.37 (m, 4H), 4.01 (d, J=8.0 Hz, 2H), 2.57-2.44 (m, 2H), 2.50-2.41 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 1.76-1.51 (m, 6H), 1.32-1.22 (m, 2H). ESI m/z 352 [M+H] ⁺ .

Preparation of 4-(1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine (Example 210) and 4-(2-(azetidin-1-yl)-1-(cyclobutylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example 211)

Example 210 and Example 211 were synthesized using a procedure similar to that used for Example 208.

Example 210 was obtained as a white solid (176 mg, 82% yield): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.16 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.41 (t, J = 5.0 Hz, 4H), 2.93-2.82 (m, 1H), 2.43 (s, 3H), 2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.90-1.76 (m, 4H). ESI m/z 368 [M+H] ⁺ .

Example 211 was obtained as a white solid (180 mg, 91% yield): ¹ H NMR (500 MHz, CD ₃ OD) δ 7.99 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 4.38 (m, 4H), 4.10 (d, J = 7.0 Hz, 2H), 2.88-2.79 (m, 1H), 2.57-2.48 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.04-1.95 (m, 2H), 1.95-1.78 (m, 4H). ESI m/z 338 [M+H] ⁺ . Preparation of 1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine (Example 222)

A solution of Example 202 (175 mg, 0.56 mmol) and phosphorus (V) oxychloride (4 mL) was heated to 110 ° C for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO ₃ aqueous solution (5 mL) and ethyl acetate (20 mL) were added. The ethyl acetate layer was separated, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to a dark yellow solid. The solid was dissolved in propionitrile (5 mL) and 4-aminotetrahydropyran (283 mg, 28.0 mmol) was added, and the stirred solution was heated to 180 ° C for 6 hours in a microwave reactor. Silica gel (10 g) and methanol (20 mL) were added to the cooled mixture and the suspension was concentrated to a dry powder. The material was loaded on silica gel (40 g) and eluted with 0-3% methanol in dichloromethane to give a yellow solid. The material was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH ₃ CN in H ₂ O and the clean fractions were frozen and lyophilized to give Example 222 as a white solid (70 mg, 31%): ¹ H NMR (500 MHz, CD ₃ OD)δ7.94(d,J＝1.5Hz,1H),7.50(d,J＝2.0Hz,1H),4.17–4.05(m,1H),4.05(d,J＝8.0Hz,2H),4.02–3.97(m,2H),3.57(t,J＝11.75H z,2H),2.44–2.36(m,1H),2.41(s,3H),2.25(s,3H),2.08–2.00(m,2H),1.78–1.64(m,6H),1.62–1.54(m,2H),1.38–1.25(m,2H). ESI m/z 396[M+H] ⁺ .

Preparation of 1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine (Example Compound 223)

Example compound 223 was synthesized using a procedure similar to that used for Example compound 222. Example compound 223 was obtained as a white solid (45 mg, 20% yield): ¹ H NMR (500 MHz, CD ₃ OD) δ 7.93 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 4.17-4.05 (m, 1H), 4.10 (d, J = 7.5 Hz, 2H), 4.03-3.97 (m, 2H), 3.56 (t, J = 11.75 Hz, 2H), 2.86-2.78 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.08-1.92 (m, 8H), 1.75-1.64 (m, 2H). ESI m/z 382 [M+H] ⁺ .

Preparation of 4-(1-benzyl-7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 241)

Step 1: To a solution of 107 (136 mg, 0.627 mmol) in THF (6 mL) was added di-tert-butyl dicarbonate (137 mg, 0.627 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was then concentrated and the residue was purified by chromatography (silica gel, 0-25% ethyl acetate/hexane) to provide an off-white solid, which was dissolved in CH ₂ Cl ₂ (3 mL) and added to benzaldehyde in CH ₂ Cl ₂ (2 mL), followed by AcOH (2 drops). The reaction was stirred at room temperature for 1 hour and NaBH(OAc) ₃ (283 mg, 1.34 mmol) was added. The reaction was then stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (2×50 mL). The combined organic solution was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 108 (97 mg, 38%) as an off-white solid: ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 7.32-7.26 (m, 4H), 7.23-7.00 (m, 1H), 6.95 (s, 2H), 4.87 (t, J=6.9 Hz, 1H), 4.31 (d, J=6.9 Hz, 2H), 3.64 (s, 3H), 1.42 (s, 9H).

Step 2: To a solution _of 108 (135 mg, 0.332 mmol) in _CH2Cl2 (5 mL) at 0°C was added TFA (0.51 mL, 6.63 mmol) and the reaction was warmed to room temperature and stirred for 16 h. The reaction was then concentrated to provide 109 (114 mg, 90%): ESI m/z 385 [M+H] ⁺ .

Step 3: Using the procedure used in step 1 of general procedure B, starting from compound 109 (114 mg, 0.296 mmol), Example compound 241 (45 mg, 38%) was obtained as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.72 (d, J=8.4 Hz, 1H), 7.36-7.26 (m, 4H), 7.03-7.00 (m, 2H), 5.81 (s, 2H), 3.13 (s, 3H), 2.27 (s, 3H), 2.09 (s, 3H); ESI m/z 402 [M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamidine (Example Compound 243) and 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamide (Example Compound 244)

Step 1: To a solution of 20 (3.00 g, 10.8 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.90 g, 13.0 mmol), tetrakis(triphenylphosphine)palladium(0) (624 mg, 0.54 mmol) and potassium carbonate (2.98 g, 21.6 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 18 h. The mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to provide 110 (3.18 g, 99%) as a yellow solid: ^1H NMR (500 MHz, CDCI ₃ ) δ 7.38 (d, J=8.3 Hz, 2H), 7.34 (t, J=7.3 Hz, 2H), 7.28 (t, J=7.1 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.55 (dd, J=1.8, 7.7 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 4.35 (s, 2H), 3.88 (s, 1H), 3.42 (s, 2H), 2.23 (s, 3H), 2.11 (s, 3H); ESI m/z 294 [M+H] ⁺ .

Step 1: To a solution of 110 (100 mg, 0.34 mmol) in acetic acid (2 mL) was added methyl 2,2,2-trichloroacetimidate (66 mg, 0.38 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then water was added. The resulting precipitate was harvested by filtration, the filter cake was washed with water, and dried under vacuum at 40 ° C to provide 111 (110 mg, 77%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.93 (dd, J = 0.4, 8.4 Hz, 1H), 7.40–7.25 (m, 4H), 7.19–7.11 (m, 3H), 5.96 (s, 2H), 2.21 (s, 3H), 2.03 (s, 3H); ESI m/z 422 [M+H] ⁺ .

Step 2: To a solution of 111 (100 mg, 0.238 mmol) in ethanol (1 mL) was added concentrated ammonium hydroxide (1 mL). The reaction mixture was heated at 120°C for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes then to 20% methanol in ethyl acetate), followed by reverse-phase HPLC on a Polaris _C18 column eluting with 10-90% _CH3CN in _H2O to provide Example Compound 243 (21 mg, 25%) and Example Compound 244 (29 mg, 35%) as off-white solids. Example compound 243: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.77 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 7.33-7.19 (m, 6H), 6.58 (s, 2H), 6.27 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 346 [M+H] ⁺ ; Example compound 244: ¹ H NMR (500 MHz, DMSO-d ₆ )δ8.38(s,1H),7.92(s,1H),7.82(d,J＝8.5Hz,1H),7.63(d,J＝1.0Hz,1H),7.3 3–7.28(m,5H),7.27–7.22(m,1H),6.02(s,2H),2.35(s,3H),2.18(s,3H);ESI m/z 347[M+H] ⁺ .

Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine (Example Compound 248)

Step 1: A solution of 81 (500 mg, 1.57 mmol) and phosphorus (V) oxychloride (2 mL) was heated to 100 ° C for 17 hours. The reaction was concentrated in vacuo and saturated aqueous NaHCO ₃ (5 mL) and ethyl acetate (20 mL) were added. The ethyl acetate layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to provide 112 (415 mg, 78%) as a light brown oil: ESI m / z 338 [M + H] ⁺ .

Step 2: A mixture of 112 (20 mg, 0.06 mmol), pyridin-3-amine (28 mg, 0.30 mmol) and p-TsOH.H ₂ O (22 mg, 0.12 mmol) in NMP was heated in a microwave reactor at 190° C. for 2 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 248 as a light brown oil: ESI m/z 396 [M+H] ⁺ .

Preparation of 3-(1-benzyl-1H-benzo[d]imidazol-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Example Compound 249)

Step 1: A solution of 113 (1.20 g, 4.51 mmol) and hydrazine monohydrate (3.27 mL, 67.65 mmol) in EtOH (20 mL) was heated to reflux for 16 h. The mixture was cooled to room temperature, the precipitate was harvested by filtration, and the filter cake was dried to afford 114 (1.02 g, 85%) as an off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 7.73–7.67 (m, 2H), 7.38–7.26 (m, 5H), 5.54 (s, 2H), 4.47 (s, 2H).

Step 2: A suspension of 114 (500 mg, 1.88 mmol) and ethyl isocyanate (160 mg, 2.26 mmol) in THF was stirred at room temperature for 5 h. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to afford 115 (610 mg, 96%) as a white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 10.09 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 7.81-7.79 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.38-7.28 (m, 5H), 6.47 (t, J = 5.4 Hz, 1H), 5.55 (s, 2H), 3.09-3.00 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

Step 3: A suspension of 115 (337 mg, 1.0 mmol) in 3N NaOH (5 mL) was heated to reflux for 16 h. The mixture was adjusted to pH 8 with 2N HCl and then extracted with CH ₂ Cl ₂ (3×50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with EtOAc/ _CH2Cl2 to provide Example Compound ₂₄₉ as an off-white solid: ^1H NMR (300 MHz, DMSO- _d6 ) δ 11.85 (s, 1H), 8.59 (s, 1H), 7.81-7.76 (m, 2H), 7.43 (dd, J=8.1, 1.5 Hz, 1H), 7.35-7.28 (m, 5H), 5.58 (s, 2H), 3.63 (q, J=7.2, Hz 2H), 0.98 (t, J=7.2 Hz, 3H); ESI m/z 320 [M+H] ⁺ .

Table 2: Example compounds

Example 1: Inhibition of tetraacetylated histone H4 binding to individual BET bromodomains

The protein was cloned and overexpressed with an N-terminal 6xHis tag and then purified by nickel affinity followed by size exclusion chromatography. Briefly, E. coli BL21 (DE3) cells were transformed with a recombinant expression vector encoding the N-terminal nickel affinity-tagged bromodomains of Brd2, Brd3, and Brd4. The cell culture was incubated with shaking at 37°C to an appropriate density and induced overnight with IPTG. The supernatant of the lysed cells was loaded onto a Ni-IDA column for purification. The protein was eluted in fractions, concentrated, and further purified by size exclusion chromatography. The fractions represented fractions of the monomeric protein, concentrated, aliquoted, and frozen at -80°C for use in subsequent experiments.

Binding of tetraacetylated histone H4 to BET bromodomains was confirmed by time-resolved fluorescence resonance energy transfer (TR-FRET). N-terminal His-tagged bromodomains (200 nM) and biotinylated tetraacetylated histone H4 peptides (25-50 nM, Millipore) were incubated in the presence of Europium cryptate-labeled streptavidin (Cisbio catalog number 610SAKLB) and XL665-labeled monoclonal anti-His antibody (Cisbio catalog number 61HISXLB) in white 96-well microtiter plates (Greiner). For inhibition assays, serially diluted test compounds were added to these reactions at a final DMSO concentration of 0.2%. Final buffer concentrations were 30 mM HEPES pH 7.4, 30 mM NaCl, 0.3 mM CHAPS, 20 mM phosphate pH 7.0, 320 mM KF, 0.08% BSA). After incubation for 2 hours at room temperature, fluorescence was measured at 665 and 620 nm using a Synergy H4 plate reader (Biotek) by FRET. Illustrative results for the first Brd4 bromodomain are shown below. Binding inhibitory activity was demonstrated by a decrease in 665 nm fluorescence relative to 620 nm. IC ₅₀ values were determined from dose response curves.

Compounds with _IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with _IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with _IC50 values between 3 and 30 μM were considered active (+).

Table 3: Inhibition of tetraacetylated histone H4 binding to Brd4 bromodomain 1 (BRD4(1) as measured by FRET

Example 2: Inhibition of c-myc expression in cancer cell lines

MV4-11 cells (CRL-9591) were seeded in 96-well U-bottom plates at a density of 2.5 x ¹⁰⁴ cells/well and treated with increasing concentrations of test compounds or DMSO (0.1%) in IMDM culture medium containing 10% FBS and penicillin/streptomycin and incubated at 37°C for 3 hours. Triplicate wells were used for each concentration. Cells were precipitated by centrifugation and harvested using an mRNA Catcher PLUS kit according to the manufacturer's instructions. The isolated eluted mRNA was then used for a one-step quantitative real-time PCR reaction using components of an RNA UltraSense ^™ one-step kit (Life Technologies) together with Applied Biosystems primers-probes for cMYC and cyclophilin. The real-time PCR plate was run on a VIa ^™ 7 real-time PCR instrument (Applied Biosystems) to analyze the data, normalize the Ct value of cMYC to an internal control, and then determine the multiple expression of each sample relative to the control.

Compounds with _IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with _IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with _IC50 values between 3 and 30 μM were considered active (+).

Table 4: Inhibition of c-myc activity in human AML MV4-11 cells

Example 3: Inhibition of cell proliferation in cancer cell lines

MV4-11 cells: 96-well plates were seeded with exponentially growing human AML MV-4-11 (CRL-9591) cells at ^5x10 cells/well and immediately treated with two-fold dilutions of test compounds ranging from 30 μM to 0.2 μM. Triplicate wells were used for each concentration, as well as medium-only wells and three DMSO control wells. Cells and compounds were incubated at 37°C, 5% _CO2 for 72 hours, after which 20 μL of CellTiter Aqueous One Solution (Promega) was added to each well and incubated at 37°C, 5% _CO2 for an additional 3-4 hours. Absorbance was acquired at 490 nm in a spectrophotometer and the percentage of proliferation relative to the DMSO-treated wells was calculated after correction from the blank wells. _IC50 was calculated using GraphPad Prism software.

Compounds with _IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with _IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with _IC50 values between 3 and 30 μM were considered active (+).

Table 5: Inhibition of cell proliferation in human AML MV-4-11 cells

Example 4: Inhibition of hIL-6 mRNA transcription

In this example, hIL-6 mRNA was quantified in tissue culture cells to measure transcriptional inhibition of hIL-6 upon treatment with compounds of the invention.

In this example, hIL-6 mRNA was quantified in tissue culture cells to measure transcriptional inhibition of hIL-6 upon treatment with compounds of the invention.

Human leukemia monocytic lymphoma U937 cells (CRL-1593.2) are seeded in 100 μ L RPMI-1640 containing 10% FBS and penicillin/streptomycin at a density of 3.2 × 104 cells/well in 96-well plates and differentiated into macrophages for 3 days at 37°C in 5% CO2 in 60ng/mL PMA (phorbol-13-myristate-12-acetate), followed by addition of target compound. Cells are pretreated for 1 hour with increasing concentrations of test compounds in 0.1% DMSO, followed by stimulation with 1ug/mL lipopolysaccharide from Escherichia coli. Triplicate wells are used for each concentration. Cells are incubated at 37°C, 5% CO2 for 3 hours, followed by harvesting. At harvest time, culture medium is removed and cells are rinsed in 200 μ L PBS. mRNA Catcher PLUS test kit is used to harvest cells according to manufacturer's instructions. Eluted mRNA was used in a one-step quantitative real-time PCR reaction using components of the RNAUltraSense ^™ One-Step Kit (Life Technologies) along with Applied Biosystems primer-probes for hIL-6 and cyclophilin. Real-time PCR plates were run on a VIa ^™ 7 real-time PCR instrument (Applied Biosystems), and data were analyzed, with hIL-6 Ct values normalized to an internal control before determining the fold expression of each sample relative to the control.

Compounds with _IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with _IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with _IC50 values between 3 and 30 μM were considered active (+).

Table 6: Inhibition of hIL-6 mRNA transcription

Example 5: Inhibition of IL-17 mRNA transcription

In this example, hIL-17 mRNA was quantified in human peripheral blood mononuclear cells to measure transcriptional inhibition of hIL-17 upon treatment with compounds of the invention.

Human peripheral blood mononuclear cells were seeded in 96-well plates (2.0 × 10 ⁵ cells / well) in 45 μL OpTimizer T cell expansion medium containing 20 ng / ml IL-2 and penicillin / streptomycin. The cells were treated with test compounds (45 μL at 2 times the concentration) and then incubated at 37 ° C for 1 hour, after which 10 times the reserve OKT3 antibody of 10 μg / ml was added to the culture medium. The cells were incubated at 37 ° C for 6 hours and then harvested. At the harvest time, the cells were centrifuged (800 rpm, 5 minutes). The spent culture medium was removed and cell lysis solution (70 μL) was added to the cells in each well and incubated at room temperature for 5-10 minutes to allow complete cell lysis and detachment. mRNA was then prepared using "mRNACatcher PLUS Plate" (Invitrogen) according to the provided protocol. After the last wash, as much wash buffer as possible was drawn without drying the wells. Elution buffer (E3, 70 μL) was then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer at 68°C for 5 minutes and then immediately placing the plate on ice.

The isolated, eluted mRNA was then used in a one-step quantitative RT-PCR reaction using components of the Ultra Sense kit along with an Applied Biosystems primer-probe mix. Real-time PCR data were analyzed and the Ct values for hIL-17 were normalized to an internal control before determining the fold induction of each unknown sample relative to the control.

Compounds with _IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with _IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with _IC50 values between 3 and 30 μM were considered active (+).

Table 7: Inhibition of hIL-17 mRNA transcription

Example 6: Inhibition of hVCAM mRNA transcription

In this example, hVCAM mRNA was quantified in tissue culture cells to measure transcriptional inhibition of hVCAM upon treatment with compounds of the present disclosure.

Human umbilical vein endothelial cells (HUVEC) are seeded in 100 μL EGM culture medium in 96-well plates (4.0 × 10 ³ cells/well) and incubated for 24 hours before adding the target compound. The cells are pretreated with the test compound for 1 hour and then stimulated with tumor necrosis factor-α. The cells are incubated for another 24 hours before harvesting. At the harvest time, the spent culture medium is removed from the HUVEC and rinsed in 200 μL PBS. Cell lysis solution (70 μL) is then added to the cells in each well and incubated at room temperature for about 5-10 minutes to allow complete cell lysis and detachment. mRNA is then prepared using "mRNA Catcher PLUS plates" (Invitrogen) according to the protocol provided. After the last wash, as much wash buffer as possible is aspirated without drying the holes. Elution buffer (E3, 70 μL) is then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer at 68°C for 5 minutes and then immediately placing the plate on ice.

The eluted mRNA thus isolated was then used in a one-step quantitative real-time PCR reaction using components of the Ultra Sense kit together with an Applied Biosystems primer-probe mix. Real-time PCR data were analyzed and the Ct values for hVCAM were normalized to an internal control before determining the fold induction of each unknown sample relative to the control.

Example 7: Inhibition of hMCP-1 mRNA transcription

In this example, hMCP-1 mRNA was quantified in human peripheral blood mononuclear cells to measure transcriptional inhibition of hMCP-1 upon treatment with compounds of the present disclosure.

Human peripheral blood mononuclear cells (1.0 × ¹⁰⁵ cells/well) are seeded in 45 μ L RPMI-1640 containing 10% FBS and penicillin/streptomycin in 96-well plates. Cells are processed with test compounds (45 μ L under 2 times of concentration), and then cells are incubated 3 hours at 37 ° C, and harvested afterwards. At harvest time, cells are transferred to V-type bottom plate and centrifuged (800rpm, 5 minutes). Remove spent culture medium and cell lysis solution (70 μ L) is added to the cell in each hole and at room temperature incubated 5-10 minute, to allow complete cell dissolution and break away from. Then mRNA is prepared according to provided scheme using " mRNACatcher PLUS plate " (Invitrogen). After the last wash, draw as much wash buffer as possible without making the hole dry. Then elution buffer (E3, 70 μ L) is added to each hole. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer at 68°C for 5 minutes and then immediately placing the plate on ice.

The isolated eluted mRNA was then used in a one-step quantitative real-time PCR reaction using components of the Ultra Sense kit together with an Applied Biosystems primer-probe mix. Real-time PCR data were analyzed and the Ct values for hMCP-1 were normalized to an internal control before determining the fold induction of each unknown sample relative to the control.

Example 8: Upregulation of hApoA-1 mRNA transcription.

In this example, ApoA-I mRNA was quantified in tissue culture cells to measure transcriptional upregulation of ApoA-I upon treatment with compounds of the invention.

Huh7 cells (2.5×10 ⁵ cells/well) were seeded in a 96-well plate using 100 μL DMEM/well (Gibco DMEM supplemented with penicillin/streptomycin and 10% FBS), and the target compound was added 24 hours later. After 48 hours of treatment, the spent medium was removed from the Huh-7 cells and placed on ice (for immediate use) or at -80°C (for future use) using the "LDH Cytotoxicity Assay Kit II" from Abcam. The remaining cells in the plate were rinsed with 100 μL PBS.

Then 85 μ L of cell lysis solution is added in each well and incubated at room temperature for 5-10 minutes, to allow complete cell dissolution and break away. Then mRNA is prepared according to the scheme provided using " mRNA CatcherPLUS plates " from Life Technologies. After the last wash, as much wash buffer as possible is drawn without drying the holes. Then elution buffer (E3, 80 μ L) is added to each well. Then by incubating the mRNA Catcher PLUS plates with elution buffer at 68 ℃ for 5 minutes and then at 4 ℃ for 1 minute to elute the mRNA. The Catcher plates of mRNA elution are kept on ice for use or stored at -80 ℃.

The isolated eluted mRNA was then used in a one-step real-time PCR reaction using components of the Ultra Sense kit along with Life Technologies primer-probe mixes. Real-time PCR data were analyzed using Ct values to determine the fold induction of each unknown sample relative to the control (i.e., relative to the control at each independent DMSO concentration).

Compounds with _EC170 values less than or equal to 0.3 μM were considered highly active (+++); compounds with _EC170 values between 0.3 and 3 μM were considered very active (++); and compounds with _EC170 values between 3 and 30 μM were considered active (+).

Table 8: Upregulation of hApoA-1 mRNA transcription.

Example compounds ApoA-1 activity 7 +++

Example 9: In vivo efficacy in an athymic nude mouse strain using an MV4-11 cell acute myeloid leukemia xenograft model:

MV4-11 cells (ATCC) were grown under standard cell culture conditions and 6-7 week old female mice of the (NCr) nu/nu fisol strain were injected in the left lower flank at 5×10 ⁶ cells/animal in 100 μL PBS+100 μL Matrigel. Approximately 18 days after the MV4-11 cell injection, mice were randomized based on an average tumor volume of approximately 120 mm ³ (L x W x H)/2). Mice were orally administered the compound in the EA006 formulation at a dose volume of 10 mL/kg body weight at 75 mg/kg twice daily and 120 mg/kg twice daily. Tumor measurements were taken with an electronic microcaliper and body weights were measured every other day starting from the dosing period. Mean tumor volume, tumor growth inhibition (TGI) % and body weight change % were compared to vehicle control animals. Mean values, statistical analyses and group comparisons were calculated using Student's t-test in Excel.

Table 9: In vivo efficacy in an athymic nude mouse strain of acute myeloid leukemia xenograft model

Example compounds In vivo activity Example 7 active

Example 10: In vivo efficacy in an athymic nude mouse strain using the OCI-3 AML cell acute myeloid leukemia xenograft model

OCI-3 AML cells (DMSZ) were grown under standard cell culture conditions and 6-7 week old female mice of the (NCr) nu/nu fisol strain were injected in the left lower flank at 10×10 ⁶ cells/animal in 100 μL PBS+100 μL Matrigel. Approximately 18-21 days after the OCI-3 AML cell injection, mice were randomized based on an average tumor volume of approximately 100-300 mm ³ (L x W x H)/2). Mice were orally administered the compound in the EA006 formulation at a dose volume of 10 mL/kg body weight at a continuous dosing schedule of 30 mg/kg twice daily and a dosing schedule of 5 days on and 2 days off. Tumor measurements were obtained with an electronic microcaliper and body weights were measured every other day from the start of the dosing period. Mean tumor volume, tumor growth inhibition (TGI) % and body weight change % were compared to vehicle control animals. Mean values, statistical analysis and group comparisons were calculated using the Student's t-test in Excel.

Example 11: Evaluation of target engagement.

MV4-11 cells (ATCC) were grown under standard cell culture conditions, and 6-7 week old female mice of the (NCr) nu/nu fisol strain were injected in the left lower flank at 5×10 ⁶ cells/animal in 100 μL PBS + 100 μL Matrigel. Approximately 28 days after MV4-11 cell injection, mice were randomized based on an average tumor volume of approximately 500 mm ³ (L x W x H)/2). Compounds were orally administered in the EA006 formulation at a dose volume of 10 mL/kg body weight, and tumors were harvested 6 hours after Bcl2 administration and analyzed for c-myc gene expression as a PD biomarker.

Example 12: In vivo efficacy in a mouse endotoxemia model assay.

Sublethal doses of endotoxin (E. coli bacterial lipopolysaccharide) were administered to animals to produce a systemic inflammatory response, which was monitored by an increase in cytokine secretion. The compound was orally administered to C57/Bl6 mice at a dose of 75 mg/kg to assess the inhibition of IL-6 and IL-17 cytokines 3 hours after intraperitoneal challenge with a 0.5 mg/kg dose of lipopolysaccharide (LPS).

Example 13: In vivo efficacy in rat collagen-induced arthritis

Rat collagen-induced arthritis is an experimental model of polyarthritis that has been widely used in the preclinical testing of many anti-arthritis agents. After using collagen, this model produces measurable polyarticular inflammation, significant cartilage destruction relevant to pannus formation, and slight to moderate bone resorption and periosteal bone hyperplasia. In this model, collagen was applied to the female Lewis strain of rats and administered with compound on the 11th to 17th day at the 1st day and the 7th day of research. Use the model that uses treatment after the disease has formed, evaluate the potentiality that test compound suppresses inflammation (comprising paw swelling), cartilage destruction and bone resorption in arthritis rats with assessment.

Embodiment 14: in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) model of MS Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the CNS mediated by T-cells, which has many clinical and histopathological features with human multiple sclerosis (MS). EAE is the most commonly used animal model of MS. T cells of both Th1 and Th17 lineages have been shown to induce EAE. Cytokines IL-23, IL-6 and IL-17 (which are critical for Th1 and Th17 differentiation or produced by these T cells) play a key and necessary role in EAE development. Therefore, the medicine targeting the production of these cytokines may have therapeutic potential in the treatment of MS.

Compounds of Formula I or Ia are administered at 50 to 125 mg/kg twice daily starting from the time of immunization of EAE mice.In this model, EAE is induced by MOG _35-55 /CFA immunization and pertussis toxin injection in female C57B1/6 mice.

Table 10: In vivo efficacy in the experimental autoimmune encephalomyelitis (EAE) model of MS

Example compounds In vivo activity Example 7 active

Example 15: Ex vivo effects on T cell function from splenocytes and lymphocyte cultures primed with external MOG stimulation

Mice were immunized with MOG/CFA and treated with compound twice daily for 11 days. Inguinal lymph nodes and spleens were harvested, and cultures of lymphocytes and splenocytes were established and challenged with external antigen (MOG) for 72 hours. Supernatants from these cultures were analyzed for TH1, Th2, and Th17 cytokines using Cytometric Bead Array assays.

Example 16: In vivo efficacy of MM1.s cells in athymic nude mice strains of multiple myeloma xenograft models

MM1.s cells (ATCC) were grown under standard cell culture conditions and (NCr)nu/nu fisol of 6-7 week old female mice was injected in the left lower flank at 10×10 ⁶ cells/animal in 100 μL PBS+100 μL Matrigel. About the 21st day after the MM1.s cell injection, mice were randomized based on an average tumor volume of approximately 120 mm ³ (L x W x H)/2). Mice were orally administered 75 mg/kg twice daily with a compound in an EA006 formulation at a 10 mL/kg body weight dose volume. Tumor measurements were taken with an electronic microcaliper and body weight was measured every other day starting from the dosing period. Average tumor volume, tumor growth inhibition (TGI) % and body weight change % were compared with respect to vehicle control animals. Student's t test was used in Excel to calculate mean values, statistical analysis and group comparisons.

Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims (12)

1. Use of a therapeutically effective amount of a compound selected from Formula IIb or its stereoisomers or pharmaceutically acceptable salts in the preparation of a medicament for treating acute myeloid leukemia: in: Z is selected from hydrogen, deuterium, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkenyl and C ₁ -C ₆ alkoxy; X is selected from -NH-, -CH ₂ -, and -CH(CH ₃ )-, wherein one or more hydrogens may be independently replaced by deuterium or halogen; _R4 is selected from an optionally substituted 3-6 membered carbocyclic ring; and _D1 is selected from the following 5-membered monocyclic heterocycles: which is optionally substituted with one or more groups independently selected from deuterium and C ₁ -C ₄ alkyl, each of which may be optionally substituted with F, -OH and/or -NH ₂ ; wherein the compound is not 2. The method according to claim 1, wherein _R4 is selected from _C3 - _C6 cycloalkyl and phenyl ring, which are optionally substituted by one or more groups independently selected from deuterium, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, halogen, _-CF3 , CN and _-C1 - _C4 thioalkyl, wherein each alkyl, alkoxy and thioalkyl group may be optionally substituted by F, Cl or Br. 3. The method according to claim 2, wherein _R4 is a phenyl ring optionally substituted by a group independently selected from hydrogen, deuterium, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, amino, halogen, _{amide, -CF3, CN, -N3 , C1} - _C4 ketone, -S(O)C1- _{C4 alkyl, -SO2C1-C4 alkyl , -C1 -C4 thioalkyl} , carboxyl and/or ester, each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, _-NH2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo. The use according to claim 3, wherein _C1 - _C4 alkyl is selected from methyl, ethyl, propyl, isopropyl and butyl; _C1 - _C4 alkoxy is selected from methoxy, ethoxy and isopropoxy; halogen is selected from F and Cl; and _-C1 - _C4 thioalkyl is selected from -SMe, -SEt, -SPr and -SBu. The use according to claim 1 , wherein D ₁ is optionally substituted by one or more groups independently selected from deuterium and C ₁ -C ₄ alkyl, each of which may be optionally substituted by F, —OH and/or —NH ₂ . 6. The use according to claim 1, wherein D ₁ is selected from 7. The use according to claim 6, wherein D ₁ is The use according to claim 1 , wherein X is selected from —CH ₂ — and —CH(CH ₃ )—, wherein one or more hydrogens can be independently replaced by deuterium or halogen. 9. The use according to claim 8, wherein _-XR4 is selected from _-CH2 -aryl. 10. The use according to claim 1, wherein the compound is selected from the compound of formula IIb or a stereoisomer or a pharmaceutically acceptable salt thereof, in: Z is selected from hydrogen, deuterium, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkenyl and C ₁ -C ₆ alkoxy; _D1 is X is selected from -CH ₂ - and -CH(CH ₃ )-; and R ₄ is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, —CF ₃ , CN, and —C ₁ -C ₄ thioalkyl, wherein each alkyl, alkoxy, and thioalkyl group may be optionally substituted with F, Cl, or Br. 11. Use of a therapeutically effective amount of a compound of formula IIb" or a stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acute myeloid leukemia: in: X is selected from -NH-, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ O-, -CH ₂ CH ₂ NH-, -C(O)-, -C(O)CH ₂ -, -C(O)CH ₂ CH ₂ -, and -CH ₂ C(O)-, wherein one or more hydrogens may be independently replaced by deuterium, hydroxy, methyl, halogen, -CF ₃ , or ketone; _R4 is selected from optionally substituted 3-6 membered carbocyclic and heterocyclic rings; _D1 is selected from the following 5-membered monocyclic heterocycles: which is optionally substituted with hydrogen, deuterium, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, amino, halogen, amide, -CF ₃ , CN, -N ₃ , C ₁ -C ₄ ketone, -S(O)C ₁ -C ₄ alkyl, -SO ₂ C ₁ -C ₄ alkyl, -C ₁ -C ₄ thioalkyl, -COOH and/or ester, each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH ₂ , -NHMe, -OMe, -SMe, oxo and/or thio-oxo; and Z is selected from: -Me, -CF ₃ , -Et, CH ₃ CH ₂ O-, CF ₃ CH ₂ -, -SMe, -SOMe, -SO ₂ Me, -CN, wherein the compound is not 12. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 11 or a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acute myeloid leukemia, wherein the compound is administered in combination with other therapies.