HK40010367A - Bicyclic bromodomain inhibitors - Google Patents

Description

Bicyclic bromodomain inhibitors

The application is a divisional application of international application with application number PCT/US2014/043423 and invented as "new bicyclic bromodomain inhibitor" filed on 6/20/2014, which enters the Chinese national stage on 18/12/2015, and the application number is 201480034817.9.

This application claims priority to U.S. provisional patent application No. 61/837,841, filed on 21/6/2013, 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 the prevention and treatment of diseases and conditions associated with bromodomain and extra-terminal domain (BET) proteins.

Background

Post-translational modification of histones (PTMs) is involved in the regulation of gene expression and chromatin organization in eukaryotic cells. Histone acetylation at specific lysine residues is PTM regulated by Histone Acetylases (HAT) and deacetylases (HDAC). Peserico, A. and C.Simone, "Physical and functional HAT/HDAC interpolyated protein amplification balance," J Biomed Biotechnol,2011:371832 (2011). Small molecule inhibitors of HDACs and HAT are under investigation as cancer therapies. Hoshino, i.e., and h.matsubara, "decentralized approaches in histone deacetylase targeted cancer therapy" Surg Today 40(9):809-15 (2010); vernareci, S., F.Tosi and P.Filetii, "Tuning impregnated chromatographic with HAT inhibitors: a novel tool for therapy" adhesives 5(2):105-11 (2010); bandyopadhyay, K. et al, "sperm-CoA-based HAT inhibitors block DNA repair and precursor cancer-specific chemi-and radiosensitization," Cell Cycle8(17):2779-88 (2009); arif, M. et al, "Protein lysine catalysis in cellular functions and roles in cancer simulation," Biochim Biophys Acta 1799(10-12):702-16 (2010). Histone acetylation controls gene expression by recruiting protein complexes that bind directly to acetylated lysine via bromodomains. Sanchez, R. and M.M.Zhou, "The role of human bromodomains in hematology and gene transfer," Curr Opin Drug Discov device 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 branched-associating chromamat adaptor Brd4and descriptive 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 commonly associated with diseases characterized by dysregulation of cell cycle control, inflammatory cytokine expression, viral transcription, hematopoietic differentiation, insulin transcription, and lipogenesis. Belkina, A.C. and G.V.Denis, "BET domain co-regulation in vivo, migration and Cancer," Nat Rev Cancer12(7):465-77 (2012). BET inhibitors are believed to be useful in the treatment of diseases or conditions associated with systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, and the prevention and treatment of viral infections. Belkina, A.C. and G.V.Denis, "BET domain co-ligands in identity, inflammation and Cancer," Nat Rev Cancer12(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).

The autoimmune Disease (which is usually chronic and debilitating) is the result of a deregulated immune response that causes the body to attack its own Cells, tissues and organs, including IL-1 β, TNF- α, IL-6, MCP-1 and IL-17, the expression of IL-17 defines a subset of T Cells called Th17Cells, the Th 25 Cells are partially differentiated by IL-6and drive many pathogenic consequences of autoimmune diseases, therefore the IL-6/Th17 axis represents an important potential pro-forming target of autoimmune Disease therapy, Kimura, A. and T.Kishimoto, "IL-6: regulator of Treg/Th 36balance," Eur J Immunol 40(7):1830-5, (2012) BET inhibitors are expected to have anti-inflammatory and immunomodulatory properties, such as (I, D-7, I-7, NO: A. 7, NO: A. C. and G.V.Dennis. Denis, D.7, NO. 11, NO. 7, NO. 11, NO. 7.

The anti-inflammatory and immunomodulatory effects of BET inhibition have also been demonstrated in vivo. BET inhibitors prevent endotoxin or bacterial sepsis-induced death and caecal ligation perforation-induced death in mice, demonstrating the utility of BET inhibitors in sepsis and acute inflammatory conditions. Nicode, E.et al, "compression of information by enzymic histone mix," Nature 468(7327):1119-23 (2010). BET inhibitors have been shown to ameliorate inflammation and kidney injury in HIV-1 transgenic mice (an animal model of HIV-associated nephropathy) in part by inhibiting the interaction of Brd4 with NF- κ B. Zhang, G., et al, "Down-regulation of NF-kappaB transitional activity in HIVassociated Kidney Disease by BRD4Inhibition," J Biol Chem,287(34):8840-51 (2012). The utility of BET inhibition in autoimmune diseases is demonstrated in a mouse model of multiple sclerosis, where BET inhibition results in abrogation of clinical signs of disease, in part, by inhibiting IL-6and IL-17. Jahagirdar, S.M. et al, "An organic biological Small molecules RVX-297 SignificantlyDescriptions in a Motor Model of Multiple Sclerosis," WorldCongress of Inflammation, Paris, France (2011). These results are supported in a similar mouse model, where treatment with BET inhibitors was shown to inhibit the in vitro differentiation of T cells into pro-autoimmune Th 1and Th17 subsets, and also to abrogate the disease induced by pro-inflammatory Th1 cells. Bandaukwala, H.S., et al, "Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-mycoides," Proc Natl Acad Sci USA,109(36):14532-7 (2012).

BET inhibitors may be useful in the treatment of a variety of chronic autoimmune inflammatory conditions. Accordingly, one aspect of the present invention provides compounds, compositions and methods for treating autoimmune and/or inflammatory diseases by administering one or more compounds of the present invention or pharmaceutical compositions comprising one or more of those compounds. Autoimmune and inflammatory diseases, disorders and syndromes that may be treated using the compounds and methods of the present invention include, but are not limited to, pelvic inflammatory Disease, urethritis, sunburn of the skin, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis (Zhang, g., et al, "Down-regulation of NF-kappaB transformed Activity in hivas suggested kinetic Disease by BRD4Inhibition," J Biol Chem,287(34):8840-51(2012), osteomyelitis, myositis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, crohn's Disease, irritable bowel syndrome, ulcerative colitis (Prinjha, r.k., J. therington and k.leire, "diseases of the liver Disease," 33-33 ", collagen: (3), collagen: (33), collagen:, 3:, 33:" diseases of the liver diseases, "diseases of the stomach:" 3: "diseases of the liver diseases," 3-33: "diseases, 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 autoimmnity by BET protein and c-Myc inhibition," Proc nature Acad Sci USA,109(36):14532-7(2012), scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, goodpasture syndrome, atherosclerosis, addison's disease, parkinson's disease, alzheimer's disease, type I diabetes mellitus (belka, a.c. and g.v. deniers, "diabetes-associated BET and BET), NatRev Cancer12(7):465-77(2012), septic shock (Zhang, G., et al, "Down-regulation of NF-kappaB Transcriptional Activity in HIVassociated Kidney Disease byBRD4Inhibition," J Biol Chem,287(34):8840-51(2012), Systemic Lupus Erythematosus (SLE) (Prinjha, R.K., J.Wittington and K.Lee, "Place your BETs: the thermoconductive tissue of brodomotidomotidasins," Trends Pharmacol Sci 33(3): Med.146-53 (2012), rheumatoid arthritis (Denis, G.V., "Broomain arthritis, type2, 9, three, four, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, uveitis, dry eye disease, scleroderma, mycosis fungoides, and Graves' disease.

BET inhibitors may be useful in treating a wide variety of acute inflammatory conditions, and thus, one aspect of the present 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 may be useful in the prevention and treatment of diseases or conditions involving inflammatory responses to bacteria, viruses, fungi, parasites, and their toxins, such as, but not limited to, sepsis syndrome, septic shock (nicoderme, e., et al, "Suppression of inflammation by a synthetic shock mimics," 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, post-operative syndrome, sarcoidosis, hernans reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronavirus. Belkina, A.C. and G.V.Denis, "BET domain co-regulation in vivo, migration and Cancer," Nat Rev Cancer12(7):465-77 (2012). Accordingly, one aspect of the present invention provides compounds, compositions and methods for treating these inflammatory responses to diseases or conditions responsive to inflammation of the bacteria, viruses, fungi, parasites, and their toxins described herein.

Cancer is a group of diseases caused by dysregulated cell proliferation. Therapeutic approaches aim at reducing the number of cancer cells by inhibiting cell replication or by inducing cancer cell differentiation or death, but there remains a significant unmet medical need for more effective therapeutic agents. Cancer cell accumulation alters the genetic and epigenetic changes in 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 modification of the regulation of chromatin structure, including dysregulation of histone PTMs. Watson, J.D., "Curing 'curable' Cancer," Cancer Discov1(6):477-80 (2011); morin, R.D., et al, "free simulation of hormone-modifying genes in non-Hodgkinlymphoma" Nature 476(7360): 298-.

In one aspect of the invention, there is provided a compound, composition and method for the treatment of human cancers, including, but not limited to, cancers caused by abnormal translocation or overexpression of BET proteins (e.g., NUT Midline Carcinoma (NMC) (French, c.a., "NUT midline Cancer," Cancer gene 203(1):16-20(2010) and B-cell lymphoma (Greenwald, r.j., et al, "E mu-BRD2transgenic tumor cell along B-cell lymphoma and ineukemia," Blood103(4):1475-84 (2004)). NMC tumor cell growth is driven by translocation of either the BRD4 or the BRD3 gene to the nutlin1 gene, filippogloss, p., et al, "tissue surgery of tumor 4," betaimmune therapy, "bebronmias 3527," natbroomodies ", but effective for the inhibition of Cancer transplantation of tumor activity in a model of human Cancer, No. 7-2010, No. BET 73, but No. 7-r (r) is provided by a model for the effective inhibition of tumor cell transplantation of BET protein activity in a mouse model (NMC 10673), such cancers include, but are not limited to, cancers that rely 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 Biol16(4):318-30 (2006). These cancers include burkitt's lymphoma, acute myelogenous leukemia, multiple myeloma, and aggressive human medulloblastoma. Vita, M.and M.Henriksson, "The Myc oncoprotein as a therapeutic target for human Cancer," Semin Cancer Biol16(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 lead to tumor regression through inactivation of c-myc transcription. Dawson, M.A., et al, Inhibition of BET redirection to chromatography as effective treatment for MLL-fusion Leukaemia. Nature,2011.478(7370): pages 529-33; delmore, J.E., et al, "BET branched inhibition as a thermal strategy target c-Myc," Cell 146(6):904-17 (2010); mertz, J.A., et al, "Targeting MYC delivery in cancer by inhibiting BET branched molecules," Proc Natl Acad Sci USA108(40):16669-74 (2011); ott, C.J., et al, "BET branched inhibition targets bothc-Myc and IL7R in high rise acid lymphoblastic leukemia," Blood 120(14):2843-52 (2012); zuber, J, et al, "RNAi screens identities Brd4 as a therapeutic targeting ingredient myoloid leukemia," Nature 478(7370):524-8 (2011).

Embodiments of the invention include methods for treating human cancers: cancer that relies on BET proteins and pTEFb (Cdk 9/Cyclin) to regulate oncogenes (Wang, s. and p.m. fischer, "Cyclin-dependent kinase9: a key transcriptional regulator and potential target induction, virology and cardiology," Trends Pharmacol Sci 29(6):302-13(2008)), and cancer that can be treated for apoptosis or senescence by inhibiting Bcl2, Cyclin-dependent kinase 6(Cdk6) (Dawson, m.a., et al, "Inhibition of BET specificity chemotherapy as an effective transcriptional for mll-fusion," Nature (7370): 478-33 (7370), or human telomerase (htt) cells 2011. Delmore, J.E., et al, "BET branched metallurgical strategy as a thermal strategy to target c-Myc," Cell 146(6):904-17 (2010); ruden, m, and n.puri, "Novel anticancers therapeutics targeting telemerase," Cancer Treat Rev (2012).

BET inhibitors may be used to treat cancer, including, but not limited to, adrenal cancer, acinar cell carcinoma, acoustic neuroma, lentigo acrivaa melanoma, acro sweat adenoma, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myelogenous leukemia (Dawson, M.A., et al, "Inhibition of BET recurrence to hematoma as an effective therapeutic treatment for MLL-fusion leukaemia," Nature 478(7370):529-33(2011), (mertMez, J.A., et al, "Targeting MYC differentiation by inhibiting tumor antigens," Proc Natal Acad Sci (108) (16669-74), RNAi J.2011., 2011. sub.2011., "RNA 4," tumour antigen 78, "Nat Acad. (78) (478-478) (2011.), (2011) (78) (Nature) and J.A., et al," Targeting MY 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-tissue sarcoma, ameloblastic fibroma, anaplastic large-cell lymphoma, thyroid undifferentiated 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 born c-Myc and IL7R in highrisk interstitial lymphocytic leukemia," Blood 120(14):2843-52(2012), (B-cell chronic lymphocytic leukemia, B-cell lymphocytic leukemia, B-cell lymphoma (Greenwald, R.J., et al, "E mu-BRD2transgenic micro-level B-cell lymphoma and leukamia,". Blood103(4):1475-84(2004)), basal cell carcinoma, biliary tract carcinoma, bladder carcinoma, blastoma, bone carcinoma, Brennema, Brown tumor, Burkitt's lymphoma (Mertz, J.A., et al, "Targeting MYC dependent in cancer by inhibiting BETbrodomomains," Proc Natl Acad Sci USA108(40):16669-74(2011), breast carcinoma, brain carcinoma, carcinoma in situ, carcinosarcoma, chondroma, cementoma, medullary sarcoma, chondroma, plexus tumor, choriocarcinoma, choroidal tumor, papillary cell sarcoma, cutaneous T-cell sarcoma, diffuse small cell lymphoma, diffuse colorectal carcinoma, and lymphomas, Embryonic dysplastic neuroepithelial tumors, dysgerminoma, embryonal carcinoma, tumors of endocrine glands, endoblastoma, enteropathy-related T-cell lymphoma, esophageal cancer, parasitic fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, choriocarcinoma of pregnancy, giant cell fibroblast tumor, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, brain glioma, glucagonoma, gonadal blastoma, granuloma, amphoblastoma, gallbladder cancer, stomach cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericyte tumor, hematologic malignancy, hepatoblastoma, T-cell lymphoma of liver and spleen, hodgkin's lymphoma, non-hodgkin's lymphoma, invasive lobular cancer, intestinal cancer, kidney cancer, colon, Laryngeal carcinoma, lentigo maligna, lethal midline carcinoma, leukemia, Leydig (Leydig) cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia (Mertz, j.a., et al, "Targeting MYC dependy in cancer by inhibiting BET bromomas," Proc natla Sci USA108(40):16669-74(2011), chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant salamander tumor, mantle cell lymphoma, marginal zone B cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of breast, medullary thyroid carcinoma, medulloblastoma, melanoma (Miguel f, et al, "4," thermal tumor, et al, "4), "Cancer research.72(8): journal 1(2012), meningioma, Merkel (Merkel) Cell carcinoma, mesothelioma, metastatic urothelial carcinoma, Mullerian (Mullerian) mixed tumor, mixed lineage leukemia (Dawson, m.a., et al, "Inhibition of BET recurrence to lymphoma as an effective metastatic tumor for MLL-fusion leukemia," Nature 478(7370):529-33(2011), mucinous tumor, multiple myeloma (Delmore, j.e., et al, "BET recurrence Inhibition as an effective therapeutic tumor to Myc 146," Cell (6): 904-2010 (468), muscle tissue tumor, mucoid mycosis, mucinous fatty sarcoma, mucinous sarcoma, nasopharyngeal carcinoma, neuroblastoma, myxoma, p, et al, p, et al, BET 3, myxoma, et al, eye cancer, oligoastrocytoma, oligodendroglioma, eosinophiloma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, panchromatosis, papillary thyroid carcinoma, paraganglioma, pineal gland tumor, pituitary cell tumor, pituitary adenoma, plasmacytoma, polyembroma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, peritoneal pseudomyxoma, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, schwaomotoma (schwaomotosis), seminoma, Sertoli (Sertoli) cell tumor, sex-interstitial gonadal tumor, Signet cell carcinoma, skin carcinoma, small cyanobacterial cell carcinoma, small cell carcinoma, soft tissue sarcoma, somatostatin tumors, sooty warts, spinal tumors, splenic marginal zone lymphomas, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small bowel carcinoma, squamous carcinoma, gastric carcinoma, testicular carcinoma, theca cell tumor, thyroid carcinoma, transitional cell carcinoma, laryngeal carcinoma, umbilical duct carcinoma, genitourinary carcinoma, urothelial carcinoma, uveal melanoma, uterine carcinoma, verrucous carcinoma, retinoids, vulvar carcinoma, vaginal carcinoma, waldenstrom's macroglobulinemia, voxin, and wilms ' tumor. Accordingly, 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 adenomas, nasal polyps, pituitary tumors, prolactinomas, pseudocerebroma, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal nodules, polyps and cysts, Castleman (Castleman) disease, chronic Tibetan hair disease, skin fibromas, hair cysts, purulent granulomas, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, post-operative stenosis, keloid formation, scleroderma, and cardiac fibrosis. See, e.g., Tang, X et al, "Assessment of Brd4Inhibition of Idiopathic Pulmonary Fibrosis Lung fibers and in Vivo Models of Lung fibers,". Am J Pathology in press (2013). Accordingly, 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, "heartdisese and string statistics-2012 update: a report from the American HeartAssociation, "Circulation 125(1): e2-e220 (2012). Atherosclerosis (the underlying 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 the aforementioned anti-inflammatory effects and the ability to increase transcription of ApoA-I (the major component of HDL). Mirguet, O.et al, "From ApoA1 alignment to BET family bromodomain inhibition: discovery of I-BET151," Bioorg Med Chem Lett22(8):2963-7 (2012); chung, C.W., et al, "discovery and characterization of small molecule inhibitors of the BET family of Fabry-Perodromins," J Med Chem54(11):3827-38 (2011). Accordingly, one aspect of the present invention provides compounds, compositions and methods for the treatment of cardiovascular disease, including but not limited to atherosclerosis.

Up-regulation of ApoA-I is considered a useful strategy for the treatment of atherosclerosis and CVD. Degoma, E.M. and D.J.rader, "Novel HDL-directed pharmacotherapeutic strategies," Nat Rev Cardiol8(5):266-77 (2011). BET inhibitors have been shown to increase ApoA-I transcription and protein expression. Mirguet, O.et al, "From ApoA1 alignment to BET family bromodomain inhibition: discovery of I-BET151," Bioorg Med Chem Lett22(8):2963-7 (2012); chung, C.W., et al, "discovery and characterization of small molecule inhibitors of the BET family of Fabry-Perodromins," J Med Chem54(11):3827-38 (2011). It has also been shown that BET inhibitors bind directly to BET proteins and inhibit their binding to acetylated histones at the ApoA-1 promoter, indicating the presence of BET protein inhibitory complexes on the ApoA-1 promoter, which may be functionally disrupted by BET inhibitors. It follows that BET inhibitors may be useful in the treatment of disorders of lipid metabolism disorders such as hypercholesterolemia, dyslipidemia, atherosclerosis (Degoma, e.m. and d.j.rader, "Novel HDL-directed pharmacotherapeutic disorders," Nat Rev heart 8(5):266-77(2011), and alzheimer's disease, as well as other neurological disorders, by modulating ApoA-I and HDL. Elliott, D.A., et al, "Apolipoproteins in the hair: antibiotics for neurological and psychiatric disorders," Clin Lipidol 51(4): 555-. Accordingly, one aspect of the present invention provides compounds, compositions and methods for treating cardiovascular disorders by up-regulating ApoA-1.

BET inhibitors may 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.withington, and k.lee, "Place your points: the therapeutic potential of branched animals," Trends Pharmacol Sci 33(3):146-53(2012)), renal reperfusion injury, organ transplantation, coronary artery bypass transplantation, cardiopulmonary bypass surgery, hypertension, pulmonary, renal, hepatic, gastrointestinal, or peri-limb embolism. Accordingly, one aspect of the present invention provides compounds, compositions and methods for the prevention and treatment of conditions associated with ischemia-reperfusion injury described herein.

Obesity-related inflammation is a marker of Type II diabetes, insulin resistance and other metabolic disorders belkinina, a.c. and g.v.denis, "BET domain co-regulation in obesity, inflammation and Cancer," NatRev Cancer12(7):465-77(2012), "Denis, g.v.," Bromodomain coactivators in Cancer, obesity, Type2diabetes, and inflammation, "decov Med10(55):489-99(2010) consistent with the ability of BET inhibitors to inhibit inflammation, gene disruption of Brd2 in mice eliminates inflammation and protects animals from obesity-induced insulin resistance, wang.f., et al," Brd 2diabetes mellitus calcium, and pancreatic hormone, beta-protein, beta-.

Host-encoded BET proteins have been shown to be important for transcriptional activation and suppression of viral promoters. Brd4 interacts with the E2 protein of Human Papilloma Virus (HPV) to achieve E2-mediated transcription of the E2-target gene. Gagnon, D.E., et al, "developmental definition of the papillomavir E2 protein inhibited by overexpression of branched-linking protein4," J Virol 83(9):4127-39 (2009). Similarly, Brd2, Brd3, and Brd4 all bind to latent nuclear antigen 1(LANA1) encoded by kaposi's sarcoma-associated herpesvirus (KSHV), thereby promoting LANA 1-dependent proliferation of cells infected with KSHV. You, J, et al, "Kaposi's sarcoma-associated chimeric peptides viral genes, expressed-by-associated nuclear polypeptides, with branched proteins Brd4 on host viral chromosomes," J Virol 80(18):8909-19 (2006). BET inhibitors have been shown to inhibit Brd 4-mediated recruitment of the transcriptional elongation complex pTEFb to the Epstein-Barr virus (EBV) viral C promoter, indicating therapeutic value against EBV-associated malignancies. Palermo, R.D., et al, "RNA polymerase II standing protein occlusion and pTEFb recovery to drive immunological occlusion by Epstein-Barr virus," PLoS Patholog 7(10): e1002334 (2011). Furthermore, BET inhibitors reactivate HIV in a model of latent T cell infection and latent monocyte infection, potentially allowing viral eradication by complementary antiretroviral therapy. Zhu, J., et al, "reaction of late HIV-1by Inhibition of BRD4," Cell Rep (2012); banerjee, C., et al, "BET bromodomain inhibition as a noveltration for reactivation of HIV-1," J Leukoc Biol (2012); bartholomeeusen, K., et al, "BET brodomain inhibition activities transcription via a trans-mittease of P-TEFb from7SK snRNP," J Biol Chem (2012); li, Z, et al, "The BETbromodomain inhibitor JQ1 activities, HIV latency through anti mutagenesis Brd4inhibition of Tat-transformation," Nucleic Acids Res (2012).

BET inhibitors may be used for the prevention and treatment of episomal-based DNA viruses, including, but not limited to, human papilloma virus, herpes virus, epstein-barr virus, human immunodeficiency virus (Belkina, a.c. and g.v. denis, "BET domain co-ligands in immunity, inflammation and Cancer," Nat Rev Cancer12(7):465-77(2012)), adenovirus, poxvirus, hepatitis b virus, and hepatitis c virus. Accordingly, the present invention also provides compounds, compositions and methods for the treatment and prevention of episome-based DNA virus infection as described herein.

Some Central Nervous System (CNS) diseases are characterized by disorders of epigenetic processes. Brd2 haploid deficits have been linked to neuronal deficits and epilepsy. Velisek, L.et al, "GABAergic neuron specific as inert genetic engineered eplication mechanism" the role of BRD2 ha ploison in jravenile myoclonic eplication, "PLoS One6(8): e23656 (2011). SNPs in various bromodomain-containing proteins have also been associated with 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 useful in Alzheimer's disease therapy, thereby accounting for the proposed relationship between increased ApoA-I and Alzheimer's disease and other neurological disorders. Elliott, D.A., et al, "Apolipoproteins the hair: antibiotics for neurological and psychiatric disorders," ClinLipidol 51(4): 555-. Accordingly, 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 family of proteins, essential for chromatin remodeling during spermatogenesis. Gaucher, J., et al, "Bromodomain-dependent stage-specific mass genetic programming by Brdt," EMBO J31(19):3809-20 (2012); shang, E., et al, "The first model of Brdt, a testics-specific member of The BET sub-family of double-branched-relating proteins, is assessment for a large gem cell identification," Development 134(19):3507-15 (2007). Genetic deletion of BRDT or inhibition of BRDT interaction with acetylated histones by BET inhibitors leads to a contraceptive effect in mice, which is reversible when small molecule BET inhibitors are used. Matzuk, M.M., et al, "Small-Module Inhibition of BRDT for MaleContraceion," Cell 150(4): 673-; berkovits, B.D., et al, "The test-specific double branched conjugated protein BRDT for a complex with multiple specific primers for mRNA labeling and 3' -UTTRUCTION in round primers," Nucleic Acids Res 40(15):7162-75 (2012). These data indicate the potential utility of BET inhibitors as novel and effective methods of male contraception. Accordingly, 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-1in cardiovascular diseases: molecular mechanism and clinical indications," 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, which can develop into atherosclerotic plaques. Dawson, J.et al, "targeted monoclonal chemoattractrant protein-1signalling in disease," Expert Opin 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 of hyperlipidemia background. Boring, L., et al, "classified delivery formation in CCR2-/-mice a roll for chemikiness interaction of atherosclerosis," Nature 394(6696):894-7 (1998); gosling, J., et al, "MCP-1, specificity of reproduction to exothermic in micro hormone apolipoprotein B," J Clin Invest 103(6):773-8 (1999); gu, L., et al, "Absence of monoclonal chemoattractant protein-1 process exothermic sensitivity promoter-specific mice," Mol Cell 2(2):275-81 (1998); aiello, R.J., et al, "Monocyte chemoattractant protein-1 acellular thermal degradation in apolipoprotein E-default microorganism," Arterioscler Thromb Vascbiol 19(6):1518-25 (1999). These reports demonstrate that elimination of MCP-1 signaling results in reduced macrophage infiltration into 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-1in cardiovascular diseases: molecular mechanism and clinical indications," Clin Sci (Lond)117(3):95-109 (2009). MCP-1 and its receptor are overexpressed in human atherosclerotic plaques by endothelial cells, smooth muscle cells, and infiltrating monocytes/macrophages. Nelken, N.A., et al, "Monocyte chemoattractant protein-1in human atheromatous plants," 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 atherosclerotic burden, and incidence of Coronary Heart Disease (CHD). De o, R., et al, "Association atmospheric levels of unicyte chemoattrantprotein-1, and biochemical cardiac disorders, and" J Am Coll diol 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 monoclonal chemoattractrant protein-1and long-tertiary amino groups in tissues with access computer architecture 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 heart transplant rejection. Niu, J. and P.E.Kolattukudy, "Role of MCP-1in cardiac diseases," molecular mechanisms and clinical applications, "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 macrophage and lymphocyte infiltration into the joint in RA and is overexpressed in the synovial fluid of RA patients. Koch, A.E., et al, "Enhanced production of monoclonal antibody protein-1in rhematoid 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 cadence-active CCR2 antagnostist, INCB3344," J Immunol 175(8):5370-8 (2005); bruhl, H., et al, "Dual roll of CCR2 reduction initiation and progression of collagen-induced arthritis of CCR2+ T cells," J Immunol 172(2):890-8 (2004); gong, J.H., et al, "Anantagnostist 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-on set inhibition of music using combined chemokinetic therapy," Rheumatology (Oxford 43(1):39-42 (2004)).

Overexpression of MCP-1in brain, cerebrospinal fluid (CSF) and blood has also been associated with chronic and acute MS in humans. Mahad, D.J. and R.M. Ransohoff, "The role of MCP-1(CCL2) and CCR2 in multiple sclerosis and Experimental Autoimmune Encephamyetis (EAE)," Semin Immunol15(1):23-32 (2003). MCP-1 is overexpressed by various cell types in the brain during disease progression and contributes to macrophage and lymphocyte infiltration, which mediates MS-associated tissue damage. Genetic deletion of MCP-1 or CCR2 in an Experimental Autoimmune Encephalomyelitis (EAE) mouse model, a model resembling human MS, results in resistance to disease, primarily due to reduced macrophage infiltration into the CNS. Fife, B.T., et al, "CC chemokine 2 interference for indication of experimental autoimmu encephalyitis," J ExpMed 192(6): 899-; huang, D.R., et al, "Absence of monoclonal chemoattractant protein 1in micro leaves to secreted local macromolecular receptor and antigen-specific T-cell type 1immune response in experimental autoimmune pharmacology," J Exp Med 193(6):713-26 (2001).

Preclinical data have shown that small and large molecule inhibitors of MCP-1 and CCR2 have potential as therapeutics 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 CCR 2.

Disclosure of Invention

Accordingly, 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 the treatment and prevention of diseases and conditions, including but not limited to cancer, autoimmune, and cardiovascular diseases. The compounds of the invention are defined by formula Ia or formula IIa:

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

wherein:

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

with the proviso that A cannot be substituted or unsubstituted

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

y is selected from N, C and CH;

W₁selected from N and CR₁；

W₂Selected from N and CR₂；

W₃Selected from N and CR₃；

W₄And W₅Independently selected from N, CH and C or alternatively, W₄And W₅Both C (see, e.g., formulae Ib and IIb below);

W₁、W₂and W₃May be the same as or different from each other;

R₁and R₂Independently 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;

R₃selected from hydrogen, -NH₂、-CN、-N₃Halogen and deuterium; or alternatively, R₃Is selected from-NO₂、-OMe、-OEt、-NHC(O)Me、NHSO₂Me, cyclic amino, cyclic amido, -OH, -SO₂Me、-SO₂Et、-CH₂NH₂、-C(O)NH₂and-C (O) OMe;

x is selected from-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-, wherein one or more hydrogens may be independently replaced by deuterium, halogen, -CF₃Ketone substitution, and wherein S may be oxidized to a sulfoxide or sulfone; or alternatively, X may be selected from-NH-, -CH (OH) -, -CH (CH)₃) -and hydroxymethyl, wherein one or more hydrogens may be independently replaced by deuterium, halogen, -CF₃Ketone substitution, and wherein S may be oxidized to a sulfoxide or sulfone;

R₄selected from 4-7 membered carbocycles and heterocycles; or alternatively, R₄Is a 3-membered carbocyclic or heterocyclic ring;

D₁selected from the group consisting of 5-membered monocyclic carbocycles and heterocycles; or alternatively, D₁Is a monocyclic heterocycle, wherein D₁(ii) is attached to the B ring via a carbon atom that is part of a double bond;

with the proviso that if R₃Is hydrogen and A is a 5-membered ring, then D₁Can not be

And provided that if D₁Is composed ofAnd R is₂And R₃Is hydrogen and R₁is-OMe, then the A-B bicyclic ring is not

And provided that if D₁Is composed ofAnd R is₁、R₂、R₃Each of which is hydrogen, then the A-B bicyclic ring is not

Unless ring B is substituted;

and with the proviso that if R₁、R₂、R₃Each of which is hydrogen, then the A-B bicyclic ring is not

And with the proviso that if R₁、R₂、R₃Each of which is hydrogen, then the A-B bicyclic ring is not

In certain embodiments a is a five membered ring. In some embodiments Y is N or C. In some embodiments, R₁And R₂Independently selected from hydrogen, deuterium, alkyl, -OH, -NH₂-thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide, sulfonamide, and-CN. In some embodiments, the compound of formula Ia is a compound of formula Ib, i.e., wherein W of formula I₄And W₅Are all C.

In some embodiments, the compound of formula IIa is a compound of formula IIb, i.e., wherein W of formula I₄And W₅Are all C.

In another aspect of the present invention, there is provided 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.

In a further aspect of the invention, there is provided a compound of formula Ia, formula Ib, formula IIa and/or formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising such a compound, for use in therapy, in particular in the treatment of a disease or condition for which a bromodomain inhibitor is indicated.

In a further aspect of the invention, there is provided a compound of formula Ia, formula Ib, formula IIa and/or formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of a disease or condition for which a bromodomain inhibitor is indicated.

Definition of

As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. 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 mediated by BET inhibition exemplary cardiovascular diseases (including cholesterol or lipid related disorders) include, but are not limited to, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial mixed hyperlipidemia, hypo α lipoproteinemia, hypertriglyceridemia, hyper β lipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia reperfusion injury, ischemic heart disease, myocardial ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal arteriosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient cerebral ischemia, and diseases associated with alzheimer's disease, impotence, obesity, multiple sclerosis, parkinson's disease, inflammatory disease, and inflammatory disease of the heart and circulatory system.

As used herein, "inflammatory disease" 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 post-transplant and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia reperfusion injury, post-angioplasty restenosis, Chronic Obstructive Pulmonary Disease (COPD), glomerulonephritis, graves' disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina, and small artery disease.

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 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 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.

By "subject" is meant an animal, such as a mammal, that has been or will be the subject of treatment, observation or experiment. The methods described herein are useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.

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

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

A connection number ("-") that is not between two letters or symbols is used to indicate a point of connection for a substituent. For example, -CONH₂Through carbon atom toAnd (6) connecting.

"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. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined below. It will be understood by those skilled in the art that, with respect to any group containing one or more substituents, the group is not intended to introduce any sterically impractical, synthetically non-feasible and/or inherently unstable substitution or substitution pattern.

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

The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched chain group of 2 to 8 carbon atoms, referred to herein as (C)₂-C₈) An alkenyl group. 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.

The term "alkoxy" as used herein refers to an alkyl (-O-alkyl-) group attached to an oxygen. "alkoxy" also includes alkenyl ("alkenyloxy") or alkynyl ("alkynyloxy") linked to oxygen. Exemplary alkoxy groups include, but are not limited to, groups having alkyl, alkenyl, or alkynyl groups of 1-8 carbon atoms, referred to herein as (C)_1-C₈) An alkoxy group. Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy.

The term "alkyl" as used herein 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 (C)_1-C₈) An alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methylThe group-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 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-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

The term "alkynyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched chain group of 2 to 8 carbon atoms, referred to herein as (C)_2-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.

The term "amide" as used herein refers to the form-NR_aC(O)(R_b) -or-C (O) NR_bR_cWherein R is_a、R_bAnd R_cEach independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide may be through carbon, nitrogen, R_bOr R_cTo another group. The amides may also be cyclic, e.g. R_bAnd R_cMay be joined to form a 3to 8 membered ring, such as a 5 or 6 membered ring. The term "amide" encompasses groups such as sulfonamides, ureas, ureidos, carbamates and cyclic versions thereof. The term "amide" also encompasses amide groups attached to a carboxyl group, for example-amide-COOH or salts such as-amide-COONa; an amino group attached to a carboxyl group (e.g., -amino-COOH or a salt such as-amino-COONa).

The term "amine" or "amino" as used herein refers to the form-NR_dR_eor-N (R)_d)R_e-, wherein R_dAnd R_eIndependently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amino group may be linked to the parent molecular group through nitrogenAnd (4) clustering. The amino group may also be cyclic, e.g. R_dAnd R_eAny two of which may be joined together or to the N to form a 3to 12 membered ring (e.g. morpholino or piperidinyl). The term amino also includes any of the corresponding quaternary ammonium salts of amino groups. Exemplary amino groups include alkylamino groups, wherein R is_dOr R_eAt least one of which is an alkyl group. In some embodiments, Rd and Re are each optionally substituted with hydroxy, halo, alkoxy, ester, or amino.

The term "aryl" as used herein refers to a mono-, bi-, or other multicyclic, aromatic ring system. The aryl group may be optionally fused to one or more rings selected from the group consisting of 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 thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7, 8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems, wherein the ring contains 6 carbon atoms, referred to herein as "(C)₆) Aryl ".

The term "arylalkyl" as used herein 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 rings contain 6 carbon atoms, referred to herein as "(C)₆) An arylalkyl group ".

The term "carbamate" as used herein refers to the form-R_gOC(O)N(R_h)-、-R_gOC(O)N(R_h)R_i-or-OC (O) NR_hR_iWherein R is_g、R_hAnd R_iEach independently selected from alkyl, alkenyl, alkynyl, aryl,Arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. Exemplary carbamates include, but are not limited to, aryl carbamates or heteroaryl carbamates (e.g., wherein R is_g、R_hAnd R_iAt least one of which is independently selected from aryl or heteroaryl groups, such as pyridine, pyridazine, pyrimidine and pyrazine).

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

The term "carboxy" as used herein refers to-COOH or its corresponding carboxylate (e.g., -COONa). The term carboxy also includes "carboxycarbonyl", e.g., a carboxy group attached to a carbonyl group, 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.

The term "cycloalkyl" as used herein refers to a 3-12 carbon or 3-8 carbon saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group derived from a cycloalkane, referred to herein as "(C)₃-C₈) Cycloalkyl groups ". Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups 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 thioketone. The cycloalkyl group may be fused to other cycloalkyl groups, saturated or unsaturated aryl groups, or heterocyclic groups.

The term "dicarboxylic acid" as used herein refers to groups 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. The dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione. Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-) -malic acid, (+)/(-) tartaric acid, isophthalic acid and terephthalic acid. Dicarboxylic acids also include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides (e.g., succinic anhydride and succinimide).

The term "ester" refers to the structures-C (O) O-, -C (O) O-Rj_-、-R_kC(O)O-Rj_-or-R_kC (O) O-, wherein O is not bound to hydrogen, and Rj and R_kMay be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. R_kMay be hydrogen, but Rj cannot be hydrogen. The ester may be cyclic, e.g. carbon and Rj, oxygen and R_kOr Rj and R_kMay be joined to form a 3to 12 membered ring. Exemplary esters include, but are not limited to, alkyl esters, wherein Rj or R_kAt least one of which is an alkyl group, such as-O-C (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 those having the structure-R_kC (O) the reverse ester of O-, wherein oxygen is bonded to the parent molecule. Exemplary reverse esters include succinate, D-arginine, L-lysine, and D-lysine. Esters also include carboxylic acid anhydrides and acid halides.

The term "halo" or "halogen" as used herein refers to F, Cl, Br or I.

The term "haloalkyl" as used herein 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.

The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or other polycyclic aromatic ring system containing one or more heteroatoms, e.g., 1-3 heteroatoms, such as nitrogen, oxygen and sulfur. The heteroaryl group 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 thione. Heteroaryl groups can also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl (pyrazyl), triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, pyrimidinyl (pyrimidinyl), tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, 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-C₅) Heteroaryl group ".

The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein refers to a saturated or unsaturated 3,4, 5,6 or 7 membered ring containing one, two or three heteroatoms independently selected from nitrogen, oxygen and sulfur. Heterocycles can be aromatic (heteroaryl) or non-aromatic. The heterocyclic ring 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. Heterocyclic also includes 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, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuranyl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridinyl, pyrimidinyl (pyrimidyl), pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, Tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms "hydroxy" and "hydroxyl" as used herein refer to-OH.

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

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

The term "ketone" as used herein refers to the structure-C (O) -Rn (e.g., acetyl, -C (O) CH)₃) or-R_n-C(O)-R_o-. Ketones can be obtained by R_nOr R_oTo another group. R_nOr R_oMay be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_nOr R_oMay be joined to form a 3to 12 membered ring.

The term "monoester" as used herein refers to an analog of a dicarboxylic acid in which one carboxylic acid is functionalized as an ester and the other carboxylic acid is the free carboxylic acid or a salt of the 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.

The term "phenyl" as used herein 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 thione.

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

The "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, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N. The substituents may be branched to form a substituted or unsubstituted heterocyclic or cycloalkyl group.

As used herein, suitable substitution on an optionally substituted substituent refers to a group that does not negate the synthetic or pharmaceutical utility of the compounds of the present disclosure or intermediates used to prepare the compounds. Examples of suitable substitutions include, but are not limited to: c_1-8Alkyl, alkenyl or alkynyl; c_1-6Aryl radical, C_2-5A heteroaryl group; c₃₇A cycloalkyl group; c_1-8An alkoxy group; c₆An aryloxy group; -CN; -OH; oxo; halo, carboxy; amino radicals, e.g. NH (C)_1-8Alkyl), -N (C)_1-8Alkyl radical)₂、-NH((C₆) Aryl) or-N ((C)₆) Aryl radical)₂(ii) a A formyl group; ketones, e.g. -CO (C)_1-8Alkyl), -CO ((C)₆Aryl) esters, e.g. -CO₂(C_1-8Alkyl) and-CO₂(C₆Aryl). One skilled in the art can readily select suitable substitutions based on the stability and pharmacological activity as well as the synthetic activity of the compounds of the present disclosure.

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

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

The term "pharmaceutically acceptable prodrug" as used herein means those prodrugs of the compounds of the present disclosure which 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, and other deleterious effects commensurate with a reasonable benefit/risk ratio and which are effective for their intended use, as well as the zwitterionic forms (where possible) of the compounds of the present disclosure. Discussion is provided in Higuchi et al, "Prodrugs as Novel delivery systems," ACS Symposium Series, Vol.14, and Roche, E.B., eds Bioreversible Carriersin Drug Design, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. The essentially basic compounds included in the compositions of the present invention are capable of forming a wide variety of salts with a wide variety of 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, gentisate, 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, the compounds included in the present compositions that include an amino moiety can form pharmaceutically acceptable salts with a variety of amino acids. The acidic in nature compounds 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, specifically, 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 thus exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. The term "stereoisomer" as used herein is composed of all geometric isomers, enantiomers and diastereomers. These compounds may be designated by the symbol "R" or "S" depending on the configuration of the substituents around the stereoisomeric carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but the skilled artisan will recognize that a structure may implicitly represent a chiral center.

The individual stereoisomers of the compounds of the present disclosure may 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 of ordinary skill in the art. These resolution methods are exemplified by the following: (1) the enantiomeric mixture is linked to a chiral auxiliary, the resulting diastereomeric mixture is separated by recrystallization or chromatography and the optically pure product is released from the auxiliary, (2) a salt is formed with an optically active resolving agent, or (3) the mixture of optical enantiomers is separated directly on a chiral liquid chromatography column. Stereoisomeric mixtures may also be resolved into their component stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers may also be obtained from stereoisomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

Geometric isomers may also be present in the compounds of the present disclosure. The present disclosure encompasses various geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or around a carbocyclic ring, and mixtures thereof. Substituents around a carbon-carbon double bond are designated as being in either the "Z" or "E" configuration, where the terms "Z" and "E" are used according to the IUPAC standard. 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" represents substituents on the same side of the double bond and "trans" represents substituents on the opposite side of the double bond. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans". The term "cis" denotes substituents on the same side of the plane of the ring, while the term "trans" denotes substituents on the opposite side of the plane of the ring. Mixtures of compounds in which the substituents are arranged on the same and opposite sides of the plane of the ring are 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 disclosure, although only one tautomeric structure is depicted.

Exemplary embodiments of the invention

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

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

wherein:

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

with the proviso that A cannot be substituted or unsubstituted

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

y is selected from N and C;

W₁selected from N and CR₁；

W₂Selected from N and CR₂；

W₃Selected from N and CR₃；

W₄And W₅Independently selected from N, CH and C, if present;

W₁、W₂and W₃May 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 (CH)₃) -, wherein one or more hydrogens may be independently replaced by deuterium, hydroxymethyl, halogen, -CF₃Ketone substitution, and wherein S may be oxidized to a sulfoxide or sulfone;

R₄selected from 3-7 membered carbocycles and heterocycles;

D₁selected from 5-membered monocyclic heterocycles, wherein D₁Through being D₁The carbon atoms of the part of the double bond in the ring are attached to the B ring.

R₁And R₂Independently selected from hydrogen, deuterium, alkyl, -OH, -NH₂-thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide, sulfonamide, and-CN;

R₃selected from hydrogen, -NH₂、-CN、-N₃Halogen, deuterium, -NO₂、-OMe、-OEt、-NHC(O)Me、NHSO₂Me, cyclic amino, cyclic amido, -OH, -SO₂Me、-SO₂Et、-CH₂NH₂、-C(O)NH₂and-C (O) OMe;

with the proviso that if R₃Is hydrogen and A is a 5-membered ring, then D₁Can not be

And provided that if D₁Is composed ofAnd R is₂And R₃Is hydrogen and R₁is-OMe, then the A-B bicyclic ring is not

And provided that if D₁Is composed ofAnd R is₁、R₂、R₃Each of which is hydrogen, then the A-B bicyclic ring is not

Unless ring B is substituted;

and with the proviso that if R₁、R₂、R₃Each of which is hydrogen, then the A-B bicyclic ring is not

And with the proviso that if R₁、R₂、R₃Each of which is hydrogen, then the A-B bicyclic ring is not

In some embodiments, the a ring of a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Alkyl (C), alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆). In some embodiments, Z is selected from

-Me、-CF₃、-Et、CH₃CH₂O-、CF₃CH₂-、SMe、-SOMe、-SO₂Me、-CN、

In some embodiments, a compound of any one 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, -NH₂Amino (such as NH (C)₁-C₅) Carbocyclic ring (C)₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Hetero ring (C)₄-C₆) Carbocyclic ring (C)₄-C₆) Halogen, -CN, -OH, -CF₃Alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) (ii) a X, R therein₄And D₁As defined for any of the embodiments disclosed herein.

In some embodiments, a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Heterocyclic ring (C)₄-C₆) Carbocyclic ring (C)₄-C₆) Halogen, -CN, -OH, -CF₃Alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) (ii) a X, R therein₄And D₁As defined for any of the embodiments disclosed herein.

In some embodiments, a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Hetero ring (C)₄-C₆) Carbocyclic ring (C)₄-C₆) Halogen, -CN, -OH, -CF₃Alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) (ii) a X, R therein₄And D₁As defined for any of the embodiments disclosed herein.

In some embodiments, a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Hetero ring (C)₄-C₆) Carbocyclic ring (C)₄-C₆) Halogen, -CN, -OH, -CF₃Alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) (ii) a X, R therein₄And D₁As defined for any embodiment disclosed herein.

In some embodiments, a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Alkyl (C), alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) (ii) a A carboxyl group;

D₁is composed of

X is selected from-CH₂-and-CH (CH)₃) -; and

R₄is a phenyl ring, which is optionalIndependently selected from one or more independently selected from deuterium, alkyl (C)₁-C₄) Alkoxy (C)₁-C₄) Halogen, -CF₃CN and-thioalkyl (C)₁-C₄) Wherein each of alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl or Br.

In certain embodiments, R₄Is a phenyl ring optionally substituted with one or more alkyl groups (C) selected from methyl, ethyl, propyl, isopropyl and butyl₁-C₄) (ii) a Alkoxy (C) selected from methoxy, ethoxy and isopropoxy₁-C₄) (ii) a Halogen selected from F and Cl; and thioalkyl (C) selected from the group consisting of-SMe, -SEt, -SPr and-Sbu₁-C₄) And (4) substitution.

In some embodiments, the a-B bicyclic ring in a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Alkyl (C), alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆)。

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

Which may be optionally substituted with groups independently selected from: hydrogen, deuterium, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo.

In some embodiments of any of formulas Ia, Ib, IIa, and 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: hydrogen, deuterium, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo.

In some embodiments, the a-B bicyclic ring in a compound of any one of formula Ia, formula Ib, formula IIa, and formula 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo.

In some embodiments, the a-B bicyclic ring of a compound of any one of formula Ia, formula Ib, formula IIa, and formula 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, sulfonamide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo.

In some embodiments, the a-B bicyclic ring in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected fromWhich may be optionally substituted with groups independently selected from: hydrogen, deuterium, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, sulfonamide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo.

In some embodiments, the a ring in a compound of any one 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 fused to the B ring.

In some embodiments, Y in a compound of any one 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, D in a compound of any one of formula I, formula Ia, or formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Selected from 5-membered monocyclic heterocycles, such as but not limited to:

optionally substituted by hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), -COOH and/or an ester (such as-C (O) OMe, -C (O) OEt, -C (O) OBu), each of which groups may be optionally substituted by: hydrogen, F, Cl, Br, -OH, -NH₂、-NHMe、-OMe-SMe, oxo and/or thio-oxo.

In some embodiments, D in a compound of any one of formulas Ia, Ib, IIa or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof₁Is a monocyclic heterocycle optionally substituted with hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), -COOH and/or an ester (such as-C (O) OMe, -C (O) OEt, -C (O) OBu), each of which groups may be optionally substituted by: hydrogen, F, Cl, Br, -OH, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, D in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Selected from the group consisting of 5-membered monocyclic heterocycles containing one oxygen and one or two nitrogens, wherein said heterocycle is connected to the remainder of the molecule via a carbon-carbon bond, and which is optionally substituted with hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NHC alkyl), haloElements (such as F, Cl), amides (such as-NHC (O) Me, -NHC (O) Et, -C (O) NHMe, -C (O) NEt₂、-C(O)NiPr)、-CF₃、CN、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), -COOH and/or an ester (such as-C (O) OMe, -C (O) OEt, -C (O) OBu), each of which groups may be optionally substituted by: hydrogen, F, Cl, Br, -OH, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, D in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Is isoxazole optionally substituted by: hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), -COOH and/or an ester (such as-C (O) OMe, -C (O) OEt, -C (O) OBu), each of which groups may be optionally substituted by: hydrogen, F, Cl, Br, -OH, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, D in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Selected from the group consisting of 5-membered monocyclic heterocycles optionally substituted with hydrogen, deuterium, alkyl (C1-C4) (such as methyl, ethyl, propyl), each of which may optionally be substituted with hydrogen, -OH, -F and-NH₂And (4) substitution.

In some embodiments, D in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Selected from the group consisting of 5-membered monocyclic heterocycles containing one oxygen and one or two nitrogens, wherein said heterocycle is connected to the remainder of the molecule via a carbon-carbon bond, and which is optionally substituted with hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl), each of which may be optionally substituted with: hydrogen, -OH, -F and-NH₂。

In some embodiments, D in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Is isoxazole or pyrazole optionally substituted by hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl), each of which may be optionally substituted with: hydrogen, -OH, -F and-NH₂。

In some embodiments, D in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Is D in some embodiments, a compound of any one of formula Ia, formula Ib, formula IIa and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof₁In some embodiments, formula I_aD1 for the compounds of formula Ib, formula IIa and formula IIb or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof is

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Is CR₁。

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₂Is CR₂。

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁And W₂At least one of which is nitrogen.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Is CH.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₂Is CR₂Wherein R is₂Selected from hydrogen, deuterium, -OH, -NH₂Methyl, halogen and-CN.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₂Is CH.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄And W₅Is carbon.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄And W₅At least one of which is nitrogen.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₃Is nitrogen.

In some embodiments, W in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₃Is CR₃Wherein R is₃Selected from hydrogen, -NH₂And a halogen.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₃Selected from hydrogen and-NH₂。

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₃is-NH₂。

In some embodiments, X in a compound of any one 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) NH-, -C (O) O-, -C (O) S-, wherein one or more hydrogens may be independently replaced by deuterium, halogen, and wherein S may be oxidized to sulfoxide or sulfone.

In some embodiments, a compound of any of formula I, formula Ia, or formula II, or a pharmaceutically acceptable salt thereofX in the stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate is selected from-CH₂and-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 a 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 a halogen.

In some embodiments, X in a compound of any one 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 in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁Selected 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 in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₂Selected 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, a compound of any of formula I, formula Ia, or a pharmaceutically acceptable salt thereofR in a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate₁And R₂Independently selected from hydrogen, deuterium, alkyl, -NH₂-thioalkyl, alkoxy, amino, amide, halo, carbocycle, heterocycle and-CN.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁And R₂Independently selected from hydrogen, deuterium, alkyl (C)₁-C₆)、-NH₂-thioalkyl (C)₁-C₆) Alkoxy (C)₁-C₆) Amino and amide.

In some embodiments, R₁And R₂Is hydrogen.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₁、R₂And R₃At least one of which is not hydrogen.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 5-6 membered carbocycles and heterocycles.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 5-6 membered heterocyclic rings.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 5-6 membered heterocyclic rings containing 1 or 2 nitrogens, such as unsubstituted and substituted pyrimidinyl rings, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 6-membered heterocyclic rings containing at least one nitrogen, such as unsubstituted and substituted pyridyl rings, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R in a compound of any one of formula I, formula Ia, or formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Is selected from

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Is isoxazole or pyrazole, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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,-NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 5-membered heterocyclic rings containing one or two nitrogens.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 5-6 membered carbocyclic rings, such as phenyl rings, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Is a phenyl ring, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such asSuch as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from aryl, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, -X-R₄Is selected from-CH₂And (4) an aryl group.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from pyridyl, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer thereofR in tautomers, pharmaceutically acceptable salts or hydrates₄Optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Selected from 5-6 membered carbocyclic rings.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Is selected from lower cycloalkyl (C)₃-C₆) And a phenyl ring optionally substituted with one or more independently selected from deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy and isopropoxy), halogen (such as F and Cl), -CF₃CN and-thioalkyl (C)₁-C₄) (such as, for example,e.g., -SMe, -SEt, -SPr, and-Sbu), wherein each alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl or Br.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Is a phenyl ring optionally substituted with one or more substituents independently selected from deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy and isopropoxy), halogen (such as F and Cl), -CF₃CN and-thioalkyl (C)₁-C₄) (such as, for example, -SMe, -SEt, -SPr, and-Sbu), wherein each alkyl, alkoxy, and thioalkyl may optionally be substituted with F, Cl or Br.

In some embodiments, R in a compound of any one of formula Ia, formula Ib, formula IIa, and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof₄Is aryl, optionally substituted with one or more independently selected from deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy and isopropoxy), halogen (such as F and Cl), -CF₃CN and-thioalkyl (C)₁-C₄) (such as, for example, -SMe, -SEt, -SPr, and-Sbu), wherein each alkyl, alkoxy, and thioalkyl may optionally be substituted with F, Cl or Br.

In some embodiments, in a compound of any one 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: hydrogen, deuterium, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo;

D₁is composed of

X is selected from-CH₂-and-c (o) -;

R₄is a phenyl ring, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), 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、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (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 said groups may be optionally substituted with: hydrogen, F, Cl, Br, -OH, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, in a compound of any one 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 fromWhich may be optionally substituted with groups independently selected from: hydrogen, deuterium, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₇) -NH carbocycle (C₄-C₇) Hetero ring (C)₄-C₇) Carbocyclic ring (C)₄-C₇) Halogen, -CN, -OH, -CF₃Sulfone, sulfoxide, sulfonamide, alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) Alkoxy (C)₁-C₆) Ketone (C)₁-C₆) Esters, ureas, carboxylic acids, carbamates, amides (C)₁-C₆) Oxo and thio-oxo.

D₁Is composed of

X is selected from-CH₂-、–CH(CH₃) -, -CH (OH) -and-NH-;

R₄is a phenyl ring, optionally independently selected from hydrogen, deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as-NH)₂、-NHMe、-NHEt、-NHiPr、-NHBu-NMe₂、NMeEt、-NEt₂-NEtBu, -NHC (O) NH alkyl), halogen(s)E.g. F, Cl), amides (such as-NHC (O) Me, -NHC (O) Et, -C (O) NHMe, -C (O) NEt₂、-C(O)NiPr)、-CF₃、CN、-N₃Ketone (C)₁-C₄) (such as acetyl, -C (O) Et, -C (O) Pr), -S (O) alkyl (C₁-C₄) (such as-S (O) Me, -S (O) Et), -SO₂Alkyl radical (C)₁-C₄) (such as-SO)₂Me、-SO₂Et、-SO₂Pr), -thioalkyl (C)₁-C₄) (such as-SMe, -SEt, -SPr, -SBu), carboxy (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, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

In some embodiments, in a compound of any one of formula Ia, formula Ib, formula IIa and formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, -X-R₄is-CH₂And (4) an aryl group.

In some embodiments, in a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Alkyl (C), alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) A carboxyl group;

D₁is composed ofAnd is

X is selected from-CH₂-and-CH (CH)₃) -; and

R₄is a phenyl ring optionally independently selected from one or more independently selected from deuterium, alkyl (C)₁-C₄) Alkoxy (C)₁-C₄) Halogen, -CF₃CN and-thioalkyl (C)₁-C₄) Wherein each of alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl or Br.

In some embodiments, in a compound of any one 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, -NH₂Amino (such as-NH (C)₁-C₅)、-N(C₁-C₅)₂-NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C)₄-C₆) -NH carbocycle (C₄-C₆) Alkyl (C), alkyl (C)₁-C₆) Thioalkyl (C)₁-C₆) Alkenyl (C)₁-C₆) And alkoxy (C)₁-C₆) (ii) a A carboxyl group;

D₁is composed of

X is selected from-CH₂-and-CH (CH)₃) -; and

R₄is a phenyl ring optionally substituted with one or more substituents independently selected from deuterium, alkyl (C)₁-C₄) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C)₁-C₄) (such as methoxy, ethoxy and isopropoxy), halogen (such as F and Cl), -CF₃CN and-thioalkyl (C)₁-C₄) (such as, for example, -SMe, -SEt, -SPr, and-Sbu), wherein each alkyl, alkoxy, and thioalkyl may optionally be substituted with F, Cl or Br.

In certain embodiments of the 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 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-dimethylisoxazoles

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-dimethylisoxazoles

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-yl formate

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-dimethylisoxazoles

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) isoxazoles

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-dimethylisoxazoles

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- (thiophen-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-dimethylisoxazoles

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

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-methylthiophen-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

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

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-dimethylisoxazoles

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- (thiophen-3-ylmethyl) -1H-pyrazolo [4,3-b ] pyridin-6-yl) isoxazoles

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-dimethylisoxazoles

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-dimethylisoxazoles

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-dimethylisoxazoles

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-dimethylisoxazoles

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-dimethylisoxazoles

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-dimethylisoxazoles

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-phenethyl) -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-carboxamidine;

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 invention provides methods for inhibiting BET protein function 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, 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, due to the potent effect of BET inhibitors on IL-6and IL-17 transcription in vitro. The following autoimmune diseases are suitable for inhibiting the therapeutic effect 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 pronounced effect of IL-6 and/or IL-17: acute disseminated encephalomyelitis (Ishizu, T., et al, "CSF Cytokine and chemical profiles in induced pharmacological inflammation," JNeuromimetic 175(1-2):52-8(2006)), agalactia globulinemia (Gonzalez-Serrano, M.E., et al, "incorporated Pro-inflammatory Cytokine Production After cellulose delivery infection in tissue and X-linked amyloid inflammation," J collagen 32(5):967-74(2012), allergic diseases (McKinley, L., et al, "17 cells mediated-fatty acid and chemical resistance of spinal cord inflammation," T-7- (5), "T-14, T-7-32," T-14, T-23, "T-5, T-9, T-7-9 (1-32), and" T-7-32 "(1, T-7, D-9, G-7-32, G-7-9, G-7, G-32, G-7-9, G-7-9, G-7, G-D- giant cells, "Am J Kidney Dis26(1):72-9(1995)), antiphospholipid syndrome (" Soltesz, P., et al, "Immunological disorders of primary anti-phospholipid syndrome with endogenous regenerative function," Rheumatology (Oxford)47(11):1628-34(2008)), autoimmune aplastic anemia (Gu, Y., et al, "Interleukin IL (17) proteins monoclonal products IL-8, IL-6and tumor necrosis factor-alpha autoimmune disease," Br J Haeto 142(1):109-14(2008), autoimmune hepatitis (zhuk, L., et al, "Zohea J autoimmune gene-2011 autoimmune disease," human antigen of human tissue (894), phospholipid antigen of human antigen, III, L., et al, human antigen of human antigen, sperm antigen of human antigen, III, "Adv Octozoan (59: 75-83(2002)), autoimmune myocarditis (Yamashita, T., et al," IL-6-mediated Th17differentiation of high myocardial Inflammation(s) for the initiation of autoimmune myocardial ischemia, "Cardiovasc Res 91(4):640-8(2011)," autoimmune Pancreatitis (Ni, J., et al, "invasion of Interleukin-17A in pathological Dama information Experimental hypertension(s) differentiation Patches," infection (2012)), autoimmune retinopathy (Hohki, S., et al, "Block of autoimmune-6 signaling epithelial hypertension(s) infiltration of platelet differentiation, (Th 17-32) IFN-11 (s., et al," TGF-11, Th17 infection of autoimmune myocardial ischemia, TGF-2, TGF-11 infection of platelet apoptosis (s, S., T., Th 17) and IFN-32 (s.), (Th 17) infiltration of autoimmune myocardial ischemia-6 differentiation, TGF-2, TGF-11, TGF-2, TGF-7, TGF-2, TGF-7, and 32-2-one of autoimmune myocardial ischemia, "Ann blood 87(11):899-904 (2008)", "Behcet's disease (Yoshimura, T., et al," investment of Th17cells and the effect of anti-IL-6 heat in autoimmunity "Rheumatology (Oxford)48(4):347-54 (2009)", bullous pemphigoid (D ' Autoria, L., P. et al, "Cytokines and bullous epidemiology" 10(2):123-34(1999)), Karstmann disease (El-Osta, H.E. 2012 and R.Kurzrock, "chess's disease: facial tissue to tissue, H.E. 167, and" latex "mammary gland" 167. It "2. It. 1. isobuim, No. 2, latex 1. 23. 1. isobuim, No. 2, latex 1. 12. isobuical, No. 2. isopropyl-13, No. 2, and No. 5. 7. isobuim, No. 2. 7 Dune-s syndrome (Fujioka, A., et al, "the analysis of mRNA expression of cytokines from skin suspensions in Churg-Strauss syndrome," J Dermatol 25(3), "171-7 (1998)), Crohn's disease (Holtta, V., et al," IL-23/IL-17immunity a hallmark of Crohn's disease, "Inflamm Boll Dis 14(9)," 1175-84(2008)), Kogen syndrome (Shibuya, M., et al, "Successful patent with clinical drape of Cogan's syndrome," modified tissue syndrome, "modulation of proteins," Mukurome complex of Regulation, "diabetes mellitus of human, Anuk syndrome," Anjingle syndrome of diabetes, Mukurome 1, Murraya, et al, "self-healing Pacific disease of human," cold syndrome, "Mukurome 1, Murray 3, Murray et al," cold syndrome of human cold tissue, Murray, et al, "cold syndrome of human cold syndrome," Ankayak 1, Murray, etc., interleukin-6and turour diabetes factor alpha in mixotrophic tissue, "Arthritis Rheum 60(12):3841-7(2009)), dermatomyositis (Chevrel, G., et al," Interleukin-17 inventions of IL-1beta Cells: regulatory for The roll of T Cells in The pathophysiology, "J neuron 137(1-2):125-33(2003), Vickers disease (Linhares, U.C., et al," The clinical Exvo product of IL-6and IL-21by CD4(+) T Cells of diabetes mellitus, tissue encephalitis, TGF-19, III, eosinophilic esophagitis (Dias, P.M. and G.Banerjee, "The Role of Th17/IL-17on Eosinophilic Inflammation," J Autoimmun (2012)), Eosinophilic fasciitis (Dias, P.M. and G.Banerjee, "The Role of Th17/IL-17on Eosinophilic Inflammation," Jautoimuun (2012)), erythema nodosum (Kahawita, I.P. and D.N.Lockwood, "Toward intersection of The pathology of enteronosum lesion," ns R C1 Hyg102(4): 329-37) giant cell arteritis (Deng, J., et al, "Th 35T-cell 513," renal cell syndrome, "Cho-7, J.," renal glomerulus (2010), renal glomerulus syndrome, "T-7: 15, 15: 14J., 9, 7, 15, 14, 7, 5, 15, 14, 7, 5, 14, 7, 15, 7, 5, 7, 15, 7, 5, 7, 15, 5, 7, 15, 7, three, "Pathological design of interstitial anti-inflammatory-induced granulomatosis with multinuclear tissue cells," Am J Kidney disease (1):72-9(1995)), granulomatosis with polyangitis (Wegener) (Nakahama, H., et al, "Distington responses of interstitial-6 and interstitial tissue diseases in interstitial tissue Wegenerer's," Intern Med 32 (2012 2):189-92(1993)), Graves disease (m, S.E., Ki et al, "The interstitial tissue-17, N.E.)," interstitial tissue-induced granulomatosis, "thyroid of interstitial tissue J-2011 (1-32, 99-92, J.P.), (III-250, g.J.), n. et al, "incorporated circulating pro-inflammatory and Th17 lymphoid in Hashimoto's thyroid hormones," J Clin Endocrinol Metab 95(2), "953-62 (2009)," hemolytic anemia (Xu, L., et al, "Critical role of Th17cell differentiation of autoimmune hematopoietic and," Exp Hematol (2012), "HuntingSenseus-Schonlein purpura (Jen, H.Y., et al," introduced serum tumor-17 and epithelial cells Th17cells with embedded serum tumor cell of 2012, "epithelial cell tumor-Schonlein neuron 1," platelet Alrgy 22-8, "IgA-862, J., IgA, et al," IgA protein J., IgA, S.9, IgA, S.S. Pat. No. 8, 7,8, 7cell, 7-8, 7-7, IgA, 7-5, 7-5, IgA, 9, IgA, J.S. 5, IgA, 7,8, IgA, 7,8, 7, 5, 7, 5, 7, "Neurology 57(9)," 1561-5(2001), ", type I diabetes (Belkina, A.C. and G.V.Denis," BET domain co-regulation in diabetes, "inflammation and Cancer," Nat Rev Cancer12(7):465-77(2012), "interstitial cystitis (Lamale, L.M., et al," Interleukin-6, histamine, and Methhalistane as diagnostic markers for interstitial cystitis, "Uogliony 68(4):702-6(2006)," Kawasaki disease (Jia, S., et al, "The T help type 17/regulation T cell immune system in tissues with inflammation and disease," blood vessel lysis "No. 2, No. 162," blood vessel lysis test (2010, LV) (2010, No. 2, "; association with protein cells, "Eur J Haematole 76(3):265-8(2006), lichen planus (Rhodus, N.L., et al," protein cells In salvabenfore and after treatment of Oral tissue with dexamethosone, "Oral Dis12(2):112-6(2006)), lupus (SLE) (Mok, M.Y., et al," The correlation of interstitial tissue 17(IL-17) and IL-23to cell 1/2 and differential tissue cells In vitro tissue culture system, "J hematemesis 37(10):2046-52," tissue of intravascular tissue, et al, "expression of intravascular tissue, et al," expression of endothelial tissue, tissue expression of endothelial tissue, et al, "expression of endothelial tissue, et al," expression of endothelial tissue, expression of endothelial tissue, et al, "expression of endothelial tissue, expression of endothelial cell, et al," expression of endothelial tissue, expression of endothelial cell, expression, Multiple sclerosis (Jadi-nitroarag, F. and Mirshafiey A., "Th 17cell," the new plane neural tissue process in multiple sclerosis, "Scand J Immunol 74(1):1-13(2011), myasthenia gravis (Aricha, R., et al," Blocking of IL-6 subset experimental tissue biology gravis, "J Autoimmun 36(2):135-41(2011), myositis (Chevrel, G., et al," Interleun-17 reciprocal of the effects of IL-1beta cells: arrangement for the purpose of the tissue of interest, T cell of the same, "nerve of R. and E. 9," neural tissue of the same, "R. E. and E. J., (R.)," Blocking of IL-6 subset tissue process in tissue culture, "JScan J. 11. 1, J. (23) tissue of the same, R. 1, J. 7. 9. tissue of the same, R. 9, J. 9. and E. 7. the like, e, et al, "TNFalpha and IL-6 area mediators in the polymerization process of pemphigus," Int J Dermatol 40(3):185-8(2001)), POEMS syndrome (Kallen, K.J., et al, "New considerations in IL-6 depending biology and therapy: where do we stand and where are the options? "Expert oping Drugs 8(9):1327-49(1999), polyarteritis nodosa (Kawakami, T., et al)," Serum levels of interfacial-6 in tissues with cosmetic polyarteritis, "Acta der vascular 92(3):322-3(2012), primary biliary cirrhosis (Harada, K., et al)," interfacial-17 production in association with cosmetic association of interfacial and cosmetic association of psoriasis of pulmonary fibrosis of pathologic biologic vascular sclerosis, and "Clin expression Drugs 157(2), (261-70), 2009 psoriasis, S21, 23, 21, 2, 23, 21, 17, 23, 17, 16, 21, 23, 2, 24, 23, 21, 2, 23, 16, 21, 17, 21, 16, 21, 7, 21, 7, 2, 21, 2, Pyoderma gangrenosum (Kawakami, T., et al, "Reduction of intercenuin-6, intercenuin-8, and anti-phosphatadylis-prothrombin complex anti-biodistribution," Am J Gastroenterol 104(9), "2363-4 2009," relapsing polychondritis (Kawai, M., et al, "refractory to cementitious, anti-intercenuin-2012-6, in two different forms of psoriasis, "Int J immunopathol Pharmacol13(2):61-67(2000)), scleroderma (Radstake, T.R., et al," The prounounce dTh17profile in system complications (SSc) tissue with intracellular expression of TGFbeta and IFNgamma distingorgans SSc pharmaceuticals, "PLoS One,4(6): e5903(2009)), Sjogren's syndrome (Katsifisis, G.E., et al," System and local intercity-17 and intercity tissue with Sjogren's syndrome, "Am JPatchool 175(3)," 7-arteria 2009, "MMP 23-9, J.P.J.," My J.J.: 20, J.23, J.P.P.P., "My J.P.P.J.," My.P.J., "My. 21, J.P.S. J. (14, J.P.P.S. J.," My. J., "My-2, J.S.P.S. 7-7, J. (MMP 23, J.)," My. J.S. J. 23, S. J., Ulcerative colitis (Mudter, J. and M.F. nerve, "Il-6 signalling in inflammatory bowwell disease: pathetic scientific and clinical requirement," Inflamm Bowel Dis 13(8):1016-23(2007)), uveitis (Haruta, H., et al, "Blocke of interstitial in-6 signalling repair not only of 17 but also of grape ocular insulation of inflammatory tissue receptor diagnostic protein-specific Th 1by stimulating the regulatory repair T cell in experimental autoimmune tissue of inflammation," investigational optionylvin of vitiligo of Picture 52(6):3264-71, and "gradient of Patch of 2011 of 7135. Patch of 19) (2011) and" Patch of vitiligo of 7135. Patch of 19). Accordingly, 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 such diseases.

Acute and chronic (non-autoimmune) inflammatory diseases characterized by increased expression of pro-inflammatory cytokines including IL-6, MCP-1 and IL-17 would also be suitable for therapeutic BET suppression. These include, but are not limited to, sinusitis (Bradley, D.T. and S.E.Kountakis, "Role of interferuptin and transforming growth-factor-beta in chronic rhinosinitis and nasal polyposis," Laryngscope 115(4):684-6(2005)), pneumonia (Besnard, A.G., et al, "inflow-IL-1-Th 17 responding to infection in tissue" J Mol Cell Biol4(1):3-10 2012), osteomyelitis (Yoshii, T., et al, "Local of interstitial-1 a, -4, -6and tumor factor in tissue protein (1): 3-10), osteomyelitis (Yoshii, T., et al," Local of interstitial-1, beta-4, -6and tumor necrosis factor, and "interstitial-32" (bile-2), bovine biliary tissue, beta-2, bovine tissue protein, No. (No. 23), bovine tissue protein, beta-2, bovine tissue protein, No. 2, No. 3-10, 4, bovine tissue protein, and bovine tissue, 2, and bovine tissue, and porcine tissue, and bovine tissue, and porcine tissue, enteritis (Mitsuyama, K., et al, "STAT 3 activating connections to ileitis in SAMP 1/YItMicroe," Gut55(9):1263-9 (2006)), gingivitis (Johnson, R.B., et al, "Interleukin-11 and IL-17and producing diseases of periodontal disease," J periodon 75(1):37-43(2004), appendicitis (Latifi, S.Q., et al, "persistence of epithelial tissues with respect to said drugs) through said reaction with length of reaction, of" Pedification 39(10): 8-52, tissue of reaction with tissue of reaction, tissue of reaction with length of "Pedification," Pentium 4, tissue of reaction-11, tissue of reaction, No. 12, tissue of reaction, No. (No. 11-11, No. 2,82, No. (No. 2,82, P.), "Blood 113(4): (945-52) (2009)," Chronic Obstructive Pulmonary Disease (COPD) ("tracts, S.L. and L.E.Donnelly," Th17cells in air diseases, "Current Mol Med8(5):416-26(2008)," septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc.) (Nicodeme, E., et al, "supression of inflammation by a synthetic bone marrow mixture," Nature 468(7327):1119-23(2010)), Osteoarthritis (Chen, L., et al, "" IL-17 primer-media prediction of IL-6 inhibitors synthesis protein a pathological bone of Osteoarthritis, "Osteothria (13) 19-7, et al," gout of patients, "gout of diseases of 13, etc.), (13) and" gout of patients "(13, 5) and" 13 (13, 13. D) (13, 3, 5. D. A. D. A. As shown in The present in The invention, Acute lung injury (Traves, S.L. and L.E.Donnelly, "Th 17cells in advanced diseases," Curr Mol Med8(5):416-26(2008)), acute renal failure (Simmons, E.M., et al, "plasma tissue defects in tissues with acute renal failure," Kidney Int65(4):1357-65(2004)), burns (Paquet, P. and G.E.Pierard, "Interlein-6 and skin," Int Arlergy Immunol 109(4):308-17(1996)), the Hertz response (Kaplanski, G., et al, "Jarisch-Herxheimer interaction compatibility of the treatment of viral Qwind endicadiatis: eleven TNFalpha and IL-6 server levels," J Impect 37(1):83-4(1998)), and SIRS associated with viral infection (Belkina, A.C. and G.V.Denis, "BET domain co-regulators in vivo, inflammation and Cancer," Nat Rev Cancer12(7):465-77 (2012)). Accordingly, 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 such diseases.

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, are useful for treating Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS). There is strong proprietary data on the utility of BET inhibitors in preclinical models of RA and MS. Jahagirdar, S.M. et al, "An organic biological Small molecules RVX-297 SignificantlyDeschases diseases in a Mouse Model of MultipleSclerosis," World consistency of Inflammation, Paris, France (2011). Both RA and MS are characterized by dysregulation of the IL-6and 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 thus will be particularly sensitive to BET ratio inhibition. In another embodiment, BET inhibitor compounds of formula I, formula Ia, and/or formula II are useful for treating sepsis and related afflictions. BET specific inhibition has been demonstrated to inhibit the development of sepsis, in part, by inhibiting IL-6 expression in preclinical models in both published (nicodie, e., et al, "Suppression of inflammation by a synthetic sepsis," Nature 468(7327):1119-23(2010)) and proprietary data.

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, are useful for treating cancer. Cancers with overexpressed, translocated, amplified, or rearranged c-myc or other myc family oncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition. Delmore, J.E., et al, "BET branched inhibition as adaptive strategy to target c-Myc," Cell 146(6):904-17 (2010); mertz, J.A., et al, "Targeting MYC dependency in cancer by inhibiting BET branched molecules," ProcNatl Acad Sci USA108(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 lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine cancer, medulloblastoma, melanoma, nodular melanoma, superficial diffuse melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, clear cell renal 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 Biol16(4):318-30 (2006).

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, are useful for treating cancer caused by aberrant modulation (overexpression, translocation, etc.) of BET proteins. These include, but are not limited to, NUT midline carcinoma (Brd3 or Brd4 translocated to the nutlin1 gene) (French, C.A., "NUT midline carcinoma," Cancer Genet 203(1):16-20(2010)), B-cell lymphoma (Brd2 overexpressed) (Greenwald, R.J., et al, "E mu-BRD2transgenic micro-cell B-cell lymphoma and leukoma,", Blood103(4):1475-84(2004), non-small cell lung Cancer (Brcand overexpressed) (Grungwald, C., et al, "Expression of multiple epithelial regulated Cancer/Cancer cells in the same tumor, and" T.18, T.J. Cancer 118-2 overexpressed "(BRT.S.) (BRT.A.)," T.S.) (BRT.S.), "T.S.)," T.S. 3, D.), "Cancer Lett 150(2):55-64(2000)), and colon Cancer (Brd4) (Rodriguez, R.M., et al," Abserrant epigenetic registration of branched BRD4in human colon Cancer, "Jmol Med (Berl)90(5):587-95 (2012)).

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, are useful for treating cancers that rely on pTEFb (Cdk9/cyclin T) and BET proteins to modulate oncogenes because BET inhibitors reduce Brd-dependent recruitment of pTEFb to genes involved in cell proliferation. These cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma (Tong, W.G., et al, "Phase I and pharmacological study SNS-032, a patent and selective Cdk2,7, and9 inhibitors, in patients with induced chronic lymphocytic leukemia and multiple myelomas," J Clin Oncol28(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 large cell lymphoma (Bellan, C., et al, "CDK 9/CYCLIN T1 expression therapy and negative expression therapy lymphoma," tissue neuro 8652, P. thaliana, "tissue neuro 9, P. thaliana et al," tissue neuro 9, P. 3, P. and P. neuro 8652 (tissue neuro-3, P. thaliana, P. 3, P. thaliana, "P. 3. neuro. and D. neuro 8652, P. neuro: (3. 3, P. neuro.), "Cancer Biol Ther4(3):277-81(2005)), rhabdomyosarcoma (Simone, C. and A. Giorgano," approximation of signal-dependent activation of the cdk 9/cycle T2a plex in human RD r hybridoma cells, "Cell Death Differ14(1):192-5(2007)), prostate Cancer (Lee, D.K., et al," android interaction with the lung tissue P-TEFb and the enhancement of the lung of transgenic introduction, "J Biol Chem 276(13):9978-84(2001), and breast Cancer (Barthomer K, et al," BET biological of biological expression P-7 SK)).

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, are useful for treating cancers in which BET response genes, such as CDK6, Bcl2, TYRO3, MYB, and hTERT, are upregulated. Dawson, M.A., et al, "Inhibition of BET regulation to chromatography as an effective treatment for MLL-fusion Leukaemia," Nature 478(7370):529-33 (2011); delmore, J.E., et al, "BETbro immune inhibition as a thermal 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 anticancers therapeutics targeting telemerase," Cancer Treat Rev (2012); kelly, P.N. and A.Straser, "The role of Bcl-2and its pro-subvalvulariates in tumor diagnosis and cancer therapy" Cell Death Differ18(9):1414-24 (2011); uchida, T.et al, "anti mechanism effect of bcl-2antisense phosphothioate oligodeoxynucleotides on human crude-cell carcinoma cells in vitro and in vivo," Mol Urol5(2):71-8 (2001).

Published and proprietary data have shown a direct effect of BET inhibition on cell proliferation in various cancers. 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, are useful for treating cancers for which the disclosure shows a direct effect of BET inhibition on cell proliferation and (for some cancers) proprietary in vivo and/or in vitro data. 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, "Selectivity of BET branched orains," Nature 468(7327):1067-73 (2010); dawson, M.A., et al, "Inhibition of BET regulation to chromatography as an effective treatment for MLL-fusion Leukaemia," Nature 478(7370):529-33 (2011); zuber, J., et al, "RNAiscreen identities Brd4 as a therapeutic target in acid myelioid leukemia," Nature 478(7370):524-8 (2011); miguel F.Segura, et al, "BRD 4 is a novel therapeutic target in melanoma," Cancer research.72(8): suppl 1 (2012). The compounds of the invention have shown a direct effect of BET inhibition on in vitro cell proliferation of the following cancers: neuroblastoma, medulloblastoma, lung cancer (NSCLC, SCLC) and colon cancer.

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, may be combined with other therapies, chemotherapeutic agents, or antiproliferative agents to treat human cancer and other proliferative disorders due to potential synergy or additive effects between the BET inhibitor and other cancer therapies. A list of therapeutic agents that may be combined with a BET inhibitor in the treatment of cancer includes, but is not limited to, ABT-737, azacitidine (Vildaza), AZD1152(Barasertib), AZD2281 (Olaparib), AZD6244 (Semetinib), BEZ235, bleomycin sulfate, bortezomib (velcade), busulfan (Marylan), camptothecin, cisplatin, cyclophosphamide (Clafen), CYT387, cytarabine (Ara-C), dacarbazine, DAPT (GSI-IX), decitabine, dexamethasone, doxorubicin (adriamycin), etoposide (RAD001), fusidic (Alnetocidib), Gaespib (STA-9090), gefitinib (indoxacum), idarubicin, ifosfamide (Mitoxana), IFNa2a (Roxithromycin A), melphalan (Clotrimazam), methazolatone (Methazone), metformin (Metzoxan), metformin (Nomezzolone, metolazuril), mezzanine (Nomefone, mezzanine (Nomefonamide), mefonamide (Novone), mefonamide (No, PLX4032 (vemurafenib), pomalidomide (CC-4047), prednisone (Deltasone), rapamycin, lenalidomide (lenalidomide), luzotinib (INCB018424), sorafenib (leishawa), SU11248 (sunitinib), SU11274, vinblastine, vincristine (ancove), vinorelbine (noviban), vorinostat (SAHA), and WP1130 (degranyn).

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, are useful for treating benign hyperplastic 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 tumors, nasal polyps, pituitary tumors, prolactin tumors, pseudocerebroma, seborrheic keratosis, gastric polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps and cysts, castleman's disease, chronic pilocarcinoma, cutaneous fibroids, hair cysts, pyogenic granulomas, juvenile multiple polyp syndrome, idiopathic pulmonary fibrosis, renal fibrosis, cystic fibrosis, and the like, Post-operative stenosis, keloid formation, scleroderma, and myocardial fibrosis. Tang, X et al, "Assessment of Brd4Inhibition in Idiopathic Pulmony fibers Lung fibers and in Vivo Models of Lung fibers,". Am J Pathology in press (2013).

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, are useful for treating cardiovascular diseases typically associated with atherosclerosis, arteriosclerosis, hypercholesterolemia, and hypercholesterolemia associated with ApoA-1 transcription and protein expression (Mirguet, o., et al, "From ApoA1 upper regulation to betfamide inhibition: discology of I-BET151," Bioorg Med Chem Lett22(8):2963-7 (2012); Chung, c.w., et al, "Discovery and characterization of small molecules inhibition of the BET family of cardiovascular diseases," J Chem54(11):3827-38 (2011)). (Belkina, A.C. and G.V.Denis, "BET domain co-ligands in vivo, inflammation and Cancer," Nat Rev Cancer12(7):465-77 (2012); Denis, G.V., "Bromodomain microorganisms in Cancer, inflammation, type2diabetes, and inflammation," Discov Med10(55):489-99 (2010)). In another embodiment, BET inhibitor compounds of formula I, formula Ia and/or formula II are useful for treating non-cardiovascular diseases characterized by a deficiency of ApoA-1, including Alzheimer's disease. Elliott, D.A., et al, "Apolipoproteins in the draft: pharmaceuticals for neurological and physiological disorders," Clin Lipidol 51(4): 555-.

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, are useful for patients with insulin resistance and type II diabetes. Belkina, A.C. and G.V.Denis, "BET domain co-ligands in identity, inflammation and Cancer," Nat Rev Cancer12(7):465-77 (2012); denis, G.V., "Bromodomain microorganisms in cans, objectives, type2diabetes, and inflammation," Discov Med10(55):489-99 (2010); wang, F., et al, "Brd 2 disportions mice based with out Type2diabetes," Biochem J425 (1):71-83 (2010); denis, G.V., et al, "An empirical roll for branched-associated protein chromatography and translational control of adhesives," FEBSLett 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, "inflammation process in type2diabetes: The role of cytokines," Ann N Y Acad Sci 1084:89-117 (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, due to their ability to down-regulate viral promoters, are useful as therapeutic agents for cancers associated with viruses including epstein-barr virus (EBV), hepatitis virus (HBV, HCV), kaposi's sarcoma-associated virus (KSHV), Human Papilloma Virus (HPV), merkel cell polyoma virus, and human Cytomegalovirus (CMV). Gagnon, D.E., et al, "developmental definition of the mammalian E2 protein is inhibited by overexpression of branched-linking protein4," J Virol83(9):4127-39 (2009); you, J.et al, "Kaposi's social-associated fashion viral disease latency-associated nuclear antigen Brd4 on host mitotic chromosomes," J Virol80(18):8909-19 (2006); palermo, R.D., et al, "RNA polymerase II standing protein occlusion and pTEFb recovery to drive immunological occlusion by Epstein-Barr virus," PLoS Patholog 7(10): e1002334 (2011); poreba, E.et al, "olefinic mechanisms in viruses-induced genetics," Clin olefins 2(2): 233-47.2011. In another embodiment, BET inhibitors may be used in combination with antiretroviral therapeutics for the treatment of HIV due to their ability to reactivate HIV-1 in a model of latent T cell infection and latent monocyte infection. Zhu, J., et al, "reaction of late HIV-1by Inhibition of BRD4," Cell Rep (2012); banerjee, C., et al, "BET bromodomain inhibition as a novel strategy for the reactivation of HIV-1," J Leukoc Biol (2012); bartholomeuse, K., et al, "BETbrodoman inhibition activity transfer via a transfer release of P-TEFb from7SK snRNP," J Biol Chem (2012); li, Z, et al, "The BET branched amplification blocker JQ1 activators HIV latency anti Brd4 inhibition of tat-transduction," Nucleic Acids Res (2012.)

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, may be useful for treating diseases, including, but not limited to, alzheimer's disease, parkinson's disease, huntington's disease, bipolar disorder, schizophrenia, lu-tai-bis syndrome (Rubinstein-Taybi syndrome), and epilepsy, due to epigenetic processes and the role of bromodomain-containing proteins in neurological disorders. Prinjha, R.K., J.Witherington and K.Lee, "Placeyour BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci33(3):146-53 (2012); muller, S., et al, "Bromodomains as therapeutic targets," ExpertRev Mol Med13: e29 (2011).

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, may be useful as reversible male contraceptives due to the effect of BRDT depletion or inhibition on sperm cell development. Matzuk, M.M., et al, "Small-Module Inhibition of BRDT for Large content," Cell 150(4): page 673-; berkovits, B.D., et al, "The test-specific double branched BRDT for a complex with multiple branched mRNA components and isolated for mRNA partitioning and 3' -UTR partitioning in round partitioning, and" nucleic acids Res 40(15):7162-75 (2012).

Pharmaceutical composition

The pharmaceutical compositions of the present disclosure comprise at least one compound of formulas I-II or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. The most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and on the nature of the particular compound used.

Formulations suitable for oral administration may be presented as discrete units, such as capsules, cachets, lozenges, or tablets each containing a predetermined amount of a compound of the present disclosure; powder or granules; a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil-in-water liquid emulsion or a water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable pharmaceutical process comprising the steps of: at least one compound of the present disclosure as an active compound is associated with a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The carrier can be a solid or a 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) that can contain from about 0.05% to about 95% by weight of the at least one active compound. Other pharmacologically active agents may also be present, including other compounds. The formulations of the present disclosure may be prepared by any of the well-known pharmaceutical techniques consisting essentially of admixing the components.

For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing at least one active compound of the present disclosure and optional pharmaceutical adjuvants as described herein in an excipient (e.g., like water, saline, aqueous dextrose, glycerol, ethanol, etc.) to thereby form a solution or suspension. In general, suitable formulations may be prepared by: at least one active compound of the present disclosure is uniformly and intimately admixed with a liquid or finely divided solid carrier, or both, and the product is then (if necessary) shaped. For example, tablets may 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 accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine at least one compound of the disclosure in a free-flowing form (e.g., powder or granules), optionally mixed with a binder, lubricant, inert diluent, and/or surfactant/dispersant. Molded tablets may be prepared by molding in a suitable machine in which a powdered form of at least one compound of the present disclosure is wetted with an inert liquid diluent.

Formulations suitable for buccal (sublingual) administration include lozenges comprising at least one compound of the present disclosure in a flavoured base (typically sucrose and acacia or tragacanth); and pastilles comprising at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous formulations of at least one compound of formulas I-II, or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are 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 may conveniently be prepared by mixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with blood. Injectable compositions according to the present disclosure may contain from about 0.1% w/w to about 5% w/w of the active compound.

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

Formulations suitable for topical application to the skin may take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers and excipients that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one compound of formulas I-IV or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof) is typically present at a concentration of the composition of about 0.1% w/w to about 15% w/w (e.g., about 0.5% to about 2%).

The amount of active compound administered may depend on the subject being treated, the weight of the subject, the mode of administration, and the judgment of the prescribing physician. For example, a dosing schedule may involve administering the encapsulated compound daily or semi-daily at a perceived dose of about 1 μ g to about 1000 mg. In another embodiment, intermittent administration (e.g., on a monthly or yearly basis) of the dose of the encapsulated compound may be employed. Encapsulation helps to reach the site of action and allows simultaneous administration of the active ingredients, thereby theoretically producing a synergistic effect. In accordance with standard dosing regimens, the physician will readily determine the optimal dosage and will be able to readily modify the administration to achieve such dosages.

A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic efficacy of the compound. However, the dosage may vary depending on the need of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, a therapeutically effective amount of the disclosed compounds is sufficient to produce a maximum plasma concentration. Scaling of the preliminary dose (as determined, for example, from animal testing) and the dose for human administration is performed according to art-recognized practice.

Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining LD₅₀(50% lethal dose of population) and ED₅₀(50% of the population therapeutically effective dose). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD₅₀/ED₅₀. Compositions exhibiting a greater therapeutic index are preferred.

Data obtained from cell culture assays or animal studies can be used in dosage ranges formulated for use in humans. Therapeutically effective doses 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., Freiich et al, Cancer Chemother. Reports50(4):219-244(1966) and Table I for equivalent surface area dose factors).

Table I: equivalent surface area dose factor:

the dose of the compound is preferably such that ED is included₅₀With little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. In general, a therapeutically effective amount may vary with the age, condition, and sex of the subject, as well as the severity of the medical condition of the subject. The dosage can be determined by a physician and adjusted as necessary to accommodate the observed therapeutic effect.

In one embodiment, a compound of formula I-II or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered in combination with another therapeutic agent the other therapeutic agent may provide additive or synergistic values relative to the individual administration of a compound of the disclosure the therapeutic agent may be, for example, a statin, a PPAR agonist, such as a thiazolidinedione or fibrate, niacin, RVX, FXR, or LXR agonist, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, Cholesterol Ester Transport Protein (CETP), an ion exchange resin, an antioxidant, an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor), a tyrosine phosphate kinase inhibitor (tyrophostine), a sulfonylurea-based drug, a biguanide, an α -glucosidase inhibitor, an apolipoprotein E modulator, an HMG-CoA reductase inhibitor, a microsomal triglyceride transport protein, an LDL-lowering drug, an HDL-raising drug, an HDL enhancer, a modulator of the 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, non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDS), and the like. Exemplary anti-inflammatory agents include, for example, prednisone, methylprednisoloneTriamcinolone and methotrexateHydroxychloroquineSulfasalazineLeflunomideEtanerceptInfliximabAdalimumabRituximabAbiraypuInterleukin-1, anakinra (Kineret)^TM) Ibuprofen, ketoprofen, fenoprofen, naproxen, aspirin, acetaminophen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxybutyzone, diflunisal, salsalate, oxalazine, or sulfasalazine.

Examples

General methods. Reagents and solvents were used as received from commercial suppliers unless otherwise stated. Proton nuclear magnetic resonance spectra were obtained at 300MHz on a Bruker AVANCE 300 spectrometer or 500MHz on a Bruker AVANCE 500 spectrometer or 300MHz on a Bruker AVANCE 300 spectrometer. Spectra are given in ppm (δ) units and coupling constants, J values are reported in hertz (Hz). Tetramethylsilane as¹Internal standard of H nuclear magnetic resonance. Mass spectrometry was performed in ESI or APCI mode (as appropriate) on a Watersaquity UPLC mass spectrometer, in ESI, APCI or MultiMode mode (as appropriate) on an Agilent 6130A mass spectrometer, or in ESI or APCI mode (as appropriate) on an Applied Biosystems API-150EX spectrometer. Silica gel chromatography is usually carried out in Teledyne IscoRf 200 System or TeledyneiscoOn a company 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(1.50g,8.84mmol) in DMF (50mL) was added potassium carbonate (3.64g,26.4mmol) and benzyl chloride (1.01mL,8.84 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was poured into water (100mL) and stirred for 5 minutes. The solid was harvested and dried to give 2 as a yellow solid (1.60g, 70%):^1zH NMR(300MHz,DMSO–d₆)δ8.26(s,1H),7.80(br s,2H),7.38–7.26(m,5H),5.34(s,2H)；ESI m/z260[M+H]⁺。

step 2: to a solution of 2(260mg,1.0mmol) in 1, 4-dioxane (10mL) and DMF (4mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (335mg,1.5mmol), sodium carbonate (2.0M in H)₂O, 1.0mL,2.0mmol) and tetrakis (triphenylphosphine) palladium (0) (116mg,0.1 mmol). The reaction mixture was purged with nitrogen and heated at 80 ℃ for 16 hours. The mixture was diluted with dichloromethane (20mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-5% dichloromethane/methanol) followed by trituration with EtOAc/hexanes to afford 9-benzyl-2- (3, 5-dimethylisoxazol-4-yl) -9H-purin-6-amine (example compound 1) as a white solid (110mg, 34%):¹H NMR(300MHz,DMSO–d₆)δ8.29(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(500mg,2.66mmol) in 1, 4-dioxane (15mL) was added CDI (517mg,3.19 mmol). The reaction was heated at 60 ℃ for 16 hours. The solid was harvested and dried to give 5 as a light purple solid (340mg, 60%):¹H NMR(300MHz,DMSO–d₆)δ11.58(br s,1H),11.02(br s,1H),7.19(d,J＝8.1Hz,1H),7.13(d,J＝8.1Hz,1H)。

step 2: to a solution of 5(170mg,0.79mmol) in 1, 4-dioxane (12mL) and DMF (6mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (352mg,1.58mmol), sodium carbonate (2.0M in H)₂O, 1.19mL,2.37mmol) and tetrakis (triphenylphosphine) palladium (0) (92mg,0.08 mmol). The reaction mixture was purged with nitrogen and heated at 80 ℃ for 16 hours. The mixture was diluted with dichloromethane (20mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-5% dichloromethane/methanol) to afford 6 as a white solid (130mg, 71%):¹H NMR(300MHz,DMSO–d₆)δ11.38(br s,1H),10.90(br s,1H),7.30(d,J＝7.8Hz,1H),7.07(d,J＝8.1Hz,1H),2.49(s,3H),2.33(s,3H)。

and step 3: to a solution of 6(100mg,0.43mmol) in DMF (10mL) was added potassium carbonate (72mg,0.52mmol) and di-tert-butyl dicarbonate (104mg,0.48 mmol). The reaction was stirred at room temperature for 16 hours. To the reaction mixture were added potassium carbonate (72mg,0.52mmol) and benzyl chloride (0.14mL,0.48 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100mL) 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) afforded 6(130mg, 71%) as a colorless gum:¹H NMR(300MHz,DMSO–d₆)δ7.97(d,J＝8.1Hz,1H),7.38–7.27(m,6H),5.05(s,2H),2.49(s,3H),2.29(s,3H),1.61(s,9H)。

and 4, step 4: a solution of 7(130mg,0.31mmol) in dichloromethane (4mL) and TFA (2mL) was stirred at room temperature for 2 h. The mixture was concentrated and the residue was dissolved in dichloromethane (100mL) and saturated NaHCO was used₃(50 mL. times.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 ] as an off-white solid]Pyridin-2 (3H) -one (example compound 2) (81mg, 81%):¹HNMR(300MHz,DMSO–d₆)δ11.31(s,1H),7.40(d,J＝7.8Hz,1H),7.34–7.25(m,5H),7.15(d,J＝7.8Hz,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(500mg,2.66mmol) and benzaldehyde (282mg,2.66mmol) in dichloromethane (15mL) was added acetic acid (319mg,5.32 mmol). The reaction was stirred at room temperature for 30 minutes, then NaBH (OAc) was added₃(1.69g,7.98 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (100mL) and saturated NaHCO was added slowly₃Aqueous solution (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/EtOAc to give 8 as a light brown solid (401mg, 54%):¹H NMR(300MHz,DMSO–d₆)δ7.34–7.22(m,5H),6.48(d,J＝7.8Hz,1H),6.40(d,J＝7.8Hz,1H),6.02(br s,2H),5.54(t,J＝5.7Hz,1H),4.27(d,J＝5.4Hz,2H)。

step 2: to a solution of 8(400mg,1.44mmol) in 1, 4-dioxane (10mL) was added CDI (514mg,3.17 mmol). The reaction was heated at 110 ℃ for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-40% ethyl acetate/hexanes) afforded 9(310mg, 71%) as a white solid:¹H NMR(300MHz,DMSO–d₆)δ11.96(s,1H),7.35–7.27(m,6H),7.19(d,J＝7.8Hz,1H),5.02(s,2H)。

and step 3: to a solution of 9(310mg,1.02mmol) in 1, 4-dioxane (10mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (341mg,1.53mmol), sodium carbonate (2.0M in H)₂1.02mL,2.04mmol) and tetrakis (triphenylphosphine) palladium (0) (59mg,0.05mmol) in O. The reaction mixture was purged with nitrogen and heated at 80 ℃ for 16 hours. The mixture was diluted with dichloromethane (20mL) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica gel, 0-80% EtOAc/hexanes) and triturated with EtOAc to afford 1-benzyl-5- (3, 5-dimethylisoxazol-4-yl) -1H-imidazo [4,5-b ] as a white solid]Pyridin-2 (3H) -one (example compound 3) (202mg, 62%):¹HNMR(300MHz,DMSO–d₆)δ11.76(s,1H),7.44(d,J＝7.8Hz,1H),7.36–7.28(m,5H),7.11(d,J＝7.8Hz,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(400mg,2.0mmol) in 1, 4-dioxane (10mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (669mg,1.5mmol), sodium carbonate (2.0M in H)₂O, 2.0mL,4.0mmol) and tetrakis (triphenylphosphine) palladium (0) (116mg,0.1 mmol). The reaction mixture was purged with nitrogen and heated at 80 ℃ for 16 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-8% dichloromethane/methanol) followed by trituration with EtOAc/hexanes to afford 11 as a pale yellow solid (228mg, 53%): ESI M/z 215[ M + H ]]⁺。

Step 2: to a solution of 11(220mg,1.03mmol) in CH₃CN (10mL) was added potassium carbonate (426mg,3.09mmol) and benzyl chloride (0.12mL,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 afford 4- (3-benzyl-3H-imidazo [4,5-b ] as an off-white solid]Pyridin-6-yl) -3, 5-dimethylisoxazole (example compound 4) (34mg, 11%):¹H NMR(300MHz,CDCl₃)δ8.34(d,J＝1.8Hz,1H),8.14(s,1H),7.99(d,J＝1.8Hz,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]⁺(ii) a 4- (1-benzyl-1H-imidazo [4, 5-b) as an off-white solid]Pyridin-6-yl) -3, 5-dimethylisoxazole (example compound 5) (39mg, 12%):¹H NMR(300MHz,CDCl₃)δ8.46(d,J＝1.8Hz,1H),8.29(s,1H),7.40–7.37(m,3H),7.34(d,J＝2.1Hz,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(5.00g,22.9mmol) in acetic acid (50mL), ethanol (100mL) and water (5mL) was added iron powder (6.42g,115 mmol). The reaction was heated at 80 ℃ under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate) to give 14 as a brown solid (3.27g, 76%):¹H NMR(300MHz,CDCl₃)δ6.88(d,J＝2.2Hz,1H),6.77(dd,J＝8.3,2.3Hz,1H),6.60(d,J＝8.3Hz,1H),6.00–5.20(br s,3H)。

step 2: to a solution of 14(1.50g,7.98mmol) in 1, 4-dioxane (100mL) was added 1,1' -carbonyldiimidazole (1.55g,9.58 mmol). The reaction was heated at 80 ℃ under nitrogen for 17 hours. The mixture was cooled to room temperature and 2N aqueous HCl (40mL) was added. The solution was diluted with ethyl acetate (200mL) and washed with brine (2X 50 mL). Drying the organic layer over sodium sulfateFiltered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexanes) afforded 15(1.08g, 63%) as an orange solid:¹H NMR(500MHz,DMSO–d₆)δ11.81(s,1H),7.27–7.25(m,3H)。

and step 3: to a solution of 15(150mg,0.701mmol) in acetonitrile (10mL) was added benzyl bromide (180mg,1.05mmol) and potassium carbonate (193mg,1.40 mmol). The reaction was heated at 80 ℃ for 3 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 16 as an off-white solid (195mg, 92%):¹H NMR(500MHz,CDCl₃)δ7.41–7.30(m,5H),7.22(dd,J＝8.5,1.7Hz,1H),7.08(d,J＝8.5Hz,1H),6.97(d,J＝1.6Hz,1H),4.97(s,2H)。

and 4, step 4: to a solution of 16(195mg,0.641mmol) in 1, 4-dioxane (10mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (172mg,0.769mmol), potassium carbonate (177mg,1.28mmol) and tetrakis (triphenylphosphine) palladium (0) (37mg,0.032 mmol). The reaction mixture was purged with nitrogen and heated at 100 ℃ for 4 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes). It is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN eluted Polaris column reverse phase HPLC further purified to give 3-benzyl-5- (3, 5-dimethylisoxazol-4-yl) benzo [ d ] as an off-white solid]Oxazol-2 (3H) -one (example compound 6) (115mg, 56%):¹H NMR(500MHz,DMSO–d₆)δ7.47–7.42(m,3H),7.40–7.34(m,2H),7.34–7.28(m,1H),7.23(d,J＝1.6Hz,1H),7.12(dd,J＝8.2Hz,7.7Hz,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 6- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d]Imidazol-4-amine 17(290mg,1.27mmol) in CH₃CN (15mL) was added potassium carbonate (350mg,2.54mmol) and benzyl chloride (200mg,1.59 mmol). The reaction mixture was stirred at 60 ℃ for 16 hours. The mixture was diluted with dichloromethane (20mL) and filtered through a layer of celite. The filtrate was concentrated and chromatographed (silica gel, 0-10% CH)₃OH/CH₂Cl₂) Purification to afford 1-benzyl-6- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] as an off-white solid]Imidazol-4-amine (example compound 7) (109mg, 27%):¹H NMR(300MHz,CDCl₃)δ7.95(s,1H),7.37–7.34(m,3H),7.23–7.20(m,2H),6.46(d,J＝1.2Hz,1H),6.40(d,J＝1.2Hz,1H),5.34(s,2H),2.31(s,3H),2.16(s,3H)；ESIMS m/z 319[M+H]⁺(ii) a 1-benzyl-5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] as an off-white solid]Imidazol-7-amine (example compound 8) (19mg, 4.7%):¹H NMR(300MHz,CDCl₃)δ8.15(s,1H),7.43–7.40(m,3H),7.23(d,J＝1.2Hz,1H),7.20–7.17(m,2H),6.39(d,J＝1.2Hz,1H),5.69(s,2H),2.40(s,3H),2.27(s,3H)；ESIMS m/z 319[M+H]⁺(ii) a N, 1-dibenzyl-6- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] as an off-white solid]Imidazol-4-amine (example compound 9) (40mg, 8%):¹H NMR(300MHz,DMSO–d₆)δ8.27(s,1H),7.40–7.18(m,10H),6.62(d,J＝1.2Hz,1H),6.57(t,J＝6.0Hz,1H),5.97(d,J＝1.2Hz,1H),5.41(s,2H),4.48(d,J＝6.0Hz,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 procedure used to prepare example 3 to give the product as a white solid (158mg, 47%):¹H NMR(300MHz,DMSO–d₆)δ11.81(s,1H),7.90(d,J＝2.1Hz,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(500mg,2.3mmol), benzylamine (1.2g,11.4 mmol) and pyridine (5.0mL) was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the product was purified by chromatography (silica gel, 0-10% ethyl acetate/hexanes) to afford 19 as a yellow solid (630mg, 91%):¹H NMR(500MHz,CDCl₃)δ8.38(s,1H),8.05(d,J＝9.1Hz,1H),7.40–7.32(m,5H),7.01(d,J＝1.9Hz,1H),6.79(dd,J＝9.1,1.9Hz,1H),4.51(d,J＝5.5Hz,2H)。

step 2: a mixture of 19(100mg,0.33mmol), iron powder (127mg,2.28mmol), ammonium chloride (27mg,0.5mmol), water (0.5mL) and ethanol (3mL) was heated at reflux for 0.5 h. The reaction mixture was cooled and filtered. The solvent was removed to provide 20 as an off-white solid (90mg, 100%):¹H NMR(300MHz,CDCl₃)δ7.40–7.29(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]⁺。

and step 3: 20(100mg,0.36mmol), triethylamine (48mg,0.47mmol), CH at room temperature₂Cl₂(0.5mL) and THF (1.0mL) was added a solution of ethyl bromoacetate (78mg,0.47mmol) in THF (1.0 mL). The reaction mixture was stirred for 18 hours and then heated to 75 ℃ for 1 hour. The reaction mixture was concentrated and the product was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 21(44 m) as a tan solidg,39％)：¹H NMR(500MHz,CDCl₃)δ7.38–7.29(m,4H),7.24–7.22(m,2H),6.98–6.93(m,2H),6.55(d,J＝8.3Hz,1H),5.13(s,2H),4.05(s,2H)；ESI m/z 318[M+H]⁺。

And 4, step 4: mixing 21(44mg,0.14mmol), 3(47mg,0.21mmol) and K₂CO₃A mixture of (39mg,0.28mmol), tetrakis (triphenylphosphine) palladium (0) (8mg,0.01mmol), 1, 4-dioxane (3mL) and water (0.5mL) was heated at 90 ℃ for 16 h. The reaction mixture was concentrated on silica gel and the product was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 1-benzyl-7- (3, 5-dimethylisoxazol-4-yl) quinoxalin-2 (1H) -one (example compound 11) as an off-white solid (16mg, 34%):¹H NMR(300MHz,CDCl₃)δ8.43(s,1H),7.94(d,J＝8.2Hz,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: 22(1.19g,5.53mmol) and benzaldehyde (594mg,5.60mmol) in CH₂Cl₂(50mL) and CH₃Acetic acid (0.2mL) was added as a solution in CN (50 mL). The mixture was stirred at room temperature for 1 hour. Addition of NaBH (OAc)₃(3.52g,16.59 mmol). The mixture was stirred at room temperature for 8 hours. Saturated NaHCO for reaction₃The aqueous solution (50mL) was quenched and concentrated, and the residue was suspended in EtOAc (300mL) 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 as an off-white solid (201mg, 12%):¹H NMR(300MHz,DMSO–d₆)δ8.75(d,J＝5.7Hz,1H),7.93(br.s,1H),7.55(d,J＝8.4Hz,1H),7.38–7.31(m,6H),6.76(d,J＝1.8Hz,1H),6.69(dd,J＝8.4,1.8Hz,1H),4.39(d,J＝6.0Hz,2H)。

step 2: to a solution of 23(518mg,1.70mmol) in THF (20mL) was added BH₃THF (1.0M in THF, 8.50mL,8.50 mmol). The mixture was heated to reflux for 16 hours. MeOH (40mL) was added slowly followed by 2N HCl (40 mL). The mixture was heated to reflux for 3 hours. Addition of NH₄OH (60mL), the mixture was extracted with EtOAc (200 mL. times.3). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH in dichloromethane) to afford 24 as a colorless gel (372mg, 75%):¹H NMR(300MHz,DMSO–d₆)δ7.32–7.21(m,5H),6.98(d,J＝7.8Hz,1H),6.87(t,J＝6.0Hz,1H),6.65(dd,J＝8.1,2.1Hz,1H),6.53(d,J＝2.1Hz,1H),4.33(d,J＝5.7Hz,2H),3.71(s,2H),1.92(br.s,2H)。

and step 3: using the procedure used for example compound 3, step 2, starting with compound 24(362mg,1.24mmol) gave 25(325mg, 85%) as a yellow solid:¹H NMR(300MHz,DMSO-d₆)δ7.33–7.31(m,3H),7.25–7.23(m,3H),7.09(d,J＝1.8Hz,2H),6.86(s,1H),5.05(s,2H),4.35(d,J＝1.5Hz,2H)。

and 4, step 4: using the procedure for example compound 3, step 3, starting with compound 25(317mg,1.00mmol) gave example compound 12(199mg, 60%) as a white solid:¹H NMR(500MHz,DMSO–d₆)δ7.34–7.21(m,7H),6.90(dd,J＝7.5,1.0Hz,1H),6.58(d,J＝1.0Hz,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(1.00g,5.32mmol) and 3(1.78g,7.98mmol) in 1, 4-dioxane (1, 4-dioxane35mL) and water (7.5mL) were added potassium carbonate (1.47g,10.6mmol) and tetrakis (triphenylphosphine) palladium (0) (307mg,0.27 mmol). The reaction was stirred and heated at 90 ℃ for 16 hours. The reaction mixture was diluted with methanol (20mL) and silica gel (15g) 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 hexanes. The clean product was concentrated to give 27 as a yellow-green solid (939mg, 70%):¹H NMR(500MHz,CDCl₃)δ7.45(t,J＝2.0Hz,1H),6.78(t,J＝2.0Hz,1H),2.37(s,3H),2.22(s,3H)。

step 2: to a solution of 27(300mg,1.47mmol) in 1, 2-dichloroethane (15mL) was added benzaldehyde (156mg,1.47mmol) and glacial acetic acid (200. mu.L) at room temperature. After stirring for 17 hours, CH was added₂Cl₂(20mL) then saturated NaHCO was added₃Aqueous solution (20mL, slowly). The organic layer was separated and passed over Na₂SO₄And (5) drying. The suspension was filtered and concentrated. The material was purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes) to afford a yellow solid, which was dissolved in methanol (10mL) and sodium borohydride (52mg,1.35mmol) was added at room temperature. After stirring for 1 hour, additional sodium borohydride (156mg,3.40mmol) was added and the reaction stirred for 1 hour. 2N aqueous HCl was added to the mixture until pH4(2mL), followed by saturated NaHCO₃The solution was basified to pH8(2 mL). Water (10mL) was added and the solution was extracted with ethyl acetate (3X 100 mL). The ethyl acetate extracts were combined and washed with Na₂SO₄Dried, filtered and concentrated to afford 28(401mg, 93%) as a white solid:¹HNMR(500MHz,CDCl₃)δ7.48(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)。

and step 3: to 28(350mg,1.19mmol) was added triethyl orthoacetate (3.0mL,16.4mmol) and sulfamic acid (1 mg). The mixture was heated to 100 ℃ for 1 hour. The mixture was diluted with methanol (20mL) and adsorbed onto silica gel (10 g). The material was purified by chromatography (silica gel, 0-60% ethyl acetate in hexane, then 0-5% in CH)₂Cl₂Methanol) to provide 4- (1-benzyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) -3, 5-dimethylisoxazole (example compound 13,169mg, 45%):¹H NMR(500MHz,CD₃OD)δ8.32(d,J＝1.0Hz,1H),7.78(d,J＝1.0Hz,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(1.00g,4.61mmol) in 1, 4-dioxane (40mL) and water (4mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (1.23g,5.53mmol), potassium carbonate (1.27g,9.22mmol) and tetrakis (triphenylphosphine) palladium (0) (266mg,0.231 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to give a yellow solid, which was dissolved in acetic acid (15mL) and N-bromosuccinimide (753mg,4.23mmol) was added at 0 ℃. 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 taken up with 10% NaHCO₃The aqueous solution is alkalized. The mixture was diluted with water and filtered. The filter cake was washed with water and dried in vacuo to afford 30(1.10g, 87%) as a yellow solid:¹H NMR(500MHz,CDCl₃)δ8.04(d,J＝2.1Hz,1H),7.61(d,J＝2.1Hz,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(500mg,1.60mmol) in toluene (50mL) under a nitrogen atmosphere was added 4-chlorobenzylamine (1.36g,9.62mmol), cesium carbonate (1.04g,3.02mmol), 2Dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl (114mg,0.240mmol) and tris (dibenzylideneacetone) dipalladium (0) (146mg,0.160 mmol). The reaction mixture was heated at 90 ℃ overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 31 as a red solid (290mg, 49%): ESI M/z 373[ M + H ]]⁺。

And step 3: to a mixture of 31(290mg,0.779mmol) in 1, 4-dioxane (10mL) was added 1,1' -carbonyldiimidazole (630mg,3.89mmol) and DMAP (crystal). The reaction was heated in a sealed tube at 130 ℃ for 4 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give example compound 91 as an orange solid (144mg, 46%):¹H NMR(500MHz,CD₃OD)δ7.80(d,J＝1.4Hz,1H),7.40–7.35(m,4H),7.24(d,J＝1.4Hz,1H),5.15(s,2H),2.32(s,3H),2.15(s,3H)；ESI m/z 399[M+H]⁺。

and 4, step 4: to a solution of example compound 91(70mg,0.18mmol) in tetrahydrofuran (10mL) was added sodium dithionite (183mg,1.05mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. To the residue was added 2N HCl and heated to reflux, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in MeOH and taken up with concentrated NH₄The OH was basified, concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC further purification to give example compound 90 as an off-white solid (34mg, 51%):¹H NMR(500MHz,CD₃OD)δ7.36–7.28(m,4H),6.40(d,J＝1.4Hz,1H),6.25(d,J＝1.4Hz,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(488mg,2.10mmol) and 2, 4-pentanedione (421mg,4.21mmol) in absolute ethanol (28mL) and 5N aqueous HCl (7.8mL) was heated to reflux for 3 hours. The mixture was concentrated to dryness and ethyl acetate (200mL) was added. The solution was saturated with NaHCO₃The aqueous solution (250mL) and saturated aqueous NaCl solution (250mL) were washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40% hexane/ethyl acetate) to afford 33(495mg, 92%) as an orange solid:¹H NMR(500MHz,CDCl₃)δ10.38(br s,1H),8.24(d,J＝2.0Hz,1H),8.12(d,J＝1.0Hz,1H),2.73(s,3H)。

step 2: to a mixture of 33(200mg,0.78mmol) and 3(262mg,1.17mmol) in 1, 4-dioxane (6mL) and water (1.5mL) was added potassium carbonate (216mg,1.56mmol) and tetrakis (triphenylphosphine) palladium (0) (45mg,0.04 mmol). The reaction was stirred and heated at 90 ℃ for 17 hours. The reaction mixture was diluted with methanol (20mL) and silica gel (15g) 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 as a yellow solid (187mg, 88%):¹H NMR(500MHz,CDCl₃)δ8.00(d,J＝1.5Hz,1H),7.89(s,1H),2.76(s,3H),2.45(s,3H),2.30(s,3H)。

and step 3: to a solution of 34(217mg,0.797mmol), potassium carbonate (220mg,1.59mmol), acetonitrile (5mL) and DMF (1mL) was added bromomethylcyclopropane (129mg,0.956mmol) and the reaction was heated at 60 ℃ for 17 h. The material was cooled to room temperature and poured into saturated aqueous NaCl (30 mL). Ethyl acetate (100mL) was added and the layers were separated. The ethyl acetate layer was washed with saturated aqueous NaCl (2X 20mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-90% hexane/ethyl acetate) to give example 14(178mg, 68%) as a yellow solid:¹H NMR(500MHz,CD₃OD)δ8.03(d,J＝1.5Hz,1H),7.93(d,J＝1.5Hz,1H),4.27(d,J＝7.0Hz,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]⁺

and 4, step 4: to a solution of example compound 14(160mg,0.51mmol) in THF (10mL) was added dropwise a solution of sodium dithionite (446mg,2.56mmol) in water (10mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. Aqueous 2N HCl (10mL) was added to the residue and heated to reflux for 5 minutes. After concentration to dryness, methanol (20mL) was added and saturated NaHCO was used₃Aqueous solution (10mL) the solution was adjusted to pH 8. Silica gel (10g) 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 purified by column chromatography with 10-90% in H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC purification to give example compound 75 as a white solid (131mg, 99%):¹H NMR(500MHz,CD₃OD)δ6.70(s,1H),6.44(d,J＝1.0Hz,1H),4.08(d,J＝6.5Hz,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(232mg,1.0mmol) in 1, 4-dioxane (5mL) was added CDI (194mg,1.2 mmol). The reaction was heated at 60 ℃ for 16 hours. The solid was harvested and dried to give 35 as a brown-yellow solid (202mg, 78%):¹H NMR(300MHz,DMSO–d₆)δ11.83(br s,1H),11.53(br s,1H),7.86(d,J＝1.8Hz,1H),7.43(d,J＝1.8Hz,1H)。

step 2: to a solution of 35(200mg,0.78mmol) in DMF (7mL) was added potassium carbonate (118mg,0.85mmol) and benzyl chloride (98mg,0.78 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100mL) 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/hexanes) afforded 36(101mg, 37%) as a yellow solid:¹H NMR(300MHz,DMSO–d₆)δ12.15(s,1H),7.90(d,J＝0.9Hz,1H),7.75(d,J＝1.2Hz,1H),7.36–7.28(m,5H),5.10(s,2H)。

and step 3: to a solution of 36(100mg,0.29mmol) in 1, 4-dioxane (7mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (128mg,0.57mmol), sodium carbonate (2.0M in H)₂0.43mL,0.86mmol) and tetrakis (triphenylphosphine) palladium (0) (34mg,0.03mmol) in O. The reaction mixture was purged with nitrogen and heated at 80 ℃ for 16 hours. The mixture was diluted with dichloromethane (20mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 10-50% ethyl acetate/hexanes) followed by trituration with ethyl acetate to afford example compound 15 as a yellow solid (70mg, 66%):¹H NMR(300MHz,DMSO–d₆)δ12.11(s,1H),7.72(d,J＝1.5Hz,1H),7.50(d,J＝1.5Hz,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]⁺。

and 4, step 4: to a solution of example compound 15(52mg,0.14mmol) in THF (5mL) and water (4mL) was added Na₂S₂O₄(149mg,0.86 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na was added slowly₂CO₃To adjust to pH 9. CH for the mixture₂Cl₂Extraction (100mL), organic layer was washed with brine (50mL), filtered, concentrated and purified by chromatography (silica gel, 70-100% ethyl acetate/hexanes) to afford example compound 16 as an off-white solid (30mg, 63%):¹H NMR(500MHz,DMSO–d₆)δ10.44(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(1.09g,3.49mmol) in tetrahydrofuran (30mL) was added sodium dithionite (4.86g,28.0mmol) in water (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was dissolved in MeOH/water (1:1,150mL) 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 as a yellow solid (440mg, 34%):¹H NMR(500MHz,CDCl₃)δ6.85(d,J＝1.8Hz,1H),6.51(d,J＝1.8Hz,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(4.01g,14.2mmol) in methanol (87mL) was added triethyl orthoacetate (3.45g,21.3mmol) and sulfamic acid (69mg,0.71 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (50mL) and NaHCO₃Basified and filtered. The solid was dried to afford 38 as a brown solid (4.2g, 96%):¹H NMR(300MHz,DMSO–d₆)δ12.82(br.s,1H),7.42(d,J＝1.5Hz,1H),7.31(d,J＝1.5Hz,1H),2.52(s,3H),2.40(s,3H),2.24(s,3H)。

and step 3: a mixture of 38(300mg,0.980mmol), benzyl bromide (503mg,2.94mmol) and potassium carbonate (676mg,4.90mmol) in acetonitrile (50mL) was heated in a sealed tube at 75 deg.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 a solid as an off-white solidCompound of example 121(276mg, 71%):¹H NMR(500MHz,CD₃OD)δ7.40–7.25(m,5H),7.15(d,J＝7.7Hz,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)

Example 121(80mg,0.20mmol), NaOCH₃A mixture of (108mg,2.0mmol) and CuI (57mg,0.30mmol) in MeOH (1mL) and DMF (3mL) was purged with nitrogen and heated at 100 deg.C for 6 hours. The mixture was diluted with ethyl acetate (100mL) and washed with brine (50 mL). The organic layer was washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 40-100% EtOAc/hexanes) to afford example compound 66 as an off-white solid (386mg, 55%):¹HNMR(300MHz,CDCl₃)δ7.35–7.30(m,3H),7.09–7.06(m,2H),6.64(d,J＝1.2Hz,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) -N²-ethyl-1H-benzo [ d]Imidazole-2, 4-diamine (example Compound 19)

Step 1: example Compound 15(73mg,0.668mmol) in POCl₃The mixture in (3mL) was heated at 110 ℃ for 16 hours. The reaction mixture was concentrated and the residue was dissolved in CH₂Cl₂(100mL) of the mixture, wherein,with saturated NaHCO₃(2X 50mL) 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 (2.0M,10mL) and the mixture was heated at 70 ℃ for 3 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica gel, 20-60% EtOAc/hexanes) to afford example compound 18(113mg, 43%) as an orange solid:¹HNMR(300MHz,CDCl₃)δ7.84(d,J＝1.5Hz,1H),7.42–7.35(m,3H),7.16–7.13(m,2H),7.03(d,J＝1.5Hz,1H),5.15(s,2H),4.29(t,J＝5.4Hz,1H),3.78–3.69(m,2H),2.36(s,3H),2.21(s,3H),1.27(t,J＝7.5Hz,3H)；ESI m/z 392[M+H]⁺。

step 2: to a solution of example compound 18(90mg,0.23mmol) in THF (5mL) and water (4mL) was added Na₂S₂O₄(240mg,1.38 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na was added slowly₂CO₃To adjust to pH 9. CH for the mixture₂Cl₂(100mL), the organic layer was washed with brine (50mL) and Na₂SO₄Dried, filtered, concentrated and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to afford example compound 19 as an off-white solid (60mg, 72%):¹H NMR(300MHz,DMSO–d₆)δ7.34–7.20(m,5H),6.62(t,J＝5.4Hz,1H),6.30(d,J＝1.5Hz,1H),6.21(d,J＝1.5Hz,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＝7.2Hz,3H)；ESI m/z 362[M+H]⁺。

general procedure J:

preparation of methyl 1-benzyl-6- (3, 5-dimethylisoxazol-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-4-carboxylate (example compound 20), 1-benzyl-6- (3, 5-dimethylisoxazol-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-4-carboxamide (example compound 21) and 4- (aminomethyl) -1-benzyl-6- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-2 (3H) -one (example compound 22).

Step 1: to a solution of 39(2.00g,8.70mmol) in 1, 4-dioxane (80mL) and water (8mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (2.13g,9.57mmol), potassium carbonate (2.40g,17.4mmol) and tetrakis (triphenylphosphine) palladium (0) (502mg,0.435 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 40 as an off-white solid (1.43g, 63%):¹H NMR(500MHz,CDCl₃)δ7.74(d,J＝2.1Hz,1H),7.15(dd,J＝2.1,8.4Hz,1H),6.73(d,J＝8.4Hz,1H),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(1.34g,5.45mmol) in acetic acid (40mL) was added N-bromosuccinimide (1.07g,5.99 mmol). The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in MeOH and neutralized to pH7 with 10% sodium bicarbonate. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to afford 41 as a yellow solid (1.65g, 93%):¹H NMR(500MHz,CDCl₃)δ7.74(d,J＝2.1Hz,1H),7.47(d,J＝2.1Hz,1H),6.43(bs,2H),3.90(s,3H),2.37(s,3H),2.23(s,3H)。

and step 3: to a solution of 41(500mg,1.54mmol) in toluene (40mL) under a nitrogen atmosphere were added benzylamine (823mg,7.69mmol), cesium carbonate (1.00g,2.08mmol), 2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (110mg,0.231mmol), and tris (dibenzylideneacetone) dipalladium (0) (141mg,0.154 mmol). The reaction mixture was heated at 90 ℃ overnight, cooled to room temperature and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to afford 42 as a light brown solid (310mg, 57%):¹H NMR(500MHz,CDCl₃)δ7.40–7.25(m,6H),6.56(d,J＝1.8Hz,1H),5.68(s,2H),4.36(d,J＝4.4Hz,2H),3.88(s,3H),3.68(s,1H),2.22(s,3H),2.09(s,3H)；ESI m/z 352[M+H]⁺。

and 4, step 4: to a mixture of 42(310mg,0.883mmol) in 1, 4-dioxane (10mL) was added 1,1' -carbonyldiimidazole (244mg,2.12mmol) and DMAP (a crystal). The reaction was heated in a sealed tube at 80 ℃ for 5 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford example compound 20 as an off-white solid (160mg, 48%):¹H NMR(500MHz,CD₃OD)δ7.54(d,J＝1.5Hz,1H),7.37–7.24(m,5H),7.07(d,J＝1.5Hz,1H),5.14(s,2H),3.97(s,3H),2.27(s,3H),2.09(s,3H)；HPLC>99％,t_R15.0 minutes; ESI M/z 378[ M + H ]]⁺。

And 5: to a mixture of example compound 20(50mg,0.13mmol) in formamide (4mL) was added potassium tert-butoxide (30mg,0.26 mmol). The mixture was heated in a microwave at 100 ℃ for 3 hours, concentrated, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford example compound 21 as an off-white solid (13mg, 26%):¹HNMR(500MHz,CD₃OD)δ7.41(d,J＝1.3Hz,1H),7.37–7.24(m,5H),7.00(d,J＝1.4Hz,1H),5.13(s,2H),2.28(s,3H),2.11(s,3H)；HPLC98.3％,t_R12.3 minutes; ESI M/z 363[ M + H ]]⁺。

Step 6: to a solution of example compound 21(40mg,0.11mmol) in THF (10mL) under a nitrogen atmosphere was added sodium borohydride (38mg,0.99 mmol). The mixture was heated to 65 ℃ and boron trifluoride diethyl etherate (0.2mL) was added. The mixture was heated at 65 ℃ for 2 hours. After cooling to room temperature, hydrochloric acid (2N,5mL) was added and the mixture was stirred for 2 hours. The mixture was basified with NaOH (2N,5mL), concentrated and purified by chromatography (silica gel, 0-100% CMA in dichloromethane) (CMA ═ chloroform: methanol: concentrated ammonium hydroxide ═ 80:18: 2). It is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN-eluted Polaris column reverse phase HPLC further purified to give example compound 22 as an off-white solid (16mg, 42%):¹HNMR(500MHz,CD₃OD)δ7.37–7.23(m,5H),6.99(d,J＝1.4Hz,1H),6.77(d,J＝1.4Hz,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)

Example 121(250mg,0.63mmol), BocNH₂(221mg,1.89mmol)、Xantphos(73mg,0.126mmol)、Pd₂(dba)₃(58mg,0.063mmol) and Cs₂CO₃A mixture of (720mg,2.21mmol) in 1, 4-dioxane (13mL) was purged with nitrogen and heated at 100 ℃ for 18 hours. The mixture was diluted with dichloromethane (200mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-50% EtOAc/hexanes) to provide a light brown foam, which was dissolved in CH₂Cl₂To (4mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours, concentrated, the residue dissolved in ethyl acetate (100mL) and washed with saturated NaHCO₃Washing (50 mL. times.2). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-10% MeOH/EtOAc) afforded example compound 55(146mg, 88%) as an off-white solid:¹HNMR(500MHz,CDCl₃)δ7.34–7.28(m,3H),7.09–7.08(m,2H),6.42(d,J＝1.5Hz,1H),6.36(d,J＝1.5Hz,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 solution of 43(200mg,1.0mmol) in CH₃Suspension in CN (6mL) was added ClSO₂NCO (360mg,2.5 mmol). The reaction mixture was stirred at 60 ℃ for 4 hours. After the mixture was cooled to room temperature, DMF (1mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was 30% in CHCl₃i-PrOH (50mL) in (1) was diluted and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Dissolving the crude product in CH₃CN (4mL), potassium carbonate (280mg,2.0mmol) and benzyl chloride (128mg,1.0mmol) were added. The reaction was stirred at 70 ℃ for 16 hours. The reaction mixture was filtered through a layer of celite and concentrated. The residue was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 44 as a yellow oil (16mg, 5%) and 45 as an off-white solid (12mg, 4%); 44: ESIMS M/z 312[ M + H ]]⁺；45：ESI MS m/z 321[M+H]⁺。

Step 2: using a procedure similar to that used for general procedure C, step 1, for compound 44(16mg,0.051mmol) gave example compound 88(6mg, 36%) as an off-white solid:¹H NMR(300MHz,CDCl₃)δ8.55(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]⁺。

using a procedure similar to that used for general procedure C, step 1, for compound 45(12mg,0.037mmol) gave example compound 89(8mg, 64%) as a yellow solid:¹H NMR(300MHz,CDCl₃)δ8.49(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(500mg,2.54mmol) in 1, 4-dioxane (10mL)To the solution was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (792mg,3.56mmol), sodium carbonate (538mg in 2mL H₂O, 5.08mmol) and tetrakis (triphenylphosphine) palladium (0) (294mg,0.25 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 16 hours. The mixture was filtered through a layer of celite. The filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) gave 47 as a yellow oil (700mg,>100％)：¹H NMR(300MHz,DMSO–d₆)δ11.4(s,1H),7.85(dd,J＝8.1,0.9Hz,1H),7.68(t,J＝3.0Hz,1H),7.23(d,J＝8.1Hz,1H),6.58(d,J＝2.1Hz,1H),2.49(s,3H),2.37(s,3H)。

step 2: to a solution of 47(700mg,2.54mmol) in DMF (8mL) was added NBS (497mg,2.79mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 hours. The mixture was diluted with dichloromethane (50mL) 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) afforded 48(660mg, 89%) as a brown solid:¹H NMR(300MHz,DMSO–d₆)δ11.8(s,1H),7.92(d,J＝6.0Hz,1H),7.90(s,1H),7.36(d,J＝8.4Hz,1H),2.49(s,3H),2.37(s,3H)；ESI m/z 292[M+H]⁺。

and step 3: to a solution of 48(250mg,0.86mmol) in CH₂Cl₂(5mL) solution to add NEt₃(130mg,1.28mmol), DMAP (12mg,0.1mmol) and di-tert-butyl dicarbonate (224mg,1.03 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate/hexanes) afforded 49 as an off-white solid (210mg, 70%):¹H NMR(300MHz,CDCl₃)δ8.43(d,J＝5.4Hz,1H),7.93(s,1H),7.34(d,J＝5.1Hz,1H),2.64(s,3H),2.50(s,3H),1.69(s,9H)。

and 4, step 4: to a solution of 49(100mg,0.26mmol) in 1, 4-dioxane (5mL) under a nitrogen atmosphere was added aniline (71mg,0.76mmol), cesium carbonate (250mg,0.76mmol), X-phos (24mg,0.05mmol) and tris (dibenzylideneacetone) dipalladium (0) (23mg,0.03 mmol). The reaction mixture was heated at 90 ℃ for 16 hours. The mixture was diluted with dichloromethane (10mL) andfiltration through celite bed. The filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexanes) gave a red oil, which was dissolved in dichloromethane (5mL), TFA (2mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was dissolved in dichloromethane (100mL) and saturated NaHCO was used₃(50 mL. times.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) afforded example compound 23(47mg, 64%) as a yellow solid:¹H NMR(300MHz,DMSO–d₆)δ11.1(d,J＝1.8Hz,1H),7.82(d,J＝8.4Hz,1H),7.61(d,J＝2.7Hz,1H),7.43(s,1H),7.25(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),7.07(d,J＝7.2Hz,1H),6.85(d,J＝7.5Hz,2H),6.60(t,J＝7.2Hz,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 example compound 53(85mg,0.25mmol) in CH₂Cl₂(3mL) m-CPBA (160mg,0.5mmol) was added. The reaction mixture was stirred at room temperature for 7 hours. The mixture was diluted with dichloromethane (50mL) and 10% Na₂S₂O₃The solution (10mL), 2N NaOH solution (10mL) and brine (10mL) were washed. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-70% ethyl acetate/dichloromethane) afforded example compound 24 as an off-white solid (60mg, 67%):¹H NMR(300MHz,DMSO–d₆)δ8.21(d,J＝0.9Hz,1H),7.83(d,J＝0.9Hz,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: EXAMPLE Compound 24(32mg,0.091mmol) in Ac₂The solution in O (3mL) was heated at 130 ℃ for 2 hours. The mixture was concentrated. The residue is substituted with 1:1 CH₃OH/H₂O (10mL) diluted and stirred at 80 ℃ for 10 h. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) afforded example compound 25 as an off-white solid (20mg, 63%):¹H NMR(300MHz,DMSO–d₆)δ2.0(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)

Step 1: to a solution of 50(560mg,2.57mmol) in CH₃Solution in CN (15mL) added K₂CO₃(887mg,6.43mmol) and benzyl chloride (484mg,2.83 mmol). The reaction was heated at 60 ℃ for 16 hours. The mixture was diluted with ethyl acetate (100mL), filtered and concentrated to give 51 as a yellow solid (790mg, 100%):¹H NMR(300MHz,CDCl₃)δ8.58(br s,1H),8.24(d,J＝8.4Hz,1H),7.46–7.35(m,5H),6.82(d,J＝8.7Hz,1H),4.82(d,J＝5.7Hz,2H)。

step 2: to a solution of 51(790mg,2.56mmol) in 1, 4-dioxane (25mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (1.14g,5.12mmol), sodium carbonate (2.0M in H)₂3.84mL,7.68mmol) and tetrakis (triphenylphosphine) palladium (0) (300mg,0.26mmol) in O. The reaction mixture was purged with nitrogen and heated at 90 ℃ for 8 hours. The mixture was diluted with dichloromethane (200mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-20% EtOAc/hexanes) to afford 52 as a yellow oil (500mg, 60%):¹H NMR(300MHz,DMSO–d₆)δ9.09(t,J＝6.0Hz,1H),8.51(d,J＝8.4Hz,1H),7.32–7.20(m,5H),6.96(d,J＝8.7Hz,1H),4.85(d,J＝6.3Hz,2H),2.47(s,3H),2.25(s,3H)；ESI m/z 325[M+H]⁺。

and step 3: to a solution of 52(500mg,1.54mmol) in THF (15mL) and water (12mL) was added Na₂S₂O₄(1.61g,9.24 mmol). The mixture was stirred at room temperature for 5 hours; 2N HCl (10mL) was added and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na was added slowly₂CO₃To adjust to pH 9. The mixture was extracted with ethyl acetate (100mL), and the organic layer was washed with brine (50mL), filtered and concentrated to give 53(460mg, 100%) as a brown oil:¹H NMR(300MHz,DMSO–d₆)δ7.33–7.18(m,5H),6.78(d,J＝7.5Hz,1H),6.52(d,J＝7.5Hz,1H),6.29(t,J＝5.7Hz,1H),4.94(s,2H),4.60(d,J＝5.7Hz,2H),2.36(s,3H),2.17(s,3H)；ESI m/z295[M+H]⁺。

and 4, step 4: a solution of 53(150mg,0.51mmol), trimethyl orthoformate (81mg,0.765mmol) and sulfamic acid (3mg) in MeOH (5mL) 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 provide example compound 26 as an off-white solid (100mg, 65%):¹H NMR(300MHz,DMSO–d₆)δ8.67(s,1H),8.17(d,J＝8.1Hz,1H),7.44(d,J＝8.1Hz,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 similar procedure as described for example 7:¹H NMR(300MHz,DMSO–d₆)δ8.23(s,1H),7.42(dd,J＝8.0,6.0Hz,2H),7.17(dd,J＝9.0,9.0Hz,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(35mg,0.10mmol) in dichloromethane (5mL) was added a solution of 37% formaldehyde in water (8.5. mu.L) and acetic acid (1 drop). The solution was stirred for 45 min, sodium triacetoxyborohydride (66mg,0.31mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with dichloromethane (20mL) 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 as a white solid (8mg, 22%) and example compound 29 as a clear solid (7mg, 18%). Example compound 28:¹H NMR(500MHz,DMSO–d₆)δ8.22(s,1H),7.43(dd,J＝8.8,5.5Hz,2H),7.16(dd,J＝8.8,5.5Hz,2H),6.65(d,J＝1.0Hz,1H),6.09(d,J＝1.0Hz,1H),5.85(q,J＝5.0Hz,1H),5.41(s,2H),2.83(d,J＝5.5Hz,3H),2.35(s,3H),2.17(s,3H)；ESIm/z 351[M+H]⁺(ii) a Example 29:¹H NMR(500MHz,DMSO–d₆)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＝1.0Hz,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 (54,780mg,3.58mmol) and potassium carbonate (2.28g,16.5mmol) in dry acetonitrile (50mL) was added 1- (bromoethyl) benzene (1.22g,6.60 mmol). Adding the mixture toHeat to 80 ℃ for 48 hours, then add water (20mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2X 20 mL). The combined ethyl acetate fractions were passed over Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes) to afford 55(219mg, 19%) as a yellow solid:¹H NMR(500MHz,CDCl₃)δ8.14(d,J＝5.0Hz,1H),7.84(d,J＝2.0Hz,1H),7.40–7.29(m,6H),4.64(quint,J＝6.5Hz,1H),1.67(d,J＝7.0Hz,3H)。

step 2: to a mixture of 55(261mg,0.81mmol) and 3(217mg,0.97mmol) in 1, 4-dioxane (7mL) and water (1.5mL) was added potassium carbonate (224mg,1.62mmol) and tetrakis (triphenylphosphine) palladium (0) (47mg,0.04 mmol). The reaction was stirred and heated at 90 ℃ for 17 hours. The reaction mixture was diluted with methanol (20mL) and silica gel (15g) 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 as a yellow solid (226mg, 82%):¹H NMR(500MHz,CDCl₃)δ8.19(d,J＝4.5Hz,1H),7.77(d,J＝2.0Hz,1H),7.40–7.28(m,5H),6.89(d,J＝2.0Hz,1H),4.66(quint,J＝5.0Hz,1H),2.10(s,3H),1.94(s,3H),1.71(d,J＝7.0Hz,3H)。

and step 3: to a solution of 56(226mg,0.67mmol) in THF (20mL) was added dropwise a solution of sodium dithionite (698mg,4.01mmol) in water (20mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. Aqueous 2N HCl was added to the residue and heated to reflux for 5 minutes. After concentration to dryness, methanol (10mL) was added and saturated NaHCO was used₃Aqueous solution (20mL) the solution was adjusted to pH 8. Silica gel (10g) 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 hexanes. The clean product was concentrated to give 57(96mg, 47%) as a beige solid:¹H NMR(500MHz,CDCl₃)δ7.42(d,J＝2.0Hz,1H),7.33–7.30(m,4H),7.25–7.22(m,1H),6.34(d,J＝1.5Hz,1H),4.44(quint,J＝5.0Hz,1H),4.36(br s,2H),3.70(br s,1H),2.07(s,3H),1.89(s,3H),1.58(d,J＝6.5Hz,3H)。

and 4, step 4: a mixture of 57(47mg,0.15mmol), trimethyl orthoformate (2mL,18.3mmol) and sulfamic acid (1mg) was heated in a sealed tube at 100 ℃ for 30 minutes. The mixture was cooled, concentrated and loaded on silica gel and eluted with 0-20% ethyl acetate in hexanes. The obtained material is obtained by mixing with 10-90% of H₂CH in O₃CN-eluted Polaris column reverse phase HPLC purified to afford (example compound 30) as a white solid (19mg, 39%):¹H NMR(500MHz,CD₃OD)δ8.76(s,1H),8.36(d,J＝2.0Hz,1H),7.65(d,J＝2.5Hz,1H),7.40–7.30(m,5H),4.44(q,J＝7.0Hz,1H),2.29(s,3H),2.10(s,3H),2.06(d,J＝7.0Hz,3H).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(1.00g,5.76mmol) in 1, 4-dioxane (40mL) and water (4mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (1.93g,8.64mmol), potassium carbonate (1.59g,11.5mmol) and tetrakis (triphenylphosphine) palladium (0) (333mg,0.288 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ 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(1.42g,>99％)：¹H NMR(300MHz,CDCl₃)δ9.26(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]⁺。

step 2: 59(710mg,3.03mmol) and benzyl bromide (77)A mixture of 8mg,4.55mmol) and potassium carbonate (836mg,6.06mmol) in acetonitrile (30mL) was heated in a sealed tube at 90 ℃ 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 as a brown solid (303mg, 30%):¹H NMR(500MHz,CDCl₃)δ9.26(s,1H),8.68(s,1H),7.50–7.10(m,5H),6.50(s,1H),4.65(d,J＝4.1Hz,2H),2.39(s,3H),2.19(s,3H)；ESI m/z 325[M+H]⁺。

and step 3: to a solution of 60(300mg,0.926mmol) in tetrahydrofuran (10mL) was added sodium dithionite (967mg,5.56mmol) 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 in vacuo. To the residue was added 2N HCl and heated to just boil, cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and taken up with 10% NaHCO₃Basified, concentrated and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford 61 as a grey solid (150mg, 55%):¹H NMR(500MHz,CDCl₃)δ7.99(s,1H),7.40–7.28(m,5H),6.39(s,1H),4.64(s,1H),4.43(d,J＝5.4Hz,2H),3.15(s,2H),2.33(s,3H),2.21(s,3H)；ESI m/z 295[M+H]⁺。

and 4, step 4: to a solution of 61(150mg,0.51mmol) in ethanol (5mL) was added trimethyl orthoformate (81mg,0.77mmol) and sulfamic acid (1mg,0.01 mmol). The reaction was heated in a sealed tube at 90 ℃ overnight. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give example compound 31 as a yellow solid (143mg, 92%):¹H NMR(500MHz,CD₃OD)δ9.00(d,J＝1.0Hz,1H),8.05(s,1H),7.48(d,J＝1.0Hz,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]⁺。

and 5: to a mixture of example compound 31(100mg,0.329mmol) in dichloromethane (5mL) was added 3-chloroperoxybenzoic acid (264mg, 77% aqueous solution, 1.18 mmol). The mixture was stirred at room temperature overnight, concentrated and filtered throughPurification by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford example compound 32 as an off-white solid (127mg,>99％)：¹H NMR(500MHz,CD₃OD)δ8.92(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 (268mg,0.938mmol) in DMF (2mL) was added example 32(100mg,0.313mmol) in DMF (6 mL). The mixture was stirred at room temperature for 10 minutes and heated at 100 ℃ for 1 hour. After cooling to room temperature, water and MeOH were added. The mixture was neutralized to pH7 by the addition of 10% sodium bicarbonate and concentrated. The residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford 62 as an off-white solid (30mg, 25%):¹HNMR(500MHz,CDCl₃)δ8.09(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]⁺。

and 7: to a solution of 62(30mg,0.078mmol) in toluene (10mL) under a nitrogen atmosphere were added tert-butyl carbamate (27mg,0.23mmol), cesium carbonate (51mg,0.16mmol), 2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (6mg,0.01mmol) and tris (dibenzylideneacetone) dipalladium (0) (7mg,0.008 mmol). The reaction mixture was heated at 90 ℃ overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN-eluted Polaris column reverse phase HPLC further purified to give example compound 33 as an off-white solid (10mg, 40%):¹H NMR(500MHz,CD₃OD)δ8.21(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_R10.1 min; ESI M/z320[ 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(1.0g,5.08mmol) in 1, 4-dioxane (50mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (1.47g,6.6mmol), sodium carbonate (1.10g in 8mL H₂O, 10.2mmol) and tetrakis (triphenylphosphine) palladium (0) (587mg,0.51 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 16 hours. The mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) gave 63(850mg, 79%) as a yellow solid:¹H NMR(300MHz,DMSO–d₆)δ11.4(s,1H),8.30(t,J＝2.1Hz,1H),7.75(dd,J＝1.8,0.9Hz,1H),7.70(t,J＝3.0Hz,1H),6.61–6.59(m,1H),2.42(s,3H),2.24(s,3H)。

step 2/3: to a solution of 63(500mg,2.35mmol) in DMF (10mL) was added NBS (500mg,2.82mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 hours. The mixture was diluted with dichloromethane (50mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Crude 64 continues to be used for the reaction. To a mixture of 64(300mg,1.03mmol) in DMF (1mL) and CH₃To a solution in CN (10mL) were added potassium carbonate (283mg,2.06mmol) and benzyl chloride (130mg,1.03 mmol). The reaction was stirred at 70 ℃ for 16 hours. The mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography on silica gel, 0-50% ethyl acetate/dichloromethane) afforded example compound 34(200mg, 51%) as an off-white solid:¹HNMR(500MHz,CD₃OD)δ8.33(d,J＝1.5Hz,1H),7.86(s,1H),7.80(d,J＝2.0Hz,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 reaction mixture of 46(300mg,1.5mmol) anda mixture of hexamethylenetetramine (0.32g,2.25mmol) was added to AcOH (2 mL). The reaction mixture was stirred at 120 ℃ for 6 hours and with H₂O (5mL) quench. The precipitate was harvested by filtration to afford 65 as a yellow solid (190mg, 56%):¹H NMR(300MHz,DMSO–d₆)δ12.4(s,1H),10.1(s,1H),8.58(d,J＝2.1Hz,1H),8.47(s,1H),8.18(d,J＝2.1Hz,1H)。

step 2: to a solution of 65(190mg,0.84mmol) in 1, 4-dioxane (5mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (245mg,1.09mmol), sodium carbonate (178mg in 1mL H₂O, 1.68mmol) and tetrakis (triphenylphosphine) palladium (0) (97mg,0.08 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 16 hours. The mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) gave 66 as an off-white solid (135mg, 67%):¹H NMR(300MHz,DMSO–d₆)δ12.5(s,1H),10.2(s,1H),8.51(d,J＝1.8Hz,1H),8.49(d,J＝3.0Hz,1H),7.92(d,J＝1.8Hz,1H),2.44(s,3H),2.26(s,3H)；ESIMS m/z 242[M+H]⁺。

and step 3: to a mixture of 66(92mg,0.38mmol) in DMF (0.5mL) and CH₃To a solution in CN (5mL) were added potassium carbonate (105mg,0.76mmol) and benzyl chloride (58mg,0.46 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded example compound 35(72mg, 57%) as an off-white solid:¹H NMR(300MHz,DMSO–d₆)δ10.2(s,1H),8.73(s,1H),8.53(d,J＝1.8Hz,1H),8.11(d,J＝1.8Hz,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-dimethylmethylamine (example Compound 72)

EXAMPLE 35(54mg,0.16mmol), dimethylamine (0.25mL,2M in THF, 0.49mmol) and NaBH (OAc)₃(104mg,0.49mmol) in CH₂Cl₂The solution in (3mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford example compound 72 as an off-white solid (42mg, 71%):¹H NMR(300MHz,CDCl₃)δ8.34(d,J＝1.8Hz,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 AlCl₃(313mg,2.35mmol) in CH₂Cl₂(20mL) 63(100mg,0.47mmol) and AcCl (184mg,2.35mmol) were added to the suspension. The reaction mixture was stirred at room temperature for 6 hours. The reaction was carefully quenched with methanol (10mL) and the pH adjusted to be Na solid₂CO₃And (4) neutralizing. The mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-10% methanol/dichloromethane) afforded 67 as an off-white solid (82mg, 68%):¹H NMR(300MHz,DMSO–d₆)δ12.8(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(62mg,0.24mmol) in DMF (0.5mL) and CH₃CN (5mL) was added potassium carbonate (67mg,0.48mmol) and benzyl chloride (37mg,0.29 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded example compound 36(30mg, 36%) as an off-white solid:¹H NMR(300MHz,CDCl₃)δ8.59(d,J＝1.5Hz,1H),8.22(s,1H),7.45(d,J＝1.8Hz,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(165mg,0.52mmol) in DMF (2mL) was added to POCl₃(159mg,1.03 mmol). The reaction mixture was heated at 100 ℃ for 2 hours and concentrated. Dissolving the residue in CH₂Cl₂(100mL), with saturated NaHCO₃(2X 20mL) 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) afforded example compound 37(81mg, 45%) as a yellow solid:¹H NMR(300MHz,CDCl₃)δ9.90(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(100mg,0.29mmol) in ethanol (3mL) was added 2N sodium hydroxide in water (1.46mL,2.9 mmol). The mixture was heated to 85 ℃ for 20 minutes, then cooled to room temperature and neutralized with 2mL of acetic acid. The mixture was basified with solid sodium carbonate (pH8), diluted in dichloromethane (100mL), washed with brine (20mL) and dried over anhydrous sodium sulfate. Filtering, and filtering to obtain filtrateConcentrated in vacuo and purified by chromatography (silica gel, 0-20% methanol/dichloromethane) to afford example compound 38(71mg, 68%) as a white solid:¹H NMR(300MHz,DMSO–d₆)δ8.35(d,J＝1.8Hz,1H),7.99(d,J＝2.1Hz,1H),7.94(brs,1H),7.83(d,J＝8.4Hz,2H),7.37(br s,1H),7.27(d,J＝8.4Hz,2H),5.61(s,2H),2.60(s,3H),2.39(s,3H),2.21(s,3H)；ESI m/z362[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(100mg,0.47mmol) in H₂SO₄(0.5mL) solution at 0 deg.C HNO was added₃(35mg,0.47 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour. Reaction mixture with H₂O (10mL) was diluted and adjusted with 6N NaOH solution to neutralize the pH. CH for solution₂Cl₂Extraction (30 mL). The organic layer was dried, filtered and concentrated. Purification by chromatography (silica gel, 0-10% methanol/dichloromethane) gave 68(82mg, 68%) as a yellow solid:¹H NMR(300MHz,DMSO–d₆)δ12.9(s,1H),8.85(s,1H),8.58(d,J＝2.1Hz,1H),7.95(d,J＝1.8Hz,1H),2.45(s,3H),2.26(s,3H)；ESIMS m/z 259[M+H]⁺。

step 2: to a solution of 68(82mg,0.32mmol) in DMF (0.5mL) and CH₃CN (5mL) was added potassium carbonate (88mg,0.64mmol) and benzyl chloride (44mg,0.35 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded example compound 39(68mg, 61%) as an off-white solid:¹H NMR(300MHz,CDCl₃)δ8.74(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)；ESIMSm/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(200mg,0.709mmol) in tetraethoxymethane (340mg,1.77mmol) was heated at 100 ℃ for 4 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 69 as a yellow solid (177mg, 74%):¹H NMR(500MHz,CD₃OD)δ7.30–7.15(m,2H),4.57(q,J＝7.0Hz,2H),2.39(s,3H),2.23(s,3H),1.47(t,J＝7.0Hz,3H)；ESI m/z 336[M+H]⁺。

step 2: to a solution of 69(250mg,0.74mmol) in CH₃Solution in CN (8mL) and DMF (2mL) was added K₂CO₃(155mg,0.82mmol) and benzyl chloride (104mg,0.82 mmol). The reaction was heated at 60 ℃ for 16 hours. The mixture was diluted with ethyl acetate (100mL), filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to afford 70 as an off-white solid (200mg, 63%) and 71 as a colorless oil (87mg, 27%): 70:¹H NMR(300MHz,CDCl₃)δ7.34–7.29(m,3H),7.21–7.18(m,3H),6.77(d,J＝1.5Hz,1H),5.16(s,2H),4.75(q,J＝7.5Hz,2H),2.29(s,3H),2.14(s,3H),1.50(t,J＝7.0Hz,3H)；71：¹H NMR(300MHz,CDCl₃)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)。

and step 3: 70(100mg,0.235mmol), BocNH₂(82mg,0.705mmol)、Xantphos(28mg,0.048mmol)、Pd₂(dba)₃(22mg,0.024mmol) and Cs₂CO₃A mixture of (268mg,0.823mmol) in 1, 4-dioxane (8mL) was purged with nitrogen and heated at 100 ℃ for 18 hours. The mixture was diluted with dichloromethane (200mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to afford an ash72 of white solid (90mg, 83%):¹H NMR(300MHz,CDCl₃)δ7.74(br s,1H),7.41(s,1H),7.32–7.29(m,3H),7.22–7.19(m,2H),6.51(d,J＝1.5Hz,1H),5.14(s,2H),4.64(q,J＝7.2Hz,2H),2.32(s,3H),2.17(s,3H),1.49(t,J＝7.2Hz,3H),1.46(s,9H)。

and 4, step 4: 72(90mg,0.195mmol) in TFA (1mL) and CH₂Cl₂The solution in (2mL) was stirred at room temperature for 1 hour. The mixture was concentrated, the residue dissolved in ethyl acetate (100mL) and saturated NaHCO₃Washing (50 mL. times.2). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 40-100% EtOAc/hexanes) afforded example compound 17(51mg, 72%) as an off-white solid:¹H NMR(300MHz,CDCl₃)δ7.35–7.20(m,5H),6.33(d,J＝1.5Hz,1H),6.30(d,J＝1.5Hz,1H),5.13(s,2H),4.68(q,J＝6.9Hz,2H),4.30(br s,2H),2.30(s,3H),2.16(s,3H),1.49(t,J＝7.2Hz,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(50mg,0.17mmol) and tetraethyl orthocarbonate (131mg,0.68mmol) was added sulfamic acid (3mg,0.034 mmol). The mixture was then heated to 100 ℃ for 8 hours, then diluted with ethyl acetate (30mL), washed with brine (15mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford example compound 59 as an off-white solid (24mg, 41%):¹H NMR(300MHz,DMSO–d₆)δ7.75(d,J＝1.2Hz,1H),7.38–7.22(m,5H),7.18(d,J＝1.5Hz,1H),4.99(s,2H),4.34(q,J＝7.2Hz,2H),2.37(s,3H),2.18(s,3H),1.42(t,J＝7.2Hz,3H)；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-bromobenzylnitrile. Use of the procedure used for general procedure D, step 3, for compound 73(30mg,0.09mmol) gave example compound 85(10mg, 31%) as an off-white solid:¹H NMR(500MHz,CD₃OD)δ7.63(d,J＝1.5Hz,1H),7.60(d,J＝1.5Hz,1H),7.38–7.27(m,3H),7.19–7.14(m,2H),5.57(s,2H),2.69(s,3H),2.32(s,3H),2.16(s,3H)；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)

The example Compound 16(34mg,0.10mmol), acetic anhydride (12mg,0.12mmol) and i-Pr₂A solution of NEt (26mg,0.20mmol) in THF (3mL) was stirred at room temperature for 16 h. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/EtOAc) to afford example compound 111(28mg, 74%) as a white solid:¹H NMR(300MHz,DMSO–d₆)δ10.78(s,1H),9.85(s,1H),7.60–7.46(m,5H),7.28(d,J＝1.2Hz,1H),7.06(d,J＝1.2Hz,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(1.00g,3.21mmol) in toluene (70mL) under a nitrogen atmosphere was added benzylamine (1.94g,16.0mmol), potassium tert-butoxide (539mg,4.82mmol), 2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl (229mg,0.482mmol), and tris (dibenzylideneacetone) dipalladium (0) (293mg,0.321 mmol). The reaction mixture was heated at 90 ℃ overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 74 as a tan solid (700mg, 62%):¹H NMR(500MHz,CDCl₃)δ7.50(d,J＝1.8Hz,1H),7.70–7.22(m,5H),6.41(d,J＝1.6Hz,1H),6.07(s,2H),4.48(q,J＝3.5Hz,1H),3.65(s,1H),2.05(s,3H),1.90(s,3H),1.62(d,J＝6.6Hz,3H)；ESI m/z 353[M+H]⁺。

step 2: to a mixture of 74(600mg,1.70mmol) in 1, 4-dioxane (40mL) was added 1,1' -carbonyldiimidazole (2.76mg,17.0mmol) and DMAP (crystal). The reaction was heated in a sealed tube at 120 ℃ for 2 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give example compound 110 as an orange solid (420mg, 65%):¹H NMR(500MHz,CD₃OD)δ7.75(d,J＝1.3Hz,1H),7.44(d,J＝7.7Hz,2H),7.38(t,J＝7.7Hz,2H),7.31(t,J＝7.7Hz,1H),6.88(d,J＝1.3Hz,1H),5.88(q,J＝7.1Hz,1H),2.20(s,3H),2.02(s,3H),1.91(d,J＝7.2Hz,3H)；ESI m/z 377[M–H]⁺。

and step 3: to a solution of example compound 110(100mg,0.265mmol) in tetrahydrofuran (10mL) was added sodium dithionite (276mg,1.59mmol) 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 boil, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in MeOH and taken up with concentrated NH₄Basified with OH, concentrated and chromatographed (silica gel, 0)-100% hexane/ethyl acetate). It is through Polaris C₁₈Elution 10-90% in H for column reverse phase HPLC₂CH in O₃CN was further purified to give example compound 115 as an off-white solid (49mg, 53%):¹H NMR(500MHz,CD₃OD)δ7.42–7.32(m,4H),7.26(t,J＝6.9Hz,1H),6.35(s,1H),5.94(s,1H),5.78(q,J＝7.2Hz,1H),2.17(s,3H),2.00(s,3H),1.86(d,J＝7.2Hz,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(90mg,0.28mmol) and phosphorus (V) oxychloride (1mL) was heated to 110 ℃ for 5 hours and then cooled to room temperature. The mixture was concentrated, dissolved with dichloromethane (75mL) 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 2.0M morpholine in tetrahydrofuran (5.6mL,11.2mmol) and the mixture was heated to 75 ℃ 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/hexane to afford example compound 114(62mg, 57%) as a white solid:¹H NMR(500MHz,CDCl₃)δ8.24(d,J＝2.0Hz,1H),7.41–7.34(m,3H),7.15(d,J＝6.5Hz,2H),7.06(d,J＝1.0Hz,1H),5.26(s,2H),3.83(t,J＝4.5Hz,4H),3.50(t,J＝4.5Hz,4H),2.29(s,3H),2.11(s,3H)；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(218mg,0.60mmol) in 1, 4-dioxane (5mL) was added 1,1' -carbonyldiimidazole (117mg,0.72mmol) and the mixture was heated to 100 ℃ for 16 hours. The mixture was diluted with dichloromethane (70mL) 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 afford example compound 101(155mg, 66%) as a white solid:¹H NMR(500MHz,DMSO–d₆)δ11.83(s,1H),7.92(d,J＝1.5Hz,1H),7.73(d,J＝2.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.53(d,J＝2.0Hz,1H),7.35(dd,J＝8.5,2.0Hz,1H),5.05(s,2H),2.37(s,3H),2.19(s,3H)；ESI m/z 389[M+H]⁺。

general procedure S:

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 procedure of general procedure P, step 1, starting with (S) -1-phenylethylamine.

Step 1: using the procedure used in general procedure F, step 1, starting with compound 76(140mg,0.40mmol) gives example compound 125(108mg, 72%) as a yellow solid:¹H NMR(300 MHz,DMSO–d₆)δ7.87(d,J＝1.5Hz,1H),7.42-7.30(m,6H),6.11(q,J＝7.2Hz,1H),2.74(s,3H),2.23(s,3H),2.04(s,3H),1.94(d,J＝6.9Hz,3H)；ESIMS m/z 377[M+H]⁺。

step 2: using the procedure used in general procedure P, step 3, starting with the compound example compound 125(80mg,0.21mmol) gives example compound 143 as an off-white solid (53mg, 72%):¹H NMR(300MHz,DMSO–d₆)δ7.39-7.26(m,5H),6.23(d,J＝1.5Hz,1H),6.14(d,J＝1.2Hz,1H),5.86(q,J＝7.2Hz,1H),5.26(s,2H),2.58(s,3H),2.20(s,3H),2.02(s,3H),1.86(d,J＝6.9Hz,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(100mg,0.31mmol) and phosphorus (V) oxychloride (1mL) was heated to 110 ℃ for 5 hours and then cooled to room temperature. The mixture was concentrated, dissolved with dichloromethane (75mL) 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 (2.5mL), and 3-hydroxypyridine (109mg,1.15mmol) and potassium carbonate (175mg,1.27mmol) were added. The mixture was heated to 100 ℃ for 16 hours, then diluted with ethyl acetate (75mL), washed with brine (2 × 25mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford example compound 236(58mg, 47%) as a light brown solid:¹H NMR(300MHz,DMSO–d₆)δ8.74(d,J＝2.7Hz,1H),8.57(dd,J＝4.5,0.9Hz,1H),8.27(d,J＝1.8Hz,1H),8.02–7.98(m,2H),7.59(dd,J＝8.4,4.5Hz,1H),7.47(d,J＝6.9Hz,2H),7.42–7.30(m,3H),5.53(s,2H),2.40(s,3H),2.22(s,3H)；ESI m/z398[M+H]⁺。

preparation of 6- (3, 5-dimethylisoxazol-4-yl) -N-ethyl-4-nitro-1- (1-phenylethyl) -1H-benzo [ d]Imidazole-2-Amines (example Compound 127) and 6- (3, 5-Dimethylisoxazol-4-yl) -N²-ethyl-1- (1-phenylethyl) -1H-benzo [ d]Imidazole-2, 4-diamine (example Compound 134)

Step 1: to example compound 110(200mg,0.529mmol) was added phosphorus (V) oxychloride (2mL,21.5mmol) and N, N-dimethylformamide (one drop). The reaction was heated at 90 ℃ overnight. The mixture was concentrated and the residue was dissolved in tetrahydrofuran (5mL) and ethylamine (10mL,1M in tetrahydrofuran) was added. The reaction mixture was heated in a sealed tube at 70 ℃ for 2 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give example compound 127(40mg, 19%) as a yellow solid:¹H NMR(500MHz,CD₃OD)δ7.70(d,J＝1.5Hz,1H),7.45–7.30(m,5H),6.72(d,J＝1.5Hz,1H),5.86(q,J＝7.0Hz,1H),3.72(q,J＝7.2Hz,2H),2.17(s,3H),1.98(s,3H),1.90(d,J＝7.0Hz,3H),1.36(t,J＝7.2Hz,3H)；ESI m/z 406[M–H]⁺。

step 2: to a solution of example compound 127(35mg,0.086mmol) in tetrahydrofuran (10mL) was added sodium dithionite (90mg,0.52mmol) 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 boil, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in MeOH and taken up with concentrated NH₄The OH was basified, concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC further purification to give example compound 134 as an off-white solid (15mg, 47%):¹H NMR(500MHz,CD₃OD)δ7.40–7.25(m,5H),6.31(d,J＝1.5Hz,1H),5.92(d,J＝1.5Hz,1H),5.72(q,J＝6.9Hz,1H),3.53(q,J＝7.2Hz,2H),2.15(s,3H),1.99(s,3H),1.86(d,J＝7.0Hz,3H),1.33(t,J＝7.2Hz,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: example Compound 15(73mg,0.20mmol), CH₃I (85mg,0.60mmol) and K₂CO₃A mixture of (110mg,0.8mmol) in DMF (3mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (100mL) and washed with brine (3X 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated with EtOAc/hexanes to afford example compound 150 as a yellow solid (65mg, 86%):¹H NMR(300MHz,CDCl₃)δ7.48(d,J＝1.5Hz,1H),7.35–7.30(m,5H),6.84(d,J＝1.5Hz,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(57mg,0.15mmol) in THF (5mL) and water (4mL) was added Na₂S₂O₄(153mg,0.90 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1mL) was added, and the mixture was heated to reflux for 15 minutes. After cooling to room temperature, Na was slowly added₂CO₃To adjust to pH 9. CH for the mixture₂Cl₂Extraction (100mL), organic layer was washed with brine (50mL), filtered, concentrated and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to afford example compound 162 as a white solid (60mg, 72%):¹H NMR(300MHz,DMSO–d₆)δ7.36–7.24(m,5H),6.40(d,J＝1.5Hz,1H),6.39(d,J＝1.8Hz,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(100mg,0.25mmol), sodium methanesulfinate (39mg,0.38mmol), CuI (5mg,0.025mmol), L-proline (6mg,0.05mmol) and NaOH (2mg,0.05mmol) in DMSO (3mL) was heated in a microwave reactor at 150 ℃ for 2 hours. The mixture was diluted with ethyl acetate (100mL) and washed with brine (50 mL). The organic layer was washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 50-100% EtOAc/hexanes) to provide example compound 168 as an off-white solid (13mg, 13%):¹H NMR(300MHz,CDCl₃)δ7.75(d,J＝1.5Hz,1H),7.37–7.33(m,3H),7.24(d,J＝1.5Hz,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(4.4g,16.5mmol) in 1, 4-dioxane (100mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (4.4g,19.8mmol), Na₂CO₃(2.0M in H₂25mL,50.0mmol) and tetrakis (triphenylphosphine) palladium (0) (959mg,0.83 mmol). The reaction mixture was purged with nitrogen and heated at 80 ℃ for 16 hours. The mixture was diluted with EtOAc (100mL) and washed with brine (50 mL). The organic layer was washed with Na₂SO₄Dried and filtered. The filtrate was concentrated and then purified by chromatography (silica gel, 0-60% ethyl acetate/hexanes) to afford 78 as an off-white solid (2.64g, 57%):¹H NMR(300MHz,DMSO–d₆)δ7.71(s,1H),6.32(s,2H),2.22(s,3H),2.08(s,3H),2.02(s,3H)。

step 2: 78(1.3g,4.61mmol), benzylamine (2.51mL,23.05mmol), X-phos (658mg,1.38mmol), Pd₂(dba)₃A mixture of (632mg,0.69mmol) and t-BuOK (774mg,6.92mmol) in toluene (50mL) was purged with nitrogen for 10 minutes and then heated at 90 ℃ for 18 hours. The mixture was diluted with dichloromethane (200mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-100% EtOAc/hexanes) to afford 79 as a brown gel (125mg, 9%):¹H NMR(300MHz,DMSO–d₆)δ7.38(s,1H),7.31–7.22(m,5H),5.68(s,2H),4.28(t,J＝7.5Hz,1H),4.01(d,J＝7.0Hz,2H),2.14(s,3H),1.93(s,3H),1.74(s,3H)。

and step 3: AcOH (0.2mL) was added to a solution of 79(80mg,0.26mmol) in triethyl orthoacetate (2 mL). The mixture was heated to 120 ℃ for 2 hours. The mixture was concentrated, the residue dissolved in EtOAc (100mL) and washed with saturated NaHCO₃Washing (50 mL. times.2). The organic layer was washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/ethyl acetate) to provide example compound 181 as an off-white solid (39mg, 45%):¹H NMR(300MHz,CDCl₃)δ8.23(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(31mg,0.10mmol) and CDI (33mg,0.2mmol) in dioxane (3mL) was heated to 120 ℃ for 16 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 50-100% ethyl acetate/hexanes) to provide example compound 180 as an off-white solid (10mg, 30%):¹H NMR(300MHz,DMSO–d₆)δ11.89(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(660mg,3.23mmol) in acetonitrile (33mL) were added (1-bromoethyl) benzene (658mg,3.55mmol) and potassium carbonate (893mg,6.46 mmol). The mixture was heated to 60 ℃ for 16 hours, then cooled, diluted with dichloromethane (120mL) 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(256mg, 26%) as a white solid:¹HNMR(500MHz,DMSO–d₆)δ7.36(d,J＝1.5Hz,2H),7.30(t,J＝7.5Hz,2H),7.20–7.17(m,2H),6.15(d,J＝2.0Hz,1H),5.82(s,2H),5.40(d,J＝5.5Hz,1H),4.51–4.45(m,1H),2.05(s,3H),1.84(s,3H),1.48(d,J＝7.0Hz,3H)。

step 2: to a solution of 57(41mg,0.13mmol) in triethyl orthoacetate (0.24mL,1.33mmol) was added acetic acid (20. mu.L, 0.36 mmol). The mixture was heated to 100 ℃ for 1 hour, then a drop of concentrated HCl was added. The mixture was heated to 100 ℃ for 10 minutes. The mixture was basified with saturated sodium bicarbonate, diluted with dichloromethane (45mL) 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/hexane to afford example compound 108 as a white solid (11mg, 28%):¹H NMR(500MHz,DMSO–d₆)δ8.27(d,J＝2.0Hz,1H),7.44(d,J＝2.0Hz,1H),7.40–7.36(m,4H),7.33–7.30(m,1H),6.01(q,J＝7.0Hz,1H),2.70(s,3H),2.26(s,3H),2.06(s,3H),1.93(d,J＝7.0Hz,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(250mg,0.81mmol) in 1, 4-dioxane (6mL) was added 1,1' -carbonyldiimidazole (158mg,0.97 mmol). The mixture was purged with nitrogen for 5 minutes and then heated to 100 ℃ for 16 hours. The mixture was diluted with dichloromethane (100mL), filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with dichloromethane/hexane to afford example compound 112 as an off-white solid (258mg, 95%):¹H NMR(500MHz,DMSO–d₆)δ11.78(s,1H),7.87(d,J＝2.0Hz,1H),7.44(d,J＝7.5Hz,2H),7.36(t,J＝7.5Hz,2H),7.29(t,J＝7.5Hz,1H),7.09(d,J＝2.0Hz,1H),5.72(q,J＝7.0Hz,1H),2.26(s,3H),2.06(s,3H),1.84(d,J＝7.0Hz,3H)；ESI m/z 335[M+H]⁺。

step 2: a mixture of example compound 112(100mg,0.30mmol) and phosphorus (V) oxychloride (1mL) was heated to 110 ℃ for 5 hours and cooled to room temperature. The reaction mixture was concentrated, diluted with dichloromethane (75mL) 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 2.0M solution of ethylamine in tetrahydrofuran (6.0mL,12.0mmol) and the mixture was heated to 75 ℃ for 7 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) then triturated with ethyl acetate/hexane to afford example compound 113 as a white solid (52mg, 49%):¹H NMR(500MHz,DMSO–d₆)δ7.90(d,J＝2.0Hz,1H),7.40–7.28(m,6H),6.81(d,J＝2.0Hz,1H),5.84(q,J＝7.0Hz,1H),3.54–3.48(m,2H),2.20(s,3H),1.99(s,3H),1.83(d,J＝7.0Hz,3H),1.27(t,J＝7.0Hz,3H)；ESI m/z362[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(87mg) was prepared by SFC chiral HPLC (Chiralpak AS-H,30 mm. times.250 mm, mobile phase 30% in CO₂EtOH (0.2% Et)₂NH),120 bar, flow 80 mL/min) to afford example compound 218 (enantiomer a) (41mg, 46%) and example compound 219 (enantiomer B) (41mg, 46%) as an off-white solid.

Example compound 218 (enantiomer a):¹H NMR(500MHz,DMSO–d₆)δ11.77(s,1H),7.87(d,J＝2.0Hz,1H),7.44(d,J＝7.5Hz,2H),7.37(t,J＝7.5Hz,2H),7.29(t,J＝7.5Hz,1H),7.09(d,J＝2.0Hz,1H),5.72(q,J＝7.5Hz,1H),2.26(s,3H),2.06(s,3H),1.84(d,J＝7.5Hz,3H)；ESI m/z 335[M+H]⁺(ii) a HPLC (Chiralcel OD,4.6 mm. times.250 mm, 10% EtOH in heptane, 1 mL/min)>99％,t_R9.4 min.

Example compound 219 (enantiomer B):¹HNMR(500MHz,DMSO–d₆)δ11.78(s,1H),7.87(d,J＝1.5Hz,1H),7.44(d,J＝7.5Hz,2H),7.36(t,J＝7.5Hz,2H),7.29(t,J＝7.5Hz,1H),7.08(d,J＝2.0Hz,1H),5.72(q,J＝7.5Hz,1H),2.26(s,3H),2.06(s,3H),1.84(d,J＝7.5Hz,3H)；ESI m/z 335[M+H]⁺(ii) a HPLC (Chiralcel OD,4.6 mm. times.250 mm, 10% EtOH in heptane, 1 mL/min)>99％,t_R10.9 min.

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(214mg,0.77mmol) in 1, 4-dioxane (5mL) was added 1,1' -carbonyldiimidazole (150mg,0.93mmol) and the mixture was heated to 100 ℃ for 15 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate/hexanes) to afford 80 as a white solid (142mg, 61%);¹H NMR(500MHz,DMSO–d₆)δ11.13(s,1H),7.35–7.25(m,6H),7.12(dd,J＝8.5,2.0Hz,1H),6.94(d,J＝8.0Hz,1H),5.01(s,2H)。

step 2: to a solution of 80(100mg,0.33mmol) in 1, 4-dioxane (5mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (110mg,0.49mmol), potassium carbonate (91mg,0.66mmol) and water (1 mL). The mixture was purged with nitrogen for 10 minutes, tetrakis (triphenylphosphine) palladium (0) (19mg,0.016mmol) was added, and the mixture was heated to 90 ℃ for 16 hours. The mixture was diluted with dichloromethane (100mL) 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) then triturated with ethyl acetate/hexane to afford 81 as a white solid (55mg, 52%):¹H NMR(300MHz,DMSO–d₆)δ11.07(s,1H),7.40–7.23(m,5H),7.06(d,J＝8.1Hz,1H),7.02(s,1H),6.95(dd,J＝7.8,1.5Hz,1H),5.03(s,2H),2.30(s,3H),2.13(s,3H)；ESI m/z320[M+H]⁺。

and step 3: to a solution of 81(36mg,0.11mmol) in acetonitrile (3mL) were added potassium carbonate (109mg,0.79mmol) and iodoethane (80mg,0.56mmol), and the mixture was heated to 40 ℃ for 48 hours. The mixture was diluted with dichloromethane (75mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue is chromatographed (silica gel, 0-20% ethyl acetateEster/dichloromethane) and then triturated with ethyl acetate/hexane to afford example compound 122 as an off-white solid (14mg, 37%):¹H NMR(500MHz,DMSO–d₆)δ7.37(d,J＝7.5Hz,2H),7.33(t,J＝7.0Hz,2H),7.29(d,J＝8.0Hz,1H),7.26(t,J＝7.0Hz,1H),7.09(d,J＝1.5Hz,1H),7.03(dd,J＝8.0,1.5Hz,1H),5.08(s,2H),3.94(q,J＝7.0Hz,2H),2.31(s,3H),2.13(s,3H),1.26(t,J＝7.0Hz,3H)；ESI m/z 348[M+H]⁺。

preparation of 1-benzyl-N⁶- (3, 5-dimethylisoxazol-4-yl) -2-methyl-1H-benzo [ d]Imidazole-4, 6-diamine (example Compound 142)

Step 1: to a suspension of 33(790mg,3.09mmol) in acetonitrile (15mL) were added benzyl chloride (703mg,5.55mmol) and potassium carbonate (1.07g,7.71 mmol). The reaction mixture was heated to 60 ℃ for 16 hours, then concentrated, and the residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 82 as a yellow solid (813mg, 76%):¹H NMR(300MHz,DMSO–d₆)δ8.33(d,J＝1.8Hz,1H),8.12(d,J＝1.8Hz,1H),7.39–7.27(m,3H),7.13(d,J＝6.6Hz,2H),5.62(s,2H),2.60(s,3H)。

step 2: to a solution of 82(150mg,0.43mmol) in toluene (5mL) were added 83(73mg,0.65mmol), cesium carbonate (282mg,0.87mmol) and XPhos (41mg,0.087 mmol). The solution was purged with nitrogen for 5 minutes, then tris (dibenzylideneacetone) dipalladium (0) (40mg,0.043mmol) was added and heated to 110 ℃ 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(80mg, 49%) as a brown oil:¹H NMR(500MHz,DMSO–d₆)δ7.59(s,1H),7.34–7.28(m,4H),7.06(d,J＝7.0Hz,2H),6.76(d,J＝2.5Hz,1H),5.44(s,2H),2.54(s,3H),2.13(s,3H),1.91(s,3H)。

and step 3: to a solution of 84(78mg,0.21mmol) in tetrahydrofuran (5mL) was added vicinal-twoA solution of sodium sulfite (215mg,1.24mmol) in water (4 mL). The mixture was stirred at room temperature for 2 hours, then 2N HCl (1mL) 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 afford example compound 142 as a tan solid (38mg, 53%):¹H NMR(500MHz,DMSO–d₆)δ7.31(t,J＝7.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.04(d,J＝7.5Hz,2H),6.69(s,1H),5.73(d,J＝2.0Hz,1H),5.60(d,J＝2.0Hz,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 U:

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(100mg,0.29mmol) in 1, 4-dioxane (5mL) was added 5-methylisoxazole-4-boronic acid pinacol ester (91mg,0.43mmol), sodium carbonate (80mg,0.58mmol), water (1mL) and tetrakis (triphenylphosphine) palladium (0) (17mg,0.01 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 5 hours. The mixture was diluted with dichloromethane (70mL), washed with brine (25mL), 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 (4mL), a solution of sodium dithionite (159mg,0.91mmol) in water (2mL) was added and the mixture was stirred at room temperature for 2 hours. 2N HCl (1mL) was added to the mixture and the mixture was heated to reflux for 15 min. The mixture was basified by saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (40mL × 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/hexane to afford an off-white colorExample compound 201 as a solid (12mg, 25%):¹H NMR(300MHz,DMSO–d₆)δ8.69(d,J＝0.6Hz,1H),7.36–7.26(m,3H),7.15(d,J＝6.9Hz,2H),6.78(d,J＝1.5Hz,1H),6.47(d,J＝1.5Hz,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(1.5g,7.98mmol) in dichloromethane (80mL) was added benzaldehyde (931mg,8.78mmol) and acetic acid (40 drops). The mixture was stirred at room temperature for 16 hours, 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 (50mL) and sodium borohydride (815mg,21.5mmol) was added slowly. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane (100mL), washed with saturated sodium bicarbonate (40mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford 85 as an off-white solid (1.12g, 51%):¹H NMR(500MHz,DMSO–d₆)δ7.35–7.34(m,4H),7.28–7.23(m,2H),6.54(d,J＝2.0Hz,1H),5.78(s,2H),5.73(t,J＝5.5Hz,1H),4.30(d,J＝5.5Hz,2H)。

step 2: to a suspension of 85(970mg,3.49mmol) in triethyl orthoacetate (5.66g,37.9mmol) was added acetic acid (539 μ L,9.42 mmol). The mixture was heated to 100 ℃ for 40 minutes. The reaction mixture was basified with saturated sodium bicarbonate (8mL), diluted with dichloromethane (50mL) 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 as a light brown solid (305mg, 30%):¹H NMR(500MHz,DMSO–d₆)δ8.41(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.35(t,J＝7.0Hz,2H),7.30(t,J＝7.0Hz,1H),7.15(d,J＝7.0Hz,2H),5.52(s,2H),2.55(s,3H)。

and step 3: to a solution of 86(80mg,0.26mmol) in toluene (5mL) were added 83(44mg,0.40mmol), cesium carbonate (173mg,0.53mmol) and XPhos (25mg,0.053 mmol). The solution was purged with nitrogen for 5 minutes, then tris (dibenzylideneacetone) dipalladium (0) (24mg,0.026mmol) was added. The mixture was heated to 110 ℃ for 16 hours. The reaction mixture was diluted with dichloromethane (20mL), filtered through celite, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) followed by trituration with dichloromethane/hexane to afford example compound 155 as a light brown solid (40mg, 45%):¹HNMR(500MHz,DMSO–d₆)δ7.88(d,J＝2.5Hz,1H),7.34–7.30(m,3H),7.27(t,J＝7.0Hz,1H),7.05(d,J＝7.0Hz,2H),6.71(d,J＝2.5Hz,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(100mg,0.33mmol) in 1, 4-dioxane (5mL) was added 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1,2, 3-triazole (138mg,0.66mmol), K₂CO₃(137mg,0.99mmol), water (1mL), and tetrakis (triphenylphosphine) palladium (0) (19mg,0.02 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 16 hours. The mixture was diluted with ethyl acetate (70mL), washed with brine (25mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) followed by trituration with dichloromethane/hexane to afford example compound 206 as a white solid (14mg, 14%);¹H NMR(500MHz,DMSO–d₆)δ8.54(d,J＝2.5Hz,1H),8.27(d,J＝2.0Hz,1H),7.96(s,1H),7.35(t,J＝7.0Hz,2H),7.29(t,J＝7.0Hz,1H),7.21(d,J＝7.0Hz,2H),5.58(s,2H),4.07(s,3H),2.60(s,3H)；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 similar procedure as used for example compound 206 as an off-white solid:¹H NMR(500MHz,DMSO–d₆)δ8.48(d,J＝2.0Hz,1H),8.14(d,J＝2.0Hz,1H),7.50(d,J＝2.0Hz,1H),7.35(t,J＝7.0Hz,2H),7.29(t,J＝7.0Hz,1H),7.21(d,J＝7.0Hz,2H),6.46(d,J＝2.0Hz,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(100mg,0.340mmol) in 1, 4-dioxane (2mL) was added cyclopropanecarboxaldehyde (29mg,0.408mmol) and acetic acid (0.67 mL). The mixture was heated at 110 ℃ 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 as an off-white solid (68mg, 58%):¹HNMR(500MHz,DMSO–d₆)δ8.29(d,J＝2.1Hz,1H),7.95(d,J＝2.0Hz,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 percent. 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) -N₂-ethyl-1H-benzo [ d]Imidazole-2, 4-diamine (example Compound 160)

Step 1: to a mixture of 32(1.50g,6.46mmol) and 3(2.16g,9.70mmol) in 1, 4-dioxane (40mL) and water (4mL) was added potassium carbonate (1.79g,12.9mmol) and tetrakis (triphenylphosphine) palladium (0) (373mg,0.32 mmol). The reaction was stirred and heated at 90 ℃ for 17 hours. The reaction mixture was diluted with methanol (20mL) and silica gel (20g) 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 as a brown solid (585mg, 36%):¹H NMR(500MHz,CDCl₃)δ7.62(d,J＝2.0Hz,1H),6.81(d,J＝2.0Hz,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(250mg,1.01mmol), catalytic amount of DMAP and 1, 4-dioxane (4mL) in a pressure tube was added 1,1' -carbonyldiimidazole (327mg,2.01 mmol). The tube was sealed and heated to 80 ℃ for 17 hours. The reaction mixture was diluted with methanol (20mL) and silica gel (10g) was added. The suspension was concentrated to dryness and the resulting powder was supported on silica gel (40g) and eluted with 0-70% ethyl acetate in hexane. The clean product was concentrated to give 88 as an orange solid (167mg, 60%):¹H NMR(500MHz,CDCl₃)δ7.74(d,J＝1.5Hz,1H),7.17(d,J＝1.5Hz,1H),2.43(s,3H),2.28(s,3H)。

and step 3: to a solution of 88(309mg,1.13mmol), potassium carbonate (312mg,2.25mmol), acetonitrile (5mL) and DMF (2mL) in a pressure tube was added (bromomethyl) cyclopropane(183mg,1.35mmol) and the reaction was sealed and heated at 80 ℃ for 17 h. The material was cooled to room temperature and poured into saturated aqueous NaCl (30 mL). Ethyl acetate (100mL) was added and the layers were separated. The ethyl acetate layer was washed with saturated aqueous NaCl (2X 100mL) and Na₂SO₄Dry, filter and concentrate the filtrate. Will be at CH₂Cl₂The resulting oil in (10mL) was loaded on silica gel (80g) and eluted with 0-40% ethyl acetate in hexanes. The product was cleaned and then purified by washing with 10-90% hydrogen₂CH in O₃CN-eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 145 as a yellow solid (88mg, 35%):¹H NMR(500MHz,CD₃OD)δ7.82(d,J＝1.5Hz,1H),7.52(d,J＝1.0Hz,1H),3.87(d,J＝7.0Hz,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％。

and 4, step 4: a solution of example compound 145(171mg,0.521mmol) in phosphorus (V) oxychloride (4mL) was placed in a sealed tube and heated at 110 ℃ for 8 hours. The solvent was removed in vacuo and saturated NaHCO was added₃Aqueous solution (5 mL). The mixture was extracted with ethyl acetate (2X 20mL) and the combined extracts were taken over Na₂SO₄Dry, filter and concentrate the filtrate. THF (5mL) and a 2.0M solution of ethylamine in THF were then added and the reaction was heated at 70 ℃ for 12 hours. The reaction was concentrated to dryness and the residue was taken up in CH₂Cl₂(5mL) dilution. The resulting solution was supported on silica gel (40g) and eluted with 0-80% ethyl acetate in hexane. The product was cleaned and then purified by washing with 10-90% hydrogen₂CH in O₃CN-eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 159 as a yellow solid (105mg, 57%):¹H NMR(500MHz,CDCl₃)δ7.78(d,J＝1.5Hz,1H),7.44(d,J＝1.5Hz,1H),4.03(d,J＝6.5Hz,2H),3.67(q,J＝7.0Hz,2H),2.44(s,3H),2.29(s,3H),1.33(t,J＝7.0Hz,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％。

and 5: in thatA solution of example compound 145(59mg,0.215mmol) in THF (10mL) was added dropwise over 5 minutes to a solution of sodium dithionite (225mg,1.29mmol) in water (10 mL). The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. Aqueous 2N HCl (10mL) was added to the residue and heated to reflux for 5 minutes. After concentration to dryness, methanol (10mL) was added and saturated NaHCO was used₃Aqueous solution (15mL) the solution was adjusted to pH 8. Silica gel (10g) 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 product was cleaned and then purified by washing with 10-90% hydrogen₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 161 as a white solid (32mg, 50%):¹H NMR(500MHz,CD₃OD)δ6.49(d,J＝1.5Hz,1H),6.42(d,J＝1.5Hz,1H),3.75(d,J＝6.5Hz,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(90mg,0.253mmol) in THF (10mL) was added dropwise over 5 minutes to a solution of sodium dithionite (265mg,1.52mmol) in water (10 mL). The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. Aqueous 2N HCl (10mL) was added to the residue and heated to reflux for 5 minutes. After concentration to dryness, methanol (10mL) was added and saturated NaHCO was used₃Aqueous solution (15mL) the solution was adjusted to pH 8. Silica gel (10g) 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 product was then cleaned by passing it through a column of 10-90% hydrogen peroxide solution in H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC purification and freeze and lyophilize the clean fractions to give example compound 160 as a white solid (61mg, 74%):¹H NMR(500MHz,CD₃OD)δ6.49(d,J＝1.5Hz,1H),6.37(d,J＝1.5Hz,1H),3.88(d,J＝6.5Hz,2H),3.48(q,J＝7.0Hz,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(54mg,0.15mmol) in dichloromethane (5mL) was added boron tribromide (0.45mL,1M in dichloromethane, 0.45mmol) 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 is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC further purification to give example compound 129 as an off-white solid (31mg, 59%):¹H NMR(500MHz,CD₃OD)δ7.17(d,J＝8.6Hz,2H),6.72(d,J＝8.6Hz,2H),6.39(d,J＝1.3Hz,1H),6.26(d,J＝1.3Hz,1H),4.94(s,2H),2.28(s,3H),2.12(s,3H)；HPLC>99％,t_R11.0 minutes; 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(5.00g,32.5mmol) and triethylamine (9.04mL,65.0mmol) in N, N-dimethylformamide (150mL) was added tert-butylchlorodimethylsilane (5.86g,39.0mmol) 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, brine and thenDried over sodium sulfate and filtered. The filtrate was concentrated to provide 90 as a brown oil (8.59g, 98%):¹H NMR(300MHz,CDCl₃)δ7.75(dd,J＝1.3,8.9Hz,1H),6.89(dd,J＝1.2,7.6Hz,1H),6.53(dd,J＝8.8,7.6Hz,1H),6.45–6.15(bs,2H),1.03(s,9H),0.28(s,6H)。

step 2: to a solution of 90(8.59g,32.1mmol) in acetic acid (120mL) was added N-bromosuccinimide (6.28g,35.3mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated. The residue was dissolved in methanol and basified with 5% aqueous sodium bicarbonate. The precipitate formed was filtered, washed with water, and dried under vacuum to afford 91 as an orange solid (8.56g, 76%):¹H NMR(500MHz,CDCl₃)δ7.91(d,J＝2.1Hz,1H),6.96(d,J＝2.1Hz,1H),6.50–6.12(bs,2H),1.03(s,9H),0.30(s,6H)。

and step 3: to a solution of 91(5.00g,14.4mmol) in tetrahydrofuran (60mL) was added platinum carbon (1.00g, 5% Pt carbon). The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered, washed with MeOH, and the filtrate was concentrated to provide 92 as a dark brown oil (5.65g,>99％)：¹H NMR(500MHz,CDCl₃)δ6.51(d,J＝2.0Hz,1H),6.46(d,J＝2.0Hz,1H),3.50–2.50(bs,4H),1.01(s,9H),0.24(s,6H)；ESI m/z 317[M+H]⁺。

and 4, step 4: to a solution of 92(2.00g,6.31mmol) in ethanol (50mL) was added triethyl orthoacetate (3.07g,18.9mmol) and sulfamic acid (1mg,0.01 mmol). The reaction was heated in a sealed tube at 80 ℃ overnight. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford 93(2.07g, 96%) as a light red solid:¹H NMR(500MHz,CDCl₃)δ8.75(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]⁺。

and 5: a mixture of 93(200mg,0.587mmol), benzyl bromide (150mg,0.880mmol) and potassium bicarbonate (113mg,0.822mmol) in acetonitrile (20mL) was heated at 45 ℃ for 2 days. The reaction mixture was cooled to room temperature, concentrated and chromatographed (silica, 0-30%Ethyl acetate in hexanes) to afford 94 as a brown solid (303mg, 30%):¹HNMR(500MHz,CDCl₃)δ7.36–7.26(m,3H),7.01(d,J＝8.2Hz,2H),6.97(d,J＝1.6Hz,1H),6.81(d,J＝1.6Hz,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(75mg,0.17mmol) in 1, 4-dioxane (10mL) and water (1mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (58mg,0.26mmol), potassium bicarbonate (70mg,0.70mmol) and tetrakis (triphenylphosphine) palladium (0) (10mg,0.0087 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 2 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give 95 as an off-white solid (53mg, 70%):¹H NMR(500MHz,CD₃OD)δ7.33(t,J＝6.3Hz,2H),7.27(t,J＝5.1Hz,1H),7.14(d,J＝7.1Hz,2H),6.89(d,J＝1.3Hz,1H),6.58(d,J＝1.3Hz,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_R16.4 minutes; ESI M/z 448[ M + H ]]⁺。

And 7: a mixture of 95(48mg,0.11mmol) and potassium carbonate (30mg,0.22mmol) in acetonitrile (10mL) was heated in a sealed tube at 80 ℃ overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It is prepared by mixing 10-90% of the total weight of the above-mentioned raw materials with H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC further purification to give example compound 173 as an off-white solid (32mg, 87%):¹H NMR(500MHz,DMSO–d₆)δ9.84(s,1H),7.33(t,J＝7.6Hz,2H),7.26(t,J＝7.3Hz,1H),7.18(d,J＝7.1Hz,2H),6.86(d,J＝1.3Hz,1H),6.47(d,J＝1.3Hz,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(34mg,0.10mmol) and Lawson's reagent (202mg,0.5mmol) was heated to 180 ℃ 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 (C)₁₈,10–70％CH₃CN/water) to give example compound 177 as an off-white solid (13mg, 37%):¹H NMR(300MHz,DMSO–d₆)δ12.56(s,1H),7.45–7.42(m,2H),7.34–7.25(m,3H),6.44(d,J＝1.2Hz,1H),6.39(d,J＝1.5Hz,1H),5.44(s,4H),2.29(s,3H),2.11(s,3H)；ESI m/z351[M+H]⁺。HPLC 98.6％

preparation of 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 similar procedure as 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: mixing 96(70mg,0.20mmol) and CH₃I (85mg,0.60mmol) and K₂CO₃A mixture of (110mg,0.8mmol) in DMF (3mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (100mL) and washed with brine (3X 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(50mg, 68%) as a yellow solid:¹H NMR(300MHz,CDCl₃)δ7.66(d,J＝1.5Hz,1H),7.50(d,J＝1.8Hz,1H),7.36–7.30(m,5H),7.02(d,J＝1.5Hz,1H),6.27(d,J＝1.2Hz,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(45mg,0.12mmol) in THF (5mL) and water (4mL) was added Na₂S₂O₄(129mg,0.74 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na was added slowly₂CO₃To adjust to pH 9. CH for the mixture₂Cl₂Extraction (100mL), organic layer was washed with brine (50mL), filtered, concentrated and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to afford example compound 199(37mg, 90%) as a white solid:¹H NMR(300MHz,DMSO–d₆)δ7.39(d,J＝1.8Hz,1H),7.35–7.24(m,5H),6.56(d,J＝1.5Hz,1H),6.54(d,J＝1.5Hz,1H),6.20(d,J＝1.8Hz,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 mixture of 28(100mg,0.34mmol) and tetrahydro-2H-pyran-4-carboxylic acid (65mg,0.51mmol) in CH₂Cl₂EDC (131mg,0.68mmol) and i-Pr were added to the solution₂NEt (132mg,1.02mmol) and DMAP (10 mg). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100mL), with brine (50mL) and saturated NaHCO₃(50mL) washed. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in AcOH (2mL) and heated to reflux for 5 hours. The mixture was concentrated and the residue was dissolved in EtOAc (100mL) and saturated NaHCO₃(2X 50mL) 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 as a light brown solid (47mg, 36%):¹H NMR(300MHz,CDCl₃)δ8.41(d,J＝1.8Hz,1H),7.38–7.32(m,3H),7.24(d,J＝2.1Hz,1H),7.08–7.05(m,2H),5.42(s,2H),4.12(dd,J＝11.7,1.8Hz,2H),3.52(td,J＝11.7,1.8Hz,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(300mg,1.02mmol) and methyl 2,2, 2-trimethoxyacetate (1.5mL) was heated to 120 ℃ for 16 hours. The mixture was purified by chromatography (silica gel, 20-80% EtOAc/hexanes) to give a brown solid. Dissolving the solid in CH₃NH₂In THF (2M) (3mL) and heated at 80 ℃ for 16 h. The mixture is concentrated and the residue is chromatographed (C)₁₈,10–70％CH₃CN/water) to give example compound 221 as an off-white solid (45mg, 12%):¹H NMR(300MHz,DMSO–d₆)δ8.31(q,J＝4.5Hz,1H),8.27(d,J＝1.8Hz,1H),7.54(d,J＝1.8Hz,1H),7.36–7.24(m,5H),5.54(s,2H),3.00(d,J＝4.8Hz,3H),2.21(s,3H),2.00(s,3H)；ESI m/z362[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(1.14g,4.09mmol) in 1, 4-dioxane (41mL) was added 1,1' -carbonyldiimidazole (796mg,4.91 mmol). The reaction mixture was heated at 110 ℃ for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded 97(1.03g, 83%) as a white solid:¹H NMR(500MHz,DMSO–d₆)δ11.89(s,1H),8.00(d,J＝2.0Hz,1H),7.68(d,J＝2.0Hz,1H),7.37–7.32(m,4H),7.30–7.26(m,1H),5.02(s,2H)。

step 2: to a solution of 97(334mg,1.09mmol) in 1, 4-dioxane (11mL) was added 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (457mg,2.20mmol), sodium carbonate (1.0M in H)₂3.29mL,3.29mmol) and tetrakis (triphenylphosphine) palladium (0) (127mg,0.1mmol) in O. The reaction mixture was purged with nitrogen and heated at 90 ℃ for 32 hours. The mixture was diluted with dichloromethane (80mL), washed with brine (40mL), 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 afford example compound 171(173mg, 52%) as a white solid:¹H NMR(500MHz,DMSO–d₆)δ11.87(s,1H),8.04(d,J＝1.5Hz,1H),7.57(d,J＝1.5,1H),7.46(d,J＝2.0Hz,1H),7.38(d,J＝7.5Hz,2H),7.34(t,J＝7.5Hz,2H),7.27(t,J＝7.0Hz,1H),6.37(d,J＝1.5Hz,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)

A solution of example compound 39(100mg,0.29mmol) in EtOH (3mL) and AcOH (1mL) was added to iron powder (162mg,2.9 mmol). The reaction mixture was heated at 80 ℃ for 1 hour. It was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) afforded example compound 99(28mg, 27%) as a red solid:¹HNMR(300MHz,DMSO–d₆)δ10.2(s,1H),8.32(d,J＝1.8Hz,1H),8.23(s,1H),7.97(d,J＝1.8Hz,1H),7.32–7.25(m,5H),5.45(s,2H),2.40(s,3H),2.22(s,3H),2.12(s,3H)；ESI MSm/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 example compound 39(100mg,0.29mmol) in EtOH (3mL) and H₂SO₄Iron powder (162mg,2.9mmol) was added (0.5 mL). The reaction mixture was heated at 80 ℃ for 1 hour. It was diluted with EtOH (20mL) and adjusted to pH7 with 6N aqueous NaOH. The mixture was filtered through a layer of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) afforded example compound 100(12mg, 13%) as a red solid:¹H NMR(300MHz,DMSO–d₆)δ8.18(d,J＝1.8Hz,1H),7.82(d,J＝1.8Hz,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 (1.00g,4.54mmol), ethyl 2- (benzylamino) acetate (0.87g,4.5mmol) and potassium carbonate (0.78g,5.7mmol) in ethanol (15mL) and water (11mL) was heated at 85 ℃ for 10 hours, 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(1.28g, 72%) as an orange solid:¹H NMR(300MHz,DMSO–d₆):δ7.57(d,J＝8.6Hz,1H),7.37–7.21(m,6H),6.97(dd,J＝8.7,2.0Hz,1H),4.52(s,2H),3.40(s,2H)。

step 2: to a solution of 99(1.28g,3.51mmol) in acetic acid (14mL) was added iron (470mg,8.4mmol) at room temperature and the resulting slurry was heated to 90 ℃ for 2.25 hours. The mixture was cooled to room temperature and filtered through celite, dichloromethaneAnd (5) washing with alkane. 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 as a white solid (430mg, 39% yield):¹H NMR(300MHz,CDCl₃)δ8.74(br s,1H),7.39–7.26(m,5H),6.89–6.85(m,2H),6.62(d,J＝8.0Hz,2H),4.39(s,2H),3.80(s,2H)。

and step 3: using a procedure similar to that used for example compound 7, step 1, on compound 100, example compound 156 was obtained as a white solid:¹H NMR(500MHz,DMSO–d₆)δ10.58(s,1H),7.38–7.34(m,4H),7.30–7.23(m,1H),6.87(d,J＝7.9Hz,1H),6.65(d,J＝7.9Hz,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 similar to that used for example compound 7, step 1, on compound 100, example compound 166 was obtained as a white solid:¹H NMR(500MHz,DMSO–d₆)δ10.62(s,1H),7.37–7.33(m,5H),7.29–7.25(m,1H),6.90(d,J＝7.9Hz,1H),6.80(dd,J＝7.9,1.8Hz,1H),6.70(d,J＝1.6Hz,1H),6.18(d,J＝1.8Hz,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 (0.50g,2.3mmol), (R) -methyl 2- (benzylamino) propionate (0.55g,2.3mmol) and potassium carbonate (0.47g,3.4mmol) in ethanol (8mL) and water (6mL) was heated at 85 deg.C for 10 hours, 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 viscous orange solid (not weighed; used directly in the next step).

Step 2: using a procedure similar to that used for example compound 156, step 2, on compound 101 gave compound 102 as a white solid (430mg, 39% yield):¹H NMR(500MHz,DMSO–d₆)δ10.57(br s,1H),7.39–7.25(m,5H),6.87–6.66(m,3H),4.60(d,J＝15.5Hz,1H),4.29(d,J＝15.2Hz,1H),3.85(q,J＝6.9Hz,1H),1.08(d,J＝6.7Hz,3H)。

and step 3: using a procedure similar to that used for example compound 156, step 3, on compound 102 gave example compound 174 as an off-white solid:¹H NMR(500MHz,DMSO-d₆)δ10.53(s,1H),7.37–7.32(m,4H),7.26–7.23(m,1H),6.88(d,J＝7.9Hz,1H),6.66(dd,J＝7.9,1.7Hz,1H),6.42(d,J＝1.5Hz,1H),4.54(d,J＝15.6Hz,1H),4.37(d,J＝15.7Hz,1H),3.98(q,J＝6.7Hz,1H),2.11(s,3H),1.93(s,3H),1.12(d,J＝6.7Hz,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 26(2.00g,10.6mmol) in dry CH₂Cl₂(50mL) A stirred solution was added glacial acetic acid (0.61mL,10.8mmol) and cyclopropanecarboxaldehyde (0.81mL,12.3mmol). The solution was stirred at room temperature for 1 hour and cooled to 0 ℃. Sodium borohydride (1.21g,31.8mmol) was added carefully and the reaction was warmed to room temperature. After stirring at room temperature for 15 hours, saturated NaHCO was added₃The aqueous solution (20mL) was basified and the mixture was then treated with CH₂Cl₂Extraction (2X 100 mL). The combined dichloromethane layers were washed with Na₂SO₄Dry, filter and concentrate the filtrate to a brown residue. The residue is treated with CH₂Cl₂Diluted (20mL), the solution was loaded on silica gel (120g) and eluted with 0-70% ethyl acetate in hexanes to afford 103 as a yellow solid (330mg, 13%):¹H NMR(500MHz,CDCl₃)δ7.62(d,J＝2.0Hz,1H),6.83(d,J＝1.5Hz,1H),4.17(br s,2H),3.39(br s,1H),2.90(d,J＝5.0Hz,1H),2.89(d,J＝5.0Hz,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(300mg,1.24mmol) and 3(415mg,1.86mmol) in 1, 4-dioxane (10mL) and water (2.5mL) was added potassium carbonate (343mg,2.48mmol) and tetrakis (triphenylphosphine) palladium (0) (76mg,0.062 mmol). The reaction was stirred and heated at 90 ℃ for 17 hours. The mixture was diluted with methanol (20mL) and silica gel (10g) was added. The suspension was concentrated to dryness and the resulting powder was supported on silica gel (80g) and eluted with 0-80% ethyl acetate in hexane. The clean product was concentrated to give 104 as a yellow solid (312mg, 97%):¹H NMR(500MHz,CDCl₃)δ7.48(d,J＝1.5Hz,1H),6.61(d,J＝1.5Hz,1H),4.27(br s,2H),3.39(br s,1H),2.92(t,J＝6.0Hz,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)。

and step 3: to a solution of 104(310mg,1.20mmol), catalytic amount of DMAP and 1, 4-dioxane (4mL) in pressure tube was added 1,1' -carbonyldiimidazole (390mg,2.40 mmol). The tube was sealed and heated to 80 ℃ for 2 hours. The reaction mixture was diluted with methanol (20mL) and silica gel (10g) was added. The suspension was concentrated to dryness and the resulting powder was supported on silica gel (40g) and eluted with 0-80% ethyl acetate in hexane. The clean product was concentrated to give 1- (cyclopropylmethyl) -6- (3, 5-dimethylisoxazol-4-yl) -1H-imidazo [4,5-b as a yellow solid]Pyridine-2 (3)H) -ketone (275mg, 81%). 50mg of the sample was then passed through a column of 10-90% H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC purification and freeze and lyophilize the clean fractions to give example compound 118 as a white solid (37 mg):¹H NMR(500MHz,CD₃OD)δ7.90(d,J＝1.5Hz,1H),7.50(d,J＝1.5Hz,1H),3.81(d,J＝7.0Hz,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]⁺。

and 4, step 4: a solution of example compound 118(220mg,0.774mmol) in phosphorus (V) oxychloride (3mL) was placed in a sealed tube and heated at 110 ℃ for 6 hours. The solvent was removed in vacuo and saturated NaHCO was added₃Aqueous solution (5 mL). The mixture was extracted with ethyl acetate (2X 20mL) and the combined extracts were taken over Na₂SO₄Dry, filter and concentrate the filtrate. THF (5mL) and a 2.0M solution of ethylamine in THF (6mL,12.0mmol) were then added and the reaction heated at 70 ℃ for 17 hours. The reaction was concentrated to dryness and the residue was taken up in CH₂Cl₂(5mL) dilution. The resulting solution was supported on silica gel (40g) and eluted with 0-80% ethyl acetate in hexane. The product was then cleaned by passing it through a column of 10-90% hydrogen peroxide solution in H₂CH in O₃CN-eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 131 as a white solid (91mg, 38%):¹HNMR(500MHz,CDCl₃)δ7.93(d,J＝2.0Hz,1H),7.48(d,J＝1.5Hz,1H),3.98(d,J＝6.5Hz,2H),3.57(q,J＝7.0Hz,2H),2.42(s,3H),2.26(s,3H),1.30(t,J＝7.0Hz,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: 2, 3-diamino-5-bromopyridine (10.0g,0.053mol), cyclohexanecarboxaldehyde (6.08g,0.054mol) and glacial acetic acid (3.05mL) were added to dry CH₂Cl₂The mixture in (250mL) was stirred at room temperature for 1.5 h. Sodium borohydride (6.06g,0.159mol) was added portionwise over 20 minutes and the mixture was stirred at room temperature for 17 hours. Adding saturated NaHCO₃Aqueous solution until the mixture reached pH8(70mL) and the aqueous layer was washed with CH₂Cl₂(100mL) was extracted. To merge CH₂Cl₂The layers were combined, washed with water (500mL) and Na₂SO₄Dried, filtered and concentrated. The brown solid was dissolved in methanol (100mL) and silica gel (40g) 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/CH)₂Cl₂) Purified to afford 105a as a brown-gray solid (1.30g, 9%):¹H NMR(500MHz,CDCl₃)δ7.60(d,J＝2.0Hz,1H),6.85(d,J＝2.0Hz,1H),4.11(br s,2H),3.28(br s,1H),2.88(d,J＝5.0Hz,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 with cyclopentanecarboxaldehyde, 105b was prepared (14% yield; brown grey solid):¹H NMR(500MHz,CDCl₃)δ7.60(d,J＝2.0Hz,1H),6.86(d,J＝2.0Hz,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 with cyclobutanecarboxaldehyde, 105c was prepared (15% yield; brown-grey solid):¹H NMR(500MHz,CDCl₃)δ7.61(d,J＝2.0Hz,1H),6.86(d,J＝2.0Hz,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 105a (500mg,1.76mmol), 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (589mg,2.64mmol), potassium carbonate (4 mg,2.64mmol)A mixture of 87mg,3.52mmol), water (4mL) and 1, 4-dioxane (16mL) was added tetrakis (triphenylphosphine) palladium (0) and the mixture was heated to 90 ℃ for 17 hours. The biphasic mixture was diluted with methanol (20mL) and silica gel was added. After concentration to dryness, the material was purified by chromatography (silica gel, 0-80% EtOAc/hexanes) to afford 106a as a brown solid (551mg, 99%):¹H NMR(500MHz,CDCl₃)δ7.47(d,J＝2.0Hz,1H),6.62(d,J＝2.0Hz,1H),4.25(br s,2H),3.34(br s,1H),2.92(t,J＝6.0Hz,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 with 105b, 106b was prepared (96% yield; brown-grey solid):¹H NMR(500MHz,CDCl₃)δ7.47(d,J＝1.5Hz,1H),6.64(d,J＝1.5Hz,1H),4.25(br s,2H),3.28(br s,1H),2.99(t,J＝6.0Hz,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 with 105c, 106c was prepared (95% yield; brown grey solid):¹H NMR(500MHz,CDCl₃)δ7.65(d,J＝1.5Hz,1H),6.64(d,J＝2.0Hz,1H),4.26(br s,2H),3.18(br s,1H),3.09(t,J＝6.0Hz,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)。

and step 3: a solution of 106a (100mg,0.33mmol), triethyl orthoacetate (5mL) and glacial acetic acid (0.10mL) was heated in a sealed tube at 80 ℃ for 24 h. The mixture was evaporated to dryness and methanol (10mL), saturated NaHCO, was added₃Aqueous solution (5ml) and silica gel (10 g). After concentration to dryness the resulting powder was loaded on silica gel and eluted with 0-5% methanol in dichloromethane. The product was cleaned and then purified by washing with 10-90% hydrogen₂CH in O₃CN-eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 191(56mg, 52%) as a white solid:¹H NMR(500MHz,CD₃OD)δ8.30(d,J＝1.5Hz,1H),7.96(d,J＝2.0Hz,1H),4.14(d,J＝7.5Hz,2H),2.69(s,3H),2.44(s,3H),2.28(s,3H),1.95–1.82(m,1H),1.76–1.50(m,5H),1.29–1.07(m,5H)；ESIm/z 325[M+H]⁺。

starting with 106b, example compound 192(31mg, 29%) was prepared as a white solid:¹H NMR(500MHz,CD₃OD)δ8.30(d,J＝2.0Hz,1H),7.98(d,J＝2.0Hz,1H),4.26(d,J＝8.0Hz,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 with 106c, example compound 193(33mg, 30%) was prepared as a white solid:¹H NMR(500MHz,CD₃OD)δ8.30(d,J＝1.5Hz,1H),8.00(d,J＝1.5Hz,1H),4.33(d,J＝7.0Hz,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)；ESIm/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 (1.30g,4.54mmol), 1' -carbonyldiimidazole (1.47g) and N, N-dimethylaminopyridine (5mg) in 1, 4-dioxane (16mL) was heated at 80 ℃ for 2 hours and cooled to room temperature. Silica gel (10g) and methanol (20mL) were added to the mixture and the suspension was concentrated to a dry powder. This material was supported on silica gel (80g) and eluted with 0-90% ethyl acetate in hexanes to give 1.08g (76%) of example compound 202 as a yellow solid. 100mg of the product sample was then purified by mixing with 10-90% H₂CH in O₃CN eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 202 as a white solid:¹H NMR(500MHz,CD₃OD)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 with 106c, example compound 203 (76% yield, white solid) was synthesized in analogy to example compound 202:¹H NMR(500MHz,CD₃OD)δ7.89(d,J＝1.5Hz,1H),7.46(d,J＝2.0Hz,1H),3.94(d,J＝7.0Hz,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(175mg,0.56mmol) and phosphorus (V) oxychloride (4mL) was heated to 110 ℃ for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO was added₃Aqueous solution (5mL) and ethyl acetate (20 mL). Separating the ethyl acetate layer over Na₂SO₄Dry, filter and concentrate the filtrate to a dark yellow solid. The solid was dissolved in THF (5mL) and morpholine (732mg,8.40mmol) was added. The stirred solution was heated to 70 ℃ for 17 hours. Silica gel (5g) and methanol (20mL) were added to the cooled mixture and the suspension was concentrated to a dry powder. The material was supported on silica gel (40g) and eluted with 0-3% methanol in dichloromethane to give 143mg (67%) of the product as an off-white solid. The product samples were then purified by mixing with 10-90% H₂CH in O₃CN eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example compound 208 as a white solid:¹H NMR(500MHz,CD₃OD)δ8.17(d,J＝1.5Hz,1H),7.81(d,J＝2.0Hz,1H),4.14(d,J＝7.5Hz,2H),3.87(t,J＝5.0Hz,4H),3.41(t,J＝5.0Hz,4H),2.58–2.49(m,1H),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).ESIm/z 382[M+H]⁺。

example compound 209 was synthesized using a procedure similar to that used for example 208; example compound 209(166mg, 84%) was harvested as a white solid:¹H NMR(500MHz,CD₃OD)δ8.00(d,J＝1.5Hz,1H),7.59(d,J＝1.5Hz,1H),4.42–4.37(m,4H),4.01(d,J＝8.0Hz,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 harvested as a white solid (176mg, 82% yield):¹H NMR(500MHz,CD₃OD)δ8.16(d,J＝1.5Hz,1H),7.80(d,J＝2.0Hz,1H),4.24(d,J＝7.0Hz,2H),3.88(t,J＝5.0Hz,4H),3.41(t,J＝5.0Hz,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 harvested as a white solid (180mg, 91% yield):¹H NMR(500MHz,CD₃OD)δ7.99(d,J＝2.0Hz,1H),7.61(d,J＝2.0Hz,1H),4.38(m,4H),4.10(d,J＝7.0Hz,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)。ESIm/z 338[M+H]⁺. Preparation of 1- (cyclopentylmethyl) -6- (3, 5-dimethylisoxazole-4-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-b]Pyridin-2-ylamine (example 222)

A solution of example 202(175mg,0.56mmol) and phosphorus (V) oxychloride (4mL) was heated to 110 ℃ for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO was added₃Aqueous solution (5mL) and ethyl acetate (20 mL). Separating the ethyl acetate layer over Na₂SO₄Dry, filter and concentrate the filtrate to a dark yellow solid. The solid was dissolved in propionitrile (5mL) and 4-aminotetrahydropyran (283mg,28.0mmol) was added and the stirred solution was heated to 180 ℃ in a microwave reactor for 6 hours. Silica gel (10g) and methanol (20mL) were added to the cooled mixture and the suspension was concentrated to a dry powder. The material was supported on silica gel (40g) and eluted with 0-3% methanol in dichloromethane to give a yellow solid. The material is then processed by mixing with 10-90% of hydrogen₂CH in O₃CN eluted Polaris column reverse phase HPLC purification and the clean fractions were frozen and lyophilized to give example 222 as a white solid (70mg, 31%):¹H NMR(500MHz,CD₃OD)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＝11.75Hz,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 use and use with example Compound 222Procedure analogous procedure synthesis. Example compound 223 was harvested as a white solid (45mg, 20% yield):¹H NMR(500MHz,CD₃OD)δ7.93(d,J＝2.0Hz,1H),7.52(d,J＝2.0Hz,1H),4.17–4.05(m,1H),4.10(d,J＝7.5Hz,2H),4.03–3.97(m,2H),3.56(t,J＝11.75Hz,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(136mg,0.627mmol) in THF (6mL) was added di-tert-butyl dicarbonate (137mg,0.627mmol) and the reaction was stirred at room temperature for 16 h. The reaction was then concentrated and the residue was purified by chromatography (silica gel, 0-25% ethyl acetate/hexanes) to afford an off-white solid, which was dissolved in CH₂Cl₂(3mL) was added to CH₂Cl₂Benzaldehyde in (2mL) before addition of AcOH (2 drops). The reaction was stirred at room temperature for 1 hour and NaBH (OAc) was added₃(283mg,1.34 mmol). The reaction was then stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO₃Quenching and use of CH₂Cl₂Extraction (2X 50 mL). The combined organic solution was washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 108 as an off-white solid (97mg, 38%):¹H NMR(500MHz,DMSO–d₆)δ8.43(s,1H),7.32–7.26(m,4H),7.23–7.00(m,1H),6.95(s,2H),4.87(t,J＝6.9Hz,1H),4.31(d,J＝6.9Hz,2H),3.64(s,3H),1.42(s,9H)。

step 2: to the solution of 108(135mg,0.332mmol) in CH₂Cl₂(5mL) solution at 0 deg.C TFA (0.51mL,6.63mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. The reaction was then concentrated to afford 109(114mg, 90%): ESIm/z 385[ M + H ]]⁺。

And step 3: using the procedure used in general procedure B, step 1, starting with compound 109(114mg,0.296mmol) gives example compound 241 as an off-white solid (45mg, 38%):¹H NMR(300MHz,DMSO–d₆)δ7.72(d,J＝8.4Hz,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(3.00g,10.8mmol) in 1, 4-dioxane (60mL) and water (6mL) was added 3, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (2.90g,13.0mmol), tetrakis (triphenylphosphine) palladium (0) (624mg,0.54mmol) and potassium carbonate (2.98g,21.6 mmol). The reaction mixture was purged with nitrogen and heated at 90 ℃ for 18 hours. The mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to afford 110 as a yellow solid (3.18g, 99%):¹H NMR(500MHz,CDCl₃)δ7.38(d,J＝8.3Hz,2H),7.34(t,J＝7.3Hz,2H),7.28(t,J＝7.1Hz,1H),6.78(d,J＝7.8Hz,1H),6.55(dd,J＝1.8,7.7Hz,1H),6.43(d,J＝1.8Hz,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(100mg,0.34mmol) in acetic acid (2mL) was added methyl 2,2, 2-trichloroacetimidate (66mg,0.38mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then water was added. The precipitate formed was harvested by filtration, the filter cake was washed with water and dried under vacuum at 40 ℃ to afford 111 as an off-white solid (110mg, 77%):¹H NMR(300MHz,DMSO-d₆)δ7.93(dd,J＝0.4,8.4Hz,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(100mg,0.238mmol) in ethanol (1mL) was added concentrated ammonium hydroxide (1 mL). The reaction mixture was heated at 120 ℃ 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 hexane then to 20% methanol in ethyl acetate) followed by 10-90% in H₂CH in O₃CN eluted Polaris C₁₈Column reverse phase HPLC to provide example compound 243(21mg, 25%) and example compound 244(29mg, 35%) as off white solids. Example compound 243:¹H NMR(500MHz,DMSO-d₆)δ7.77(d,J＝8.3Hz,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]⁺(ii) a Example compound 244:¹H NMR(500MHz,DMSO-d₆)δ8.38(s,1H),7.92(s,1H),7.82(d,J＝8.5Hz,1H),7.63(d,J＝1.0Hz,1H),7.33–7.28(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(500mg,1.57mmol) and phosphorus (V) oxychloride (2mL) was heated to 100 ℃ for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO was added₃Aqueous solution (5mL) and ethyl acetate (20 mL). Separating the ethyl acetate layer over Na₂SO₄Dried, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford 112(415mg, 78%) as a light brown oil: ESI M/z 338[ M + H ]]⁺。

Step 2: 112(20mg,0.06mmol)Pyridine-3-amine (28mg,0.30mmol) and p-TsOH. H₂A mixture of O (22mg,0.12mmol) in NMP was heated in a microwave reactor at 190 ℃ for 2 hours. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to provide 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(1.20g,4.51mmol) and hydrazine monohydrate (3.27mL,67.65mmol) in EtOH (20mL) 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 as an off-white solid (1.02g, 85%):¹H NMR(300MHz,DMSO-d₆)δ9.74(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(500mg,1.88mmol) and ethyl isocyanate (160mg,2.26mmol) in THF was stirred at room temperature for 5 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to afford 115 as a white solid (610mg, 96%):¹H NMR(300MHz,DMSO-d₆)δ10.09(s,1H),8.57(s,1H),8.14(s,1H),7.81–7.79(m,2H),7.72(d,J＝8.4Hz,1H),7.38–7.28(m,5H),6.47(t,J＝5.4Hz,1H),5.55(s,2H),3.09–3.00(m,2H),1.00(t,J＝7.2Hz,3H)。

and step 3: a suspension of 115(337mg,1.0mmol) in 3N NaOH (5mL) was heated to reflux for 16 h. The mixture was adjusted to pH8 with 2N HCl, then CH₂Cl₂Extraction (3X 50 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated. The residue was taken up in EtOAc/CH₂Cl₂Example compound 249 milled to provide an off-white solid:¹HNMR(300MHz,DMSO-d₆)δ11.85(s,1H),8.59(s,1H),7.81–7.76(m,2H),7.43(dd,J＝8.1,1.5Hz,1H),7.35–7.28(m,5H),5.58(s,2H),3.63(q,J＝7.2,Hz2H),0.98(t,J＝7.2Hz,3H)；ESI m/z 320[M+H]⁺。

table 2: EXAMPLES Compounds

Example 1: inhibition of tetraacetylhistone H4 in combination with BET bromodomain alone

Proteins were 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 recombinant expression vectors encoding N-terminal nickel affinity-tagged bromodomains from Brd2, Brd3, Brd 4. Cell cultures were incubated at 37 ℃ to the appropriate density with shaking and induced overnight with IPTG. The supernatant of the lysed cells was loaded onto a Ni-IDA column for purification. Fractions were eluted for protein, concentrated and further purified by size exclusion chromatography. Fractions represent fractions of monomeric protein, concentrated, aliquoted and frozen at-80 ℃ for use in subsequent experiments.

Binding of tetraacetylhistone H4 to the BET bromodomain was confirmed by the time-resolved fluorescence resonance energy transfer (TR-FRET) method. The N-terminal His-tagged bromodomain (200nM) and biotinylated tetraacetylhistone H4 peptide (25-50nM, Millipore) were incubated in white 96-well microtiter plates (Greiner) in the presence of europium cryptate-tagged streptavidin (Cisbio catalog No. 610SAKLB) and XL 665-tagged monoclonal anti-His antibody (Cisbio catalog No. 61 HISXLB). For inhibition assays, serial dilutions will be usedTest compounds of (2%) were added to these reactions at 0.2% final DMSO concentration. The final buffer concentration was 30mM HEPES pH7.4, 30mM NaCl, 0.3mM CHAPS, 20mM phosphate pH7.0, 320mM KF, 0.08% BSA). After 2 hours incubation at room temperature, fluorescence was measured by FRET by SynergyH4 plate reader (Biotek) at 665 and 620 nm. Illustrative results for the first Brd4 bromodomain are shown below. Binding inhibition activity was shown by a decrease in 665nm fluorescence relative to 620 nm. Determination of IC from dose response curves₅₀The value is obtained.

IC₅₀Compounds with values less than or equal to 0.3 μ M are considered to be highly active (+++); IC (integrated circuit)₅₀Compounds with values of 0.3 to 3 μ M were considered to be very active (++); IC (integrated circuit)₅₀Compounds with values of 3 to 30. mu.M were considered active (+).

Table 3: inhibition of tetraacetylhistone 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) at 2.5X10⁴The density of individual cells/well was seeded in 96-well U-shaped bottom plates and treated with increasing concentrations of test compound or DMSO (0.1%) in IMDM medium containing 10% FBS and penicillin/streptomycin and incubated for 3 hours at 37 ℃. Triplicate wells were used for each concentration. Cells were pelleted by centrifugation and harvested using the mRNA Catcher PLUS kit according to the manufacturer's instructions. The isolated eluted mRNA was then used to use RNA UltraSense^TMComponents of a one-step kit (Life Technologies) along with Applied Biosystems for cMYC and cyclophilinPrimer-probe one-step quantitative real-time PCR reaction. Real-time PCR plate in VIa^TM7 run on real-time PCR instruments (Applied Biosystems), analyze the data, normalize Ct values of cMYC to internal controls, and then determine the fold expression of each sample relative to the controls.

IC₅₀Compounds with values less than or equal to 0.3 μ M are considered to be highly active (+++); IC (integrated circuit)₅₀Compounds with values of 0.3 to 3 μ M were considered to be very active (++); IC (integrated circuit)₅₀Compounds with values of 3 to 30. mu.M 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 5X10⁴Individual cells/well of exponentially growing human AML MV-4-11(CRL-9591) cells and immediately treated with two-fold dilutions of test compounds ranging from 30 μ M to 0.2 μ M. Triplicate wells were used for each concentration, and medium-only wells and three DMSO control wells. Cells and compounds were incubated at 37 ℃ with 5% CO₂Incubate for 72 hours, then add 20. mu.L of CellTiter Aqueous One Solution (Promega) to each well and 5% CO at 37 ℃₂Incubate for an additional 3-4 h. Absorbance was taken at 490nm in a spectrophotometer and the proliferation percentage relative to DMSO treated wells was calculated after correction from blank wells. IC calculation Using GraphPad Prism software₅₀。

IC₅₀Compounds with values less than or equal to 0.3 μ M are considered to be highly active (+++); IC (integrated circuit)₅₀Compounds with values of 0.3 to 3 μ M were considered to be very active (++); IC (integrated circuit)₅₀Compounds with values of 3 to 30. mu.M were considered active (+).

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

Example 4: inhibition of hIL-6mRNA transcription

In this example, hIL-6mRNA in tissue culture cells was quantitated to measure transcriptional inhibition of hIL-6 when treated with a compound of the invention.

In this example, hIL-6mRNA in tissue culture cells was quantitated to measure transcriptional inhibition of hIL-6 when treated with a compound of the invention.

Human leukemia monocyte lymphoma U937 cells (CRL-1593.2) were seeded in 100 μ L RPMI-1640 containing 10% FBS and penicillin/streptomycin in 96-well plates at a density of 3.2 × 104 cells/well and differentiated into macrophages in 60ng/mL PMA (phorbol-13-myristate-12-acetate) at 37 ℃ in 5% CO2 for 3 days, after which the target compound was added. Cells were pretreated for 1 hour with increasing concentrations of test compound in 0.1% DMSO prior to stimulation with 1ug/mL of lipopolysaccharide from e. Triplicate wells were used for each concentration. Cells were incubated at 37 ℃ for 3 hours with 5% CO2, after which the cells were harvested. At harvest time, the medium was removed and the cells were rinsed in 200 μ L PBS. Cells were harvested using the mRNA Catcher PLUS kit according to the manufacturer's instructions. Eluted mRNA was used for the use of RNAUltraSense^TMComponents of a one-step kit (Life Technologies) along with Applied Biosystems for hIL-6 and cyclophilinPrimer-probe one-step quantitative real-time PCR reaction. Real-time PCR plate in VIa^TM7 run on real-time PCR instruments (Applied Biosystems), analyze the data, normalize the Ct value of hIL-6 against internal controls, and then determine eachFold expression of samples relative to control.

IC₅₀Compounds with values less than or equal to 0.3 μ M are considered to be highly active (+++); IC (integrated circuit)₅₀Compounds with values of 0.3 to 3 μ M were considered to be very active (++); IC (integrated circuit)₅₀Compounds with values of 3 to 30. mu.M were considered active (+).

Table 6: inhibition of hIL-6mRNA transcription

Example 5: inhibition of IL-17mRNA transcription

In this example, hIL-17mRNA in human peripheral blood mononuclear cells was quantitated to measure transcriptional inhibition of hIL-17 when treated with a compound of the invention.

Human peripheral blood mononuclear cells were seeded in 96-well plates (2.0X 10)⁵Individual cells/well) in 45 μ L of OpTimizer T cell expansion medium containing 20ng/ml IL-2 and penicillin/streptomycin. Cells were treated with test compound (45 μ Ι _) at 2-fold concentration and then incubated at 37 ℃ for 1 hour before adding 10 μ g/ml of 10-fold stock OKT3 antibody to the medium. Cells were incubated at 37 ℃ for 6 hours and then harvested. At harvest time, cells were centrifuged (800rpm, 5 minutes). For removalThe spent medium and cell lysis solution (70 μ Ι _) was added to the cells in each well and incubated for 5-10 minutes at room temperature to allow complete cell lysis and detachment. mRNA was then prepared using the "mRNACatcher PLUS plate" (Invitrogen) according to the protocol provided. After the last wash, aspirate as much wash buffer as possible without drying the wells. Elution buffer (E3, 70 μ L) was then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plates with elution buffer for 5 minutes at 68 ℃ and then immediately placing the plates on ice.

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

IC₅₀Compounds with values less than or equal to 0.3 μ M are considered to be highly active (+++); IC (integrated circuit)₅₀Compounds with values of 0.3 to 3 μ M were considered to be very active (++); IC (integrated circuit)₅₀Compounds with values of 3 to 30. mu.M were considered active (+).

Table 7: inhibition of hIL-17mRNA transcription

Example 6: inhibition of hVCAM mRNA transcription

In this example, hVCAM mrna in tissue culture cells was quantified to measure transcriptional inhibition of hVCAM when treated with a compound of the disclosure.

Human Umbilical Vein Endothelial Cells (HUVEC) were plated in 96-well plates (4.0X 10)³Individual cells/well) were inoculated in 100 μ L EGM medium and incubated for 24 hours, after which the target compound was added. Cells were pre-treated with test compounds for 1 hour,after stimulation with tumor necrosis factor- α the cells were incubated for another 24 hours before harvesting the cells at harvest time spent media was removed from the HUVEC and rinsed in 200 μ L PBS then cell lysis solution (70 μ L) was added to the cells in each well and incubated at room temperature for about 5-10 minutes to allow complete cell lysis and detachment.

The eluted mRNA thus isolated was then used in a one-step quantitative real-time PCR reaction using the components of the Ultra Sense kit along with an applied biosystems primer-probe mixture. Real-time PCR data was analyzed, Ct values for hVCAM were normalized to internal controls, and fold induction was then determined for each unknown sample relative to the controls.

Example 7: inhibition of hMCP-1mRNA transcription

In this example, hMCP-1mRNA in human peripheral blood mononuclear cells was quantified to measure transcriptional inhibition of hMCP-1 when treated with a compound of the present disclosure.

Human peripheral blood mononuclear cells were plated in 96-well plates (1.0X 10)⁵Individual cells/well) were seeded in 45 μ L RPMI-1640 containing 10% FBS and penicillin/streptomycin. Cells were treated with test compound (45 μ Ι _ at 2-fold concentration) and then incubated at 37 ℃ for 3 hours before harvesting the cells. At harvest time, cells were transferred to V-bottom plates and centrifuged (800rpm, 5 min). The spent media was removed and a cell lysis solution (70 μ Ι _) was added to the cells in each well and incubated for 5-10 minutes at room temperature to allow complete cell lysis and detachment. Then made using "mRNAcatcher PLUS plate" (Invitrogen) according to the protocol providedPreparing mRNA. After the last wash, aspirate as much wash buffer as possible without drying the wells. Elution buffer (E3, 70 μ L) was then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plates with elution buffer for 5 minutes at 68 ℃ and then immediately placing the plates on ice.

The isolated eluted mRNA was then used in a one-step quantitative real-time PCR reaction using the components of the Ultra Sense kit along with an applied biosystems primer-probe mixture. Real-time PCR data was analyzed, Ct values for hMCP-1 were normalized to internal controls, and fold induction was then determined for each unknown sample relative to the controls.

Example 8: upregulation of hApoA-1mRNA transcription.

In this example, ApoA-I mRNA in tissue culture cells is quantified to measure transcriptional upregulation of ApoA-I upon treatment with a compound of the invention.

Huh7 cells (2.5X 10) were plated using 100. mu.L of DMEM/well (Gibco DMEM supplemented with penicillin/streptomycin and 10% FBS)⁵One/well) in 96-well plates, and the target compound is added 24 hours later. After 48 hours of treatment, spent media was removed from Huh-7 cells and placed on ice (for immediate use) or at-80 ℃ (for future use), using "LDH cytotoxicity assay kit II" from Abcam. The cells remaining in the plate were rinsed with 100 μ L PBS.

Then 85 μ Ι _ of cell lysis solution was added to each well and incubated for 5-10 minutes at room temperature to allow complete cell lysis and detachment. mRNA was then prepared according to the protocol provided using "mRNA capterplus plates" from Life Technologies. After the last wash, aspirate as much wash buffer as possible without drying the wells. Elution buffer (E3, 80 μ L) was then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer for 5 minutes at 68 ℃ and then 1 minute at 4 ℃. mRNA eluted Catcher plates were 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 the components of the Ultra Sense kit along with the life technologies primer-probe mixture. Real-time PCR data was analyzed using Ct values to determine fold induction for each unknown sample relative to controls (i.e., relative to each control of independent DMSO concentration).

EC₁₇₀Compounds with values less than or equal to 0.3 μ M are considered to be highly active (+++); EC (EC)₁₇₀Compounds with values of 0.3 to 3 μ M were considered to be very active (++); EC (EC)₁₇₀Compounds with values of 3 to 30. mu.M were considered active (+).

Table 8: upregulation of hApoA-1mRNA transcription.

EXAMPLES Compounds	ApoA-1 Activity
		7	+++

Example 9: in vivo efficacy in athymic nude mouse strains using the MV4-11 cell acute myeloid leukemia xenograft model:

MV4-11 cells (ATCC) were grown under standard cell culture conditions and the (NCr) nu/nu fisol strain from 6-7 week old female mice was treated with 5X10 in 100. mu.L PBS + 100. mu.L Matrigel⁶Individual cell/animal injectionIn the left lower abdomen. By about day 18 after MV4-11 cell injection, mice were based on an average of about 120mm³Tumor volume (L x W xH)/2) of (C). Mice were orally administered 75mg/kg twice daily and 120mg/kg twice daily to compounds in a formulation of EA006 at a dosage volume of 10mL/kg body weight. Tumor measurements were taken with an electronic caliper and body weights were measured every other day from the start of the dosing period. Mean tumor volume, percent Tumor Growth Inhibition (TGI), and percent body weight change were compared against vehicle control animals. Student's t-test was used in Excel to calculate mean, statistical analysis and comparisons between groups.

Table 9: in vivo efficacy in athymic nude mouse strains of acute myeloid leukemia xenograft model

EXAMPLES Compounds	In vivo Activity
		Example 7	Activity of

Example 10: in vivo efficacy in athymic nude mouse strains using OCI-3 AML cell acute myeloid leukemia xenograft model

OCI-3 AML cells (DMSZ) were grown under standard cell culture conditions and the (NCr) nu/nu fisol strain of 6-7 week old female mice was grown in 100. mu.L PBS + 100. mu.L Matrigel at 10X 10⁶Individual cells/animal were injected in the lower left flank. By about day 18-21 after OCI-3 AML cell injection, mice were based on an average of about 100-300mm³Tumor volume (L x W x H)/2) randomization. Mice are orally administered to a compound in a formulation of EA006 at a dosage volume of 10mL/kg body weight at a dosing regimen of 30mg/kg twice daily on a continuous dosing schedule and 2.5 to 45mg/kg daily on a dosing schedule of 5 days to 2 days. Tumor measurements were taken with an electronic caliper and body weights were measured every other day from the start of the dosing period. Mean tumor volume, percent Tumor Growth Inhibition (TGI), and percent body weight change were compared against vehicle control animals. Student's t-test was used in Excel to calculate mean, statistical analysis and comparisons between groups.

Example 11: evaluation of target engagement.

MV4-11 cells (ATCC) were grown under standard cell culture conditions and the (NCr) nu/nu fisol strain from 6-7 week old female mice was treated with 5X10 in 100. mu.L PBS + 100. mu.L Matrigel⁶Individual cells/animal were injected in the lower left flank. By about day 28 after MV4-11 cell injection, mice were based on an average of about 500mm³Tumor volume (L x W xH)/2) of (C). Tumors were harvested 6 hours after small oral administration of compound in EA006 preparations at a dose volume of 10mL/kg body weight and Bcl2 administration and analyzed for c-myc gene expression as a PD biomarker.

Example 12: in vivo efficacy in a mouse endotoxemia model assay.

A sub-lethal dose of endotoxin (e.coli bacterial lipopolysaccharide) is administered to animals to produce a systemic inflammatory response, which is monitored by an increase in cytokine secretion. Compounds were orally administered to C57/Bl6 mice at a dose of 75mg/kg to assess inhibition of IL-6 and IL-17 cytokines after 3 hours of intraperitoneal challenge with Lipopolysaccharide (LPS) at a dose of 0.5 mg/kg.

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 for preclinical testing of many anti-arthritic agents. This model produced measurable polyarthritis, significant cartilage destruction associated with pannus formation, and mild to moderate bone resorption and periosteal bone hyperplasia following collagen administration. In this model, collagen was administered to the female Lewis strain of rats on days 1 and 7 of the study and was dosed with compound on days 11 to 17. Using a model in which treatment was administered after the disease had developed, test compounds were evaluated to assess the potential to inhibit inflammation (including paw swelling), cartilage destruction, and bone resorption in arthritic rats.

Example 14: in vivo efficacy in an Experimental Autoimmune Encephalomyelitis (EAE) model of MS Experimental Autoimmune Encephalomyelitis (EAE) is a T-cell mediated autoimmune disease of the CNS that shares 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. The cytokines IL-23, IL-6 and IL-17 (which are critical for Th1 and Th17 differentiation or are produced by these T cells) play a key and essential role in EAE development. Therefore, drugs targeting the production of these cytokines may have therapeutic potential in the treatment of MS.

The compound of formula I or Ia is administered from 50 to 125mg/kg twice daily from the time of immunization of EAE mice. In this model, MOG was measured in female C57Bl/6 mice_35-55CFA immunization and pertussis toxin injection induced EAE.

Table 10: in vivo efficacy in an Experimental Autoimmune Encephalomyelitis (EAE) model of MS

EXAMPLES Compounds	In vivo Activity
		Example 7	Activity of

Example 15: ex vivo Effect on T cell function from spleen cell and lymphocyte cultures stimulated with external MOG stimulation

Mice were immunized with MOG/CFA and treated with compound for 11 days concurrently according to a twice daily schedule. Inguinal lymph nodes and spleen were harvested, cultures were established for lymphocytes and spleen cells and challenged with external antigen (MOG) for 72 hours. To be analyzed from the supernatants of these cultures for TH1, TH2 and TH17 cytokines using a Cytometric Bead Array assay.

Example 16: in vivo efficacy in athymic nude mouse strains of multiple myeloma xenograft model of MM1.s cells

MM1.s cells (ATCC) were grown under standard cell culture conditions and 6-7 week old female mice (NCr) nu/nu fisol in 100. mu.L PBS + 100. mu.L Matrigel 10X 10⁶Individual cells/animal were injected in the lower left flank. By about day 21 after MM1.s cell injection, mice were based on an average of about 120mm³Tumor volume (L x W x H)/2) randomization. Mice were orally administered 75mg/kg twice daily of the compound in a formulation of EA006 in a 10mL/kg body weight dose volume. Tumor measurements were taken with an electronic caliper and body weights were measured every other day from the start of the dosing period. Mean tumor volume, percent Tumor Growth Inhibition (TGI), and percent body weight change were compared against vehicle control animals. Average was calculated in Excel using student's t-testValues, statistical analysis and comparisons between groups.

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 as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims (28)

1. Use of a therapeutically effective amount of a compound selected from formula IIb 'and formula IId', or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating:

(a) a disease or condition associated with BET protein by inhibiting BET protein function;

(b) autoimmune disorders associated with BET proteins; and/or

(c) Inflammatory disorders associated with the BET protein,

wherein:

rings a and B may be optionally substituted with one or more groups independently selected from: deuterium, -NH₂Amino group, C₁-C₆Alkyl radical, C₁-C₆Thioalkyl, C₁-C₆Alkenyl and C₁-C₆An alkoxy group;

x is selected from-NH-, -CH₂-、-CH₂CH₂-、-CH(CH₃) -and-ch (oh) —, wherein one or more hydrogens may be independently replaced by deuterium or halogen;

R₄selected from optionally substituted 3-6 membered carbocyclic rings; and

D₁a 5-membered monocyclic heterocycle selected from:

optionally substituted with one or more substituents independently selected from deuterium and C₁-C₄Alkyl, each of which may be optionally substituted by F, -OH and/or-NH₂And (4) substitution.

2. The use according to claim 1, wherein the compound is selected from compounds of formula lib ″

Or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein Z is selected from hydrogen, deuterium, -NH₂Amino group, C₁-C₆Alkyl radical, C₁-C₆Thioalkyl, C₁-C₆Alkenyl and C₁-C₆An alkoxy group.

3. The use according to claim 1, wherein R₄Is selected from C₃-C₆Cycloalkyl and phenyl rings, optionallyIndependently is selected from deuterium, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, -CF₃CN and-C₁-C₄One or more groups of thioalkyl groups, wherein each alkyl, alkoxy, and thioalkyl group may optionally be substituted with F, Cl or Br.

4. The use according to claim 3, wherein R₄Is a phenyl ring, optionally independently selected from hydrogen, deuterium, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, amino, halogen, amide, -CF₃、CN、-N₃、C₁-C₄Ketones, -S (O) C₁-C₄Alkyl, -SO₂C₁-C₄Alkyl, -C₁-C₄Thioalkyl, carboxyl and/or ester groups, each of which may be optionally substituted with: hydrogen, F, Cl, Br, -OH, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo.

5. The use according to claim 4, wherein C₁-C₄Alkyl is selected from methyl, ethyl, propyl, isopropyl and butyl; c₁-C₄Alkoxy is selected from methoxy, ethoxy and isopropoxy; halogen is selected from F and Cl; and-C₁-C₄Thioalkyl is selected from-SMe, -SEt, -SPr and-SBu.

6. The use according to claim 1, wherein D₁Is thatOptionally substituted with one or more substituents independently selected from deuterium and C₁-C₄Alkyl, each of which may be optionally substituted by F, -OH and/or-NH₂And (4) substitution.

7. The use according to claim 1, wherein D₁Is selected from

8. Use according to claim 7, wherein D₁Is that

9. The use according to claim 1, wherein X is selected from-CH₂-、-CH(CH₃) -and-NH-, wherein one or more hydrogens may be independently replaced by deuterium or halogen.

10. The use according to claim 9, wherein X is selected from-CH₂-and-CH (CH)₃) -, wherein one or more hydrogens may be independently replaced by deuterium or a halogen.

11. Use according to claim 10, wherein-X-R₄Is selected from-CH₂-an aryl group.

12. The use according to claim 1, wherein the compound is selected from compounds of formula lib ″

Or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

z is selected from hydrogen, deuterium, -NH₂Amino group, C₁-C₆Alkyl radical, C₁-C₆Thioalkyl, C₁-C₆Alkenyl and C₁-C₆An alkoxy group;

D₁is composed of

X is selected from-CH₂-and-CH (CH)₃) -; and is

R₄Is a phenyl ring optionally substituted by one or more independently selected from deuterium, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, -CF₃CN and-C₁-C₄A thioalkyl group, wherein each of alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl or Br.

13. Use of a therapeutically effective amount of a compound selected from the group consisting of formula IIa '"and formula IIc'" in the manufacture of a medicament for treating:

(a) a disease or condition associated with BET protein by inhibiting BET protein function;

(b) autoimmune disorders associated with BET proteins; and/or

(c) Inflammatory disorders associated with the BET protein,

wherein:

z, if present, is selected from hydrogen, deuterium, -NH₂Amino group, C₁-C₆Alkyl radical, C₁-C₆Thioalkyl, C₁-C₆Alkenyl radical, C₁-C₆Alkoxy and carboxyl;

D₁is composed of

X is selected from-CH₂-and-CH (CH)₃) -; and

R₄is a phenyl ring optionally substituted by one or more independently selected from deuterium, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, -CF₃CN and-C₁-C₄Radical substitution of thioalkyl radicals, in which each alkyl, alkoxy andthioalkyl groups may be optionally substituted with F, Cl or Br.

14. The use of claim 13, wherein R is₄The phenyl ring being optionally substituted by one or more C selected from methyl, ethyl, propyl, isopropyl and butyl₁-C₄An alkyl group; c selected from methoxy, ethoxy and isopropoxy₁-C₄An alkoxy group; halogen selected from F and Cl; and C selected from the group consisting of-SMe, -SEt, -SPr and-SBu₁-C₄Thioalkyl substituted.

15. Use according to claim 13, wherein Z is selected from hydrogen and amino.

16. Use of a therapeutically effective amount of a compound of formula IIb ", or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating:

(a) a disease or condition associated with BET protein by inhibiting BET protein function;

(b) autoimmune disorders associated with BET proteins; and/or

(c) Inflammatory disorders associated with the BET protein,

wherein:

x is selected from-NH-, -CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CH₂O-、-CH₂CH₂NH-、-C(O)-、-C(O)CH₂-、-C(O)CH₂CH₂-、-CH₂C (O) -and-CH₂CH₂C (O) -, wherein one or more hydrogens may be independently replaced by deuterium, hydroxy, methyl, halogen, -CF₃Or a ketone substitution;

R₄selected from optionally substituted 3-6 membered carbocycles and heterocycles;

D₁a 5-membered monocyclic heterocycle selected from:

optionally substituted by hydrogen, deuterium, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, amino, halogen, amide, -CF₃、CN、-N₃、C₁-C₄Ketones, -S (O) C₁-C₄Alkyl, -SO₂C₁-C₄Alkyl, -C₁-C₄Thioalkyl, -COOH and/or ester, each of which groups may optionally be substituted by hydrogen, F, Cl, Br, -OH, -NH₂-NHMe, -OMe, -SMe, oxo and/or thio-oxo substitution; and is

Z is selected from:

17. the use according to claim 16, wherein Z is selected from

18. Use of a therapeutically effective amount of a compound for the manufacture of a medicament for treating:

(a) a disease or condition associated with BET protein by inhibiting BET protein function;

(b) autoimmune disorders associated with BET proteins; and/or

(c) Inflammatory disorders associated with the BET protein,

wherein said compound 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;

formic acid 1-benzyl-6- (3, 5-dimethylisoxazol-4-yl) -1H-pyrrolo [3,2-b ] pyridin-5-yl ester;

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- (thiophen-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-dimethylmethylamine;

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-methylthiophen-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;

acetic acid 6- (3, 5-dimethylisoxazol-4-yl) -1- (4-fluorobenzyl) -1H-imidazo [4,5-b ] pyridin-5-yl ester;

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- (thiophen-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- (thiophen-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-phenethyl) -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-phenethyl) -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-phenethyl) -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-carboxamidine;

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, pharmaceutically acceptable salt thereof.

19. The use according to any one of claims 1 to 18, wherein the autoimmune or inflammatory disorder is selected from acute disseminated encephalomyelitis, agammaglobulinemia, allergic disease, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome, autoimmune aplastic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, behcet's disease, bullous pemphigoid, castleman's disease, celiac disease, churg-strauss syndrome, crohn's disease, korotroot syndrome, dry eye syndrome, spontaneous mixed cryoglobulinemia, dermatomyositis, dovick's disease, encephalitis, eosinophilic esophagitis, eosinophilic fasciitis, cystic fasciitis, Erythema nodosum, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (Wegener's), Graves 'disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henry-Schoendodermia purpura, idiopathic pulmonary fibrosis, IgA nephropathy, inclusion body myositis, type I diabetes, interstitial cystitis, Kawasaki disease, Leucocyte disruption vasculitis, lichen planus, lupus (SLE), microscopic polyangiitis, multiple sclerosis, myasthenia gravis, myositis, optic neuritis, pemphigus, POEMS syndrome, polyarteritis nodosa, primary biliary cirrhosis, psoriasis, psoriatic arthritis, pyoderma gangrenosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, Gaoan's arteritis, Hodgkin's disease, Graves' disease, Transverse myelitis, ulcerative colitis, uveitis, and vitiligo.

20. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an acute or chronic non-autoimmune inflammatory disorder characterized by dysregulation of IL-6 and/or IL-17.

21. The use of claim 20, wherein the acute or chronic non-autoimmune inflammatory disorder is selected from sinusitis, pneumonia, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, Chronic Obstructive Pulmonary Disease (COPD), septic shock, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, herring's reaction, and SIRS associated with viral infection.

22. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Rheumatoid Arthritis (RA) or Multiple Sclerosis (MS).

23. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein the compound is administered in combination with other therapies.

24. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a benign proliferative or fibrotic disorder selected from the group consisting of: benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinoma, pseudocerebroma, seborrheic keratosis, gastric polyps, thyroid nodules, cystic neoplasms of pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, castleman's disease, chronic Tibetan hair disease, cutaneous fibroids, hair cysts, pyogenic granulomas, juvenile multiple polyp syndrome, idiopathic pulmonary fibrosis, renal fibrosis, post-operative stenosis, keloid formation, scleroderma, and myocardial fibrosis.

25. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of:

(a) diseases or disorders that benefit from upregulation or ApoA-I transcription and protein expression;

(b) a metabolic disease or disorder;

(c) cancer associated with viruses; and/or

(d) Infection by HIV.

26. The use according to claim 25, wherein:

(a) diseases or disorders benefiting from upregulation or ApoA-I transcription and protein expression are selected from cardiovascular disease, dyslipidemia, atherosclerosis, hypercholesterolemia, metabolic syndrome and Alzheimer's disease;

(b) the metabolic disease or disorder is selected from obesity-related inflammation, type II diabetes, and insulin resistance; and/or

(c) The virus is selected from Epstein Barr Virus (EBV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Kaposi's sarcoma-associated virus (KSHV), Human Papilloma Virus (HPV), Merkel cell polyoma virus, and human Cytomegalovirus (CMV).

27. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder selected from alzheimer's disease, parkinson's disease, huntington's disease, bipolar disorder, schizophrenia, lu-tai syndrome and epilepsy.

28. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 18, or a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for male contraception.