Dihydroquinazolinones and related analogues for inhibiting YAP / TAZ-TEAD

Abstract

The present disclosure relates to novel compounds, said compounds for use as medicaments, more particularly for the prevention or treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription, even more particularly for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to methods for the prevention or treatment of said diseases, including the use of the novel compounds. The present disclosure further relates to pharmaceutical compositions or combined preparations of the novel compounds, and compositions or preparations for use as medicaments, more preferably for the prevention or treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription, even more particularly for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to processes for preparing said compounds.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 313,846, filed February 25, 2022, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to novel compounds. The present disclosure also relates to compounds for use as medicines, more particularly for preventing or treating diseases mediated by the activity of YAP / TAZ-TEAD transcription, such as for preventing or treating cancer or fibrosis. Methods for preventing or treating diseases, including the use of novel compounds, are also disclosed herein.

[0003] The disclosure further relates to pharmaceutical compositions or combination preparations of the novel compounds, and compositions or preparations for use as medicaments, for example, for the prevention or treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription, such as the prevention or treatment of cancer or fibrosis. Processes for the preparation of the compounds are also disclosed herein. [Background technology]

[0004] Hippo signaling is essential to limit organ size through inactivation of the YAP / TAZ-TEAD transcriptional complex. In several aggressive solid cancers, Hippo signaling is inactivated by loss-of-function mutations or deletions of genes encoding upstream regulators (e.g., NF2, MST1 / 2, or LATS1 / 2), causing constitutive YAP / TAZ-TEAD transcriptional activity, resulting in uncontrolled tumor growth and metastasis. Knockout, knockdown, or pharmacological inactivation of YAP / TAZ-TEAD is sufficient to attenuate YAP / TAZ-dependent tumorigenesis. The YAP / TAZ-TEAD complex can be pharmacologically inactivated through targeted disruption of the YAP / TAZ-TEAD protein-protein interaction interface or through an allosteric autopalmitoylation pocket in TEAD.

[0005] The main physiological function of the Hippo pathway is to restrict tissue growth in adult tissues and to regulate cell proliferation, differentiation, and migration in developing organs. The core of the Hippo pathway consists of a kinase cascade, transcriptional coactivators, and DNA-binding partners. In mammals, the Ste20-like kinases MST1 / 2 (homologs of Drosophila Hippo) phosphorylate and activate Large Tumor Suppressor 1 / 2 (LATS1 / 2). NF2 is the core Hippo kinase scaffold, which promotes LATS1 / 2 activation by linking MST1 / 2 to LATS1 / 2 (Lallemand et al., 2003, Genes Dev 17, 1090-1100; Yin et al., 2013, Dev Cell 19, 27-38). LATS kinase then phosphorylates and inactivates two highly homologous transcriptional coactivators, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motifs (TAZ), by 14-3-3-mediated cytoplasmic sequestration and β-TRCP E3 ligase-induced ubiquitin-mediated degradation. When the Hippo pathway is inactive, YAP and TAZ translocate into the nucleus and bind to the TEAD transcription factor family, inducing the expression of a specific signature that promotes matrix remodeling, cell proliferation, survival, and migration. TEAD1-4 can also bind to VGLL4 in the nucleus and act as a transcriptional repressor. VGLL4 is not structurally related to YAP / TAZ, but competes with YAP / TAZ based on partially overlapping binding sites on TEAD (Johnson and Halder, 2014, Nat Rev Drug Discov 13, 63-79).

[0006] TEADs are evolutionarily conserved proteins required for cardiogenesis, myogenesis, and development of the neural crest, notochord, and trophectoderm. In mammals, there are four genes encoding four homologous TEAD family members, named TEAD1-4. Each TEAD gene has a unique, but not mutually exclusive, expression pattern. All TEAD family members are regulated by YAP / TAZ.

[0007] In Drosophila, loss of function of Hippo or Warts kinases (MST1 / 2 or LATS1 / 2 in mammals) or overexpression of Yorkie (the Drosophila homologs of YAP and TAZ) results in dramatic overgrowth of the cuticle as a result of dysregulation of cell proliferation and resistance to apoptosis, leading to increased organ size. In mice, YAP overexpression, loss of MST1 / 2 or LATS1 / 2 kinase activity, or loss of NF2 leads to upregulation of TEAD target genes and expansion of progenitor cells, resulting in overgrowth of the liver and heart, and ultimately cancer formation in the liver, small intestine, and skin. In contrast, a serine-to-alanine mutation at position 94 of YAP that cannot bind TEAD is not oncogenic (Zhao et al., 2008, Genes Dev 22, 1962-1971). Similarly, a dominant-negative TEAD mutant that cannot bind DNA overcomes YAP-driven liver tumorigenesis. Furthermore, NF2 mutant hepatocarcinomas were largely suppressed by loss of heterozygosity of Yap (Zhang et al., 2010, Dev Cell 19, 27-38). Finally, verteporfin, a small molecule that inhibits YAP-TEAD association, significantly suppressed the oncogenic activity of YAP in these models (Liu-Chittenden et al., 2012, Genes Dev 26, 1300-1305).

[0008] Genetic amplification of YAP1 (encoding YAP) and WWTR1 (encoding TAZ), as well as constitutive nuclear localization of YAP / TAZ, have been reported in many human solid malignancies, including liver, lung, breast, skin, colon, and ovarian cancers, where YAP / TAZ promotes the acquisition of several important cancer cell phenotypes, such as proliferation, apoptosis resistance, invasion, and immunosuppression (e.g., by attracting myeloid-derived suppressor cells (Wang et al., 2016, Cancer Discov 6, 80-95)). Furthermore, genetic fusions with YAP1 have been identified in several cancer types, including ependymoma, vascular carcinoma, cervical carcinoma, and porocarcinoma, which result in constitutive activation of YAP-TEAD and are oncogenic in mice (Szulzewsky et al., 2020, Genes Dev 34:1-14). Furthermore, several germline or somatic mutations in components of the Hippo pathway associated with various cancer types have been found in targeted and whole genome sequencing studies. The best-studied example is the NF2 locus, which is frequently mutated in neurofibromatosis. Loss of NF2 and LATS2 is also frequently observed in schwannomas. Another tumor type frequently associated (in about 70% of all cases) with constitutive YAP-TEAD activation via genetic inactivation of NF2, LATS1 / 2, MST1 / 2 or SAV1 is malignant mesothelioma (Bueno et al., 2016, Nat Genet 48, 407-416). Recent studies have shown that several mesothelioma cell lines with NF2 loss-of-function mutations exhibit reduced YAP phosphorylation and increased YAP-TEAD reporter activity. YAP-TEAD transcription and viability in NF2 mutant mesothelioma cell lines (but not WT mesothelioma) are sensitive to YAP siRNA (an effect that can be rescued by overexpression of siRNA-resistant YAP) and to treatment with the YAP antagonist verteporfin (Zhang et al., 2017, J Cell Mol Med 21:2663-2676).

[0009] Nuclear YAP has also emerged as a key mediator of WNT-dependent colorectal tumorigenesis. YAP-TEAD-mediated transcription of genes involved in proliferation and stem cell renewal cooperates with WNT-driven β-catenin, and YAP is required for adenoma formation after APC (adenomatous polyposis coli) inactivation (Azzolin et al., 2014 Cell 158, 157-170; Gregorieff et al., 2015 Nature 526, 715-718.). Recently, TIAM1 was identified as a suppressor of invasive metastatic colorectal cancer (CRC) by antagonizing YAP-TEAD transcription, again highlighting the role of YAP-TEAD in CRC (Diamantopoulou et al., 2017 Cancer Cell 31, 621-634).

[0010] In summary, YAP / TAZ activation has been shown to drive tumorigenesis, and YAP / TAZ is hyperactivated (often by loss-of-function mutations in upstream negative regulators) in many different types of cancer in humans. Genetic deletion or pharmacological inhibition of YAP / TAZ has been shown to suppress tumor development and progression in various types of cancer. Thus, deregulation of the Hippo tumor suppressor pathway is thought to be a key event in the development of a wide range of cancer types and malignancies. Therefore, pharmacological targeting of the Hippo cascade through inhibition of YAP, TAZ, TEAD, and / or YAP / TAZ-TEAD protein-protein interactions would be a valuable approach to treat cancers with functional alterations of this pathway.

[0011] YAP / TAZ-TEAD activation has also been shown to play an important role in diseases other than cancer, such as fibrosis and certain congenital disorders. Fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) containing cross-linked collagen fibers, which hardens tissues and ultimately leads to the dysfunction of affected organs. ECM stiffening promotes YAP / TAZ nuclear activity in cancer-associated fibroblasts, as well as liver, kidney, lung, and skin fibroblasts (Mannaerts et al., 2015, J. Hepatol. 63, 679-688; Piersma et al., 2015, Am. J. Pathol. 185, 3326-3337). Nuclear YAP / TAZ promotes fibrotic cell phenotypes, such as myofibroblast differentiation and increased matrix remodeling. Several genes encoding key secreted factors implicated in fibrosis are direct YAP / TAZ-TEAD targets. These genes include well-characterized profibrotic factors such as connective tissue growth factor (CTGF), plasminogen activator inhibitor 1 (PAI-1), and the lysyl oxidase (LOX) family of collagen cross-linking enzymes. Several lines of evidence support that YAP / TAZ contribute to fibrotic disease in vivo. These include reports of elevated YAP / TAZ levels and transcriptional activity in fibroblasts and in alveolar and airway epithelium of patients with idiopathic pulmonary fibrosis (Gokey et al., 2018 JCI Insight 3:e98738). Increased nuclear YAP has also been observed in patients with primary sclerosing cholangitis and primary biliary cirrhosis, chronic fibrotic disorders of liver injury. Expression of YAP or TAZ in hepatic ductal cells promotes fibrosis progression that parallels fibrosis in nonalcoholic fatty liver disease (Machado et al., 2015, J. Hepatol 63, 962-970). Collectively, these studies suggest that targeting aberrant YAP / TAZ activity in fibrotic diseases may hold therapeutic promise.

[0012] Neurofibromatosis type 2 is characterized by nervous system tumors including schwannomas, meningiomas, and ependymomas. Neurofibromatosis type 2 is a genetic disorder caused by inactivation of NF2 (Striedinger et al., 2008, Neoplasia 10, 1204-1210). Loss of NF2 results in constitutive activation of YAP / TAZ-TEAD. Sturge-Weber syndrome is a congenital neurocutaneous disorder characterized by port-wine stains affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary vasculature in the leptomeninges and choroids of the brain, glaucoma, seizures, strokes, and intellectual disability. Sturge-Weber syndrome and port-wine stains are caused by somatic activating mutations in GNAQ that result in activation of YAP / TAZ-TEAD transcription (Shirley et al., 2013, NEJM, 368, 1971-1979). Thus, several congenital disorders characterized by constitutive YAP / TAZ-TEAD activation may be treated with inhibitors of YAP / TAZ-TEAD.

[0013] Several publications have described inhibitors of YAP-TEAD transcriptional activation. Inventiva has featured YAP-TEAD protein-protein interaction inhibitors in WO2020 / 070181, WO2018 / 185266, and WO2017 / 064277. General Hospital Corporation, Boston has described autopalmitoylation inhibitors in WO2017 / 053706. Vivace Therapeutics, Inc. has disclosed non-fused tricyclic compounds (WO2018 / 204532), benzosulfonyl compounds (WO2019 / 040380), benzocarbonyl compounds (WO2019 / 113236), oxadiazole compounds (WO2019 / 222431), and bicyclic compounds (WO2020 / 097389) that modulate the interaction between YAP / TAZ and TEAD. Regents of the University of California and Vivace Therapeutics, Inc. described tricyclic compounds that inhibit the Hippo-YAP signaling pathway in WO2013 / 188138 and WO2017 / 058716, respectively. Kyowa Hakko Kirin Co., Ltd. published α,β-unsaturated amide compounds exhibiting anticancer activity in WO2018 / 235926 and US2019 / 0010136. Genentech, Inc. disclosed carboxamide and sulfonamide derivatives useful as inhibitors of YAP-TEAD protein-protein interaction in WO2019 / 232216 and WO2020 / 051099. Dana-Farber Cancer Institute, Inc. addressed inhibitors of TEAD transcription factors in WO2020 / 081572. The Trustees of Indiana University described small molecules that bind within the hydrophobic palmitate-binding pocket of TEAD in WO2020 / 087063. Wenchao Lu, et al. published vinylsulfonamides as covalent TEAD autopalmitoylation inhibitors (2019, European Journal of Medicinal Chemistry, 184, p. 111767).The Korean Research Institute of Chemical Technology has disclosed benzo[cd]indol-2(1H)-one derivatives that inhibit YAP-TEAD binding.

[0014] However, there remains a need for new, alternative, or better therapeutic agents for preventing or treating diseases mediated by YAP / TAZ-TEAD activation, such as cancer and fibrosis, among other possible indications. Therapeutic agents with better efficacy, fewer side effects, greater activity, less toxicity, or better pharmacokinetic or pharmacodynamic properties, or a combination thereof, would be highly welcomed.

[0015] The present disclosure provides a class of novel compounds that can be used as inhibitors of YAP / TAZ-TEAD activation mediated diseases. Summary of the Invention

[0016] The present disclosure is based on the finding that at least one of the problems mentioned above may be solved by the class of compounds described below.

[0017] The present disclosure provides new compounds that have been shown to possess inhibitory activity against YAP / TAZ-TEAD transcription. The present disclosure further demonstrates that these compounds efficiently inhibit the activity of YAP / TAZ-TEAD transcription. Thus, these compounds constitute a useful class of new potent compounds that can be used in the treatment and / or prevention of Hippo-mediated disorders in animals, mammals and humans, more specifically for the treatment and / or prevention of (i) cancer, more specifically lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma, (ii) fibrosis, and (iii) YAP / TAZ-TEAD activation-related congenital disorders, etc.

[0018] In some embodiments, the compounds described herein are useful in the treatment and / or prevention of Hippo mediated disorders in animals, mammals and humans, more specifically acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, hemangiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic ... Myeloid leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma , hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline carcinoma of the NUT (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0019] The present disclosure further relates to the use of said compounds as pharmaceuticals and to their use for the manufacture of medicines, more particularly to the use for treating and / or preventing YAP / TAZ-TEAD activation mediated diseases in animals or mammals, more particularly in humans, particularly (i) cancer, more particularly lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma, and (ii) fibrosis. The present disclosure also relates to methods for the preparation of all such compounds, and pharmaceutical compositions comprising them in effective amounts.

[0020] In some embodiments, the disclosure relates to compounds of the invention for use as medicaments, the use of said compounds as medicaments, and their use for the manufacture of medicines, more particularly their use for treating and / or preventing YAP / TAZ-TEAD activation mediated diseases, more particularly acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, and basal cell leukemia. Basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell carcinoma, glioma, neuro Glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma The present invention relates to their use for the treatment and / or prevention of uterine tumors, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0021] The present disclosure also relates to methods of treating or preventing TEAD activation mediated disorders in humans by administering one or more of the compounds, optionally in combination with one or more other pharmaceutical agents, to a patient in need thereof.The present disclosure also relates to methods of preparing the compounds disclosed herein, including steps for the synthesis of the compounds described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition The term "YAP / TAZ-TEAD activation-mediated disease" refers to a disease in which hippo signaling is inactivated, whereby YAP / TAZ-TEAD activation causes, drives, sustains, enables, etc., the disease. This may be due to loss-of-function mutations or deletions of genes encoding upstream regulators of YAP / TAZ-TEAD (e.g., NF2, MST1 / 2, LATS1 / 2, FAT1, or SAV1), which cause constitutive YAP-TEAD transcriptional activity, resulting in uncontrolled tumor growth and metastasis of some cancers. This may also be due to gene amplification, gene fusion, or activating mutations of YAP1 or WWTR1 (TAZ), or overexpression or hyperactivity of YAP / TAZ, etc. Thus, YAP / TAZ-TEAD activation-mediated disease refers to cancer, but also includes fibrosis and certain congenital disorders. Cancers included in YAP / TAZ-TEAD-mediated diseases include, but are not limited to, lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma. Also included are (i) squamous cell carcinoma of the lung, cervix, ovary, head and neck, esophagus, and / or skin, or (ii) cancers arising from neuroectodermal-derived tissues, such as ependymoma, meningioma, schwannoma, peripheral nerve-sheet tumor and / or neuroblastoma, or (iii) vascular carcinoma, such as epithelioid hemangioendothelioma. Fibrotic diseases or fibrosis included in YAP / TAZ-TEAD-mediated diseases include, but are not limited to, liver fibrosis, pulmonary fibrosis, and cardiac fibrosis. Congenital disorders included in the YAP / TAZ-TEAD-mediated diseases include, but are not limited to, Sturge-Weber syndrome and neurofibromatosis type 2.

[0023] YAP / TAZ-TEAD-mediated diseases also include cancers that have developed resistance to previous treatments, such as EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors, etc.

[0024] The term "treat" or "treating" as used herein refers to administration of a compound or composition to a subject for the purpose of providing a therapeutic or prophylactic benefit by inhibiting YAP / TAZ-TEAD transcription. Treating includes improving, relieving, alleviating, inhibiting the progression of, reducing the severity of, or preventing a disease, disorder, or condition mediated by YAP / TAZ-TEAD transcription, or one or more symptoms of the disease, disorder, or condition. "Therapeutic benefit" refers to eradicating, alleviating, improving, alleviating, inhibiting the progression of, or reducing the severity of the underlying disorder being treated. Also, in some embodiments, therapeutic benefit is achieved by eradicating or alleviating one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even if the patient suffers from the underlying disorder. In terms of prophylactic benefit, in some embodiments, the composition is administered to a patient at risk of developing a particular disease or reporting one or more of the physiological symptoms of the disease, even if the patient has not been diagnosed with the disease.

[0025] The term "subject" as used herein refers to an animal, e.g., a mammal such as a human, or a patient who has been the subject of treatment, observation or experiment, or who is in need of such treatment.

[0026] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits in a tissue system, animal or human the biological or medicinal response sought by a researcher, veterinarian, physician, or other clinician, including alleviation or partial alleviation of the symptoms of the disease or disorder being treated.

[0027] As used herein, the term "composition" is intended to encompass not only a product containing therapeutically effective amounts of the specified ingredients, but any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts.

[0028] The terms "antagonist" or "inhibitor" as used herein with respect to inhibitors of YAP / TAZ-TEAD activation refer to a compound capable of producing functional antagonism of YAP / TAZ-TEAD activation, as the context requires.

[0029] It is to be noticed that the term 'comprising', used in the claims, should not be interpreted as being restricted to the means listed thereafter: it does not exclude other elements or steps.

[0030] References throughout this specification to "one embodiment" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the disclosure. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as will be apparent to one of ordinary skill in the art from this disclosure. When an indefinite or definite article, such as "a" or "an" or "the," is used in reference to a singular noun, this includes the plural of that noun unless specifically stated otherwise.

[0031] Similarly, in describing exemplary embodiments of the present disclosure, it will be understood that various features of the present disclosure may be grouped together in a single embodiment, drawing, or description thereof for the purpose of simplifying the disclosure and aiding in the understanding of one or more of the various inventive aspects.

[0032] In each of the following definitions, the number of carbon atoms generally represents the maximum number of carbon atoms optimally present in a substituent or linker, and unless otherwise stated in this application, it is understood that the number of carbon atoms represents the optimal maximum number of carbon atoms in that particular substituent or linker.

[0033] The term "leaving group" or "LG" as used herein means a chemical group susceptible to displacement by a nucleophile, or cleavage or hydrolysis under basic or acidic conditions. In certain embodiments, the leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

[0034] The term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the overall compound. The chemical substructures of protecting groups are diverse. One function of a protecting group is to act as an intermediate in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often utilized to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions, such as the creation and cleavage of chemical bonds in an orderly and planned manner. Protection of a functional group of a compound alters the reactivity of the protected functional group as well as other physical properties such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured with common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0035] Protected compounds may also exhibit altered, and possibly optimized, properties in vitro and in vivo, such as resistance to cell membrane penetration and enzymatic degradation or sequestration. In this role, protected compounds with the intended therapeutic effect may be called prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, which releases the parent drug upon conversion in vivo. The active prodrug may be absorbed more effectively than the parent drug, so the prodrug may have higher potency in vivo than the parent drug. The protecting group is removed in vitro in the case of chemical intermediates, or in vivo in the case of prodrugs. For chemical intermediates, it is not particularly important that the product obtained after deprotection, such as an alcohol, is physiologically acceptable, although it is generally more desirable if the product is pharmacologically harmless.

[0036] As used herein, "alkyl" or "C 1-18 The term "alkyl" refers to any C1-C aryl group that does not contain any unsaturation. 18 Examples include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl- 2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl. In certain embodiments, the term alkyl is an alkyl group, as further defined herein above,1-12 Alkyl(C 1-12 Hydrocarbons), and more specifically C 1-9 Alkyl(C 1-9 Hydrocarbons), and more specifically C 1-6 Alkyl(C 1-6 Hydrocarbons).

[0037] The term "haloalkyl" as a group or part of a group refers to an alkyl group as defined above in which one, two or three hydrogen atoms are each replaced by a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.

[0038] The term “alkoxy” or “alkyloxy” as a group or part of a group refers to a group of the formula —OR b In the formula, R b is C as defined hereinabove 1-6 Alkyl. Preferred C 1-6 Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0039] The term “haloalkoxy” as a group or part of a group means a group of the formula —OR c In the formula, R c is haloalkyl as defined herein. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, and 4,4,4-trichlorobutoxy.

[0040] "Cycloalkyl" or "C 3-18 The term "cycloalkyl," as used herein, and unless otherwise specified, includes any of the following aryl groups: C, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C41, C52, C61, C72, C73, C74, C75, C76, C77, C78, ​​C79, C81, C95, C96, C97, C98, C99, C101, C112, C123, C134, C135, C146, C147, C158, C159, C166, C167, C168, C169, C171, C172, C173, C174, C175, C175, C176, C177, C178, C179, C181, C192, C193, C194, C195, C195 3-10 Monocyclic or C 7-18 means a saturated hydrocarbon monovalent radical having 3 to 18 carbon atoms, consisting of or including a polycyclic saturated hydrocarbon. In certain embodiments, the term cycloalkyl means a C 3-12 Cycloalkyl (saturated cyclic C 3-12 Hydrocarbons), and more specifically C 3-9 Cycloalkyl (saturated cyclic C 3-9 Hydrocarbons), and more particularly C 3-6 Cycloalkyl (saturated cyclic C 3-6 For the avoidance of doubt, a fused system of a cycloalkyl ring with a heterocyclic ring is considered to be heterocyclic regardless of which ring is attached to the core structure. A fused system of a cycloalkyl ring with an aryl ring is considered to be aryl regardless of which ring is attached to the core structure. A fused system of a cycloalkyl ring with a heteroaryl ring is considered to be heteroaryl regardless of which ring is attached to the core structure.

[0041] As used herein, "alkenyl" or "C 2~18 The term "alkenyl" refers to a C2-C alkyl group having at least one (usually 1-3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond. 18It is a straight chain, secondary or tertiary, linear, branched or straight chain hydrocarbon. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). The double bond may be in cis or trans configuration. In certain embodiments, the term alkenyl refers to a C alkyl group, as further defined herein above, containing at least one (usually 1-3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond. 2-12 Alkenyl (C 2-12 Hydrocarbons), and more specifically C 2-9 Alkenyl (C 2-9 Hydrocarbons), and more particularly C 2-6 Alkenyl (C 2-6 Hydrocarbons).

[0042] The term “alkenyloxy” as a group or part of a group means a group of the formula —OR d In the formula, R d is alkenyl as defined hereinabove.

[0043] As used herein, the term "cycloalkenyl" refers to an alkyl group having 5 to 18 carbon atoms, with at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond, and 5~10 Monocyclic or C 7~18 It refers to a non-aromatic hydrocarbon group consisting of or including polycyclic hydrocarbons. Examples include, but are not limited to, cyclopentenyl (-C5H7), cyclopentenylpropylene, methylcyclohexenylene, and cyclohexenyl (-C6H9). The double bonds can be in cis or trans configuration. In certain embodiments, the term cycloalkenyl refers to a C cyclic ring, as further defined herein above, containing at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond. 5-12 Cycloalkenyl (cyclic C 5-12 Hydrocarbons), and more specifically C 5-9 Cycloalkenyl (cyclic C 5-9Hydrocarbons), and more particularly C 5-6 Cycloalkenyl (cyclic C 5-6 For the avoidance of doubt, a fused system of a cycloalkenyl ring and a heterocyclic ring is considered to be heterocyclic, regardless of which ring is attached to the core structure. A fused system of a cycloalkenyl ring and an aryl ring is considered to be aryl, regardless of which ring is attached to the core structure. A fused system of a cycloalkenyl ring and a heteroaryl ring is considered to be heteroaryl, regardless of which ring is attached to the core structure.

[0044] As used herein, "alkynyl" or "C 2-18 The term "alkynyl" refers to a C-C alkyl group containing at least one (usually one to three, preferably one) site of unsaturation, i.e., a carbon-carbon triple bond. 18 alkynyl refers to a normal, secondary, tertiary, linear, branched or straight chain hydrocarbon of the formula: alkynyl (-C=CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CHC=CH). In certain embodiments, the term alkynyl refers to a C alkyl group, as further defined herein above, containing at least one (usually 1-3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp triple bond. 2-12 Alkynyl (C 2-12 Hydrocarbons), and more specifically C 2-9 Alkynyl (C 2-9 Hydrocarbons), and more specifically C 2-6 Alkynyl (C 2-6 Hydrocarbons).

[0045] The term “alkynyloxy” as a group or part of a group refers to a group of the formula —OR e In the formula, R e is alkynyl as defined hereinabove.

[0046] As used herein, the term "cycloalkynyl" refers to a cycloalkynyl group having 5 to 18 carbon atoms and containing at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp triple bond; 5-10 Monocyclic or C 7-18 It refers to a non-aromatic hydrocarbon group consisting of or including a polycyclic hydrocarbon. Examples include, but are not limited to, cyclohept-1-yne, 3-ethyl-cyclohept-1-ynylene, 4-cyclohept-1-yne-methylene, and ethylene-cyclohept-1-yne. In certain embodiments, the term cycloalkynyl refers to a C alkynyl group, as further defined herein above, containing at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp triple bond. 5-10 Cycloalkynyl (cyclic C 5-10 Hydrocarbons), and more specifically C 5-9 Cycloalkynyl (cyclic C 5-9 Hydrocarbons), and more particularly C 5-6 Cycloalkynyl (cyclic C 5-6 For the avoidance of doubt, a fused cycloalkynyl ring with a heterocyclic ring is considered to be heterocyclic, regardless of which ring is attached to the core structure. A fused cycloalkynyl ring with an aryl ring is considered to be aryl, regardless of which ring is attached to the core structure. A fused cycloalkynyl ring with a heteroaryl ring is considered to be heteroaryl, regardless of which ring is attached to the core structure.

[0047] As used herein, the term "alkylene" refers to any alkyl group having 1 to 18 carbon atoms, more specifically, C 1-12 , C 1-9 or C 1-6 (-CH2CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0048] As used herein, the term "alkenylene" refers to any alkyl group having 2 to 18 carbon atoms, more particularly, C 2-12 , C 2-9 or C 2-6 It refers to a branched or straight-chain hydrocarbon having 10,000 alkane carbon atoms, containing at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.

[0049] As used herein, the term "alkynylene" refers to an alkynylene having 2 to 18 carbon atoms, more specifically, 2-12 , C 2-9 or C 2-6 It refers to a branched or straight-chain hydrocarbon having 10,000 alkoxycarbon atoms, at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp triple bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

[0050] The term "heteroalkyl" as used herein refers to an alkyl in which one or more carbon atoms are replaced by one or more atoms selected from the group including oxygen, nitrogen, or sulfur atoms. Thus, the term heteroalkyl includes -OR b , -NR o -R b , -R a -OR b , and -SR b wherein R a is alkylene, and R b is alkyl, R o is hydrogen or alkyl as defined herein. In certain embodiments, the term is 1-12 Heteroalkyl, C 1-9 Heteroalkyl, or C 1-6In some embodiments, heteroalkyl is selected from the group including alkyloxy, alkyl-oxy-alkyl, (mono- or di-)alkylamino, (mono- or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl.

[0051] The term "heteroalkenyl" as used herein refers to an acyclic alkenyl in which one or more carbon atoms are replaced by one or more atoms selected from oxygen, nitrogen, or sulfur atoms. Thus, the term heteroalkenyl includes -OR d , -NH-(R d ), -N(R d ))2, -N(R b )(R d ), and -SR d wherein R b is alkyl, R d is alkenyl, as defined herein. In certain embodiments, the term is 2-12 Heteroalkenyl, C 2-9 Heteroalkenyl, or C 2-6 In some embodiments, the heteroalkenyl is selected from the group including alkenyloxy, alkenyl-oxy-alkenyl, (mono- or di-)alkenylamino, (mono- or di-)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl.

[0052] The term "heteroalkynyl" as used herein refers to a non-cyclic alkynyl in which one or more carbon atoms are replaced by an oxygen, nitrogen, or sulfur atom. Thus, the term heteroalkynyl includes -OR d , -N(R d )2, NHR d , -N(R b )(R e ), -N(R d )(R e ), and -SR d In particular, the formula (I) includes, but is not limited to, bis alkyl as defined herein; R e is alkynyl, and R d is alkenyl. In certain embodiments, the term is 2-12 Heteroalkynyl, C 2-9 Heteroalkynyl or C 2-6 In some embodiments, the term heteroalkynyl is selected from the group including alkynyloxy, alkynyl-oxy-alkynyl, (mono- or di-)alkynylamino, (mono- or di-)alkynyl-amino-alkynyl, alkynylthio, alkynyl-thio-alkynyl.

[0053] The term "heteroalkylene," as used herein, refers to an alkylene in which one or more carbon atoms have been replaced by one or more oxygen, nitrogen or sulfur atoms.

[0054] The term "heteroalkenylene," as used herein, refers to an alkenylene in which one or more carbon atoms are replaced by one or more oxygen, nitrogen, or sulfur atoms.

[0055] The term "heteroalkynylene," as used herein, refers to an alkynylene in which one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulfur atoms.

[0056] The term "aryl" as used herein means an aromatic hydrocarbon having 6-20 carbon atoms derived by removing a hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, one ring or two or three rings fused together derived from benzene, naphthalene, anthracene, biphenyl, and the like. In certain embodiments, the term aryl refers to an aromatic ring having ring members of 6-14 carbon atoms, and even more particularly, to an aromatic ring having ring members of 6-10 carbon atoms. A fused system of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring is considered an aryl, regardless of which ring is attached to the core structure. A fused system of an aryl ring with a heterocyclic ring is considered a heterocyclic ring, regardless of which ring is attached to the core structure. Thus, indoline, dihydrobenzofuran, dihydrobenzothiophene, and the like are considered heterocyclic rings according to the present disclosure. A fused system of an aryl ring with a heteroaryl ring is considered a heteroaryl, regardless of which ring is attached to the core structure.

[0057] The term “aryloxy” as a group or part of a group refers to a group of the formula —OR g In the formula, R g is aryl as defined hereinabove.

[0058] The term "arylalkyl" or "arylalkyl-" as used herein refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with an aryl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. An arylalkyl group contains 6 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

[0059] The term “arylalkyloxy” as a group or part of a group refers to a group of the formula —ORa -R g In the formula, R g is aryl as defined hereinabove; R a is alkylene.

[0060] The term "arylalkenyl" or "arylalkenyl-" as used herein refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl. An arylalkenyl group contains 6 to 20 carbon atoms, e.g., the alkenyl portion of the arylalkenyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

[0061] The term "arylalkynyl" or "arylalkynyl-" as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to the carbon atom is replaced with an aryl. An arylalkynyl group contains 6 to 20 carbon atoms, e.g., the alkynyl portion of the arylalkynyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

[0062] The term "arylheteroalkyl" or "arylheteroalkyl-" as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with an aryl. The arylheteroalkyl group contains 6 to 20 carbon atoms, e.g., the heteroalkyl portion of the arylheteroalkyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms. In some embodiments, the arylheteroalkyl is selected from the group including aryl-O-alkyl, arylalkyl-O-alkyl, aryl-NH-alkyl, aryl-N(alkyl)2, arylalkyl-NH-alkyl, arylalkyl-N-(alkyl)2, aryl-S-alkyl, and arylalkyl-S-alkyl.

[0063] The term "arylheteroalkenyl" or "arylheteroalkenyl-" as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl. The arylheteroalkenyl group contains 6 to 20 carbon atoms, e.g., the heteroalkenyl portion of the arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms. In some embodiments, the arylheteroalkenyl is selected from the group including aryl-O-alkenyl, arylalkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl)2, arylalkenyl-NH-alkenyl, arylalkenyl-N-(alkenyl)2, aryl-S-alkenyl, and arylalkenyl-S-alkenyl.

[0064] The term "arylheteroalkynyl" or "arylheteroalkynyl-" as used herein refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl. The arylheteroalkynyl group contains 6 to 20 carbon atoms, e.g., the heteroalkynyl portion of the arylheteroalkynyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms. In some embodiments, the arylheteroalkynyl is selected from the group including aryl-O-alkynyl, arylalkynyl-O-alkynyl, aryl-NH-alkynyl, aryl-N(alkynyl)2, arylalkynyl-NH-alkynyl, arylalkynyl-N-(alkynyl)2, aryl-S-alkynyl, and arylalkynyl-S-alkynyl.

[0065] The term "heterocycle" or "heterocyclyl" as used herein refers to a non-aromatic, fully saturated or partially unsaturated ring system of 3-18 atoms (e.g., a 3- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or one containing a total of 3-10 ring atoms) containing at least one N, O, S, or P. Each ring of the heterocycle or heterocyclyl may have 1, 2, 3, or 4 heteroatoms selected from N, O, and / or S, where the N and S heteroatoms may be optionally oxidized, the N heteroatom may be optionally quaternized, and at least one carbon atom of the heterocyclyl may be oxidized to form at least one C=O. The heterocycle may be bonded at any heteroatom or carbon atom of the ring or ring system, as permitted by valence. The rings of a polycyclic heterocyclyl or heterocycle may be fused, bridged, and / or linked through one or more spiro atoms. A fused system of a heterocycle or heterocyclyl with an aryl ring is considered to be a heterocycle or heterocyclyl regardless of which ring is attached to the core structure. A fused system of a heterocycle or heterocyclyl with a heteroaryl ring is considered to be a heteroaryl regardless of which ring is attached to the core structure.

[0066] Non-limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-imidazolinyl, pyrazolidinylimidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, , thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl , 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyi, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl. The term "aziridinyl" as used herein includes aziridin-1-yl and aziridin-2-yl. The term "oxiranyl" as used herein includes oxiranyl-2-yl. The term "thiiranyl" as used herein includes thiiran-2-yl. The term "azetidinyl" as used herein includes azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl. The term "oxetanyl" as used herein includes oxetan-2-yl and oxetan-3-yl. The term "thietanyl" as used herein includes thietan-2-yl and thietan-3-yl.The term "pyrrolidinyl" as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. The term "tetrahydrofuranyl" as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term "tetrahydrothiophenyl" as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term "succinimidyl" as used herein includes succinimid-1-yl and succinimid-3-yl. The term "dihydropyrrolyl" as used herein includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1H-pyrrol-3-yl, and 2,5-dihydropyrrol-5-yl. The term "2H-pyrrolyl" as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl, and 2H-pyrrol-5-yl. The term "3H-pyrrolyl" as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl, and 3H-pyrrol-5-yl. The term "dihydrofuranyl" as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl, and 2,5-dihydrofuran-5-yl. The term "dihydrothiophenyl" as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl, and 2,5-dihydrothiophen-5-yl. The term "imidazolidinyl" as used herein includes imidazolidin-1-yl, imidazolidin-2-yl, and imidazolidin-4-yl.The term "pyrazolidinyl" as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl, and pyrazolidin-4-yl. The term "imidazolinyl" as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl, and imidazolin-5-yl. The term "pyrazolinyl" as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4-yl, and 3-pyrazolin-5-yl. The term "dioxolanyl" as used herein, also known as "1,3-dioxolanyl", includes dioxolan-2-yl, dioxolan-4-yl, and dioxolan-5-yl. The term "dioxolyl" as used herein, also known as "1,3-dioxolyl", includes dioxol-2-yl, dioxol-4-yl, and dioxol-5-yl. The term "oxazolidinyl" as used herein, also known as "oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, and oxazolidin-5-yl. The term "isoxazolidinyl" as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl. The term "oxazolinyl" as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4-oxazolinyl-4-yl, and 4-oxazolinyl-5-yl.The term "isoxazolinyl" as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl, and 4-isoxazolinyl-5-yl. The term "thiazolidinyl" as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, and thiazolidin-5-yl. The term "isothiazolidinyl" as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, and isothiazolidin-5-yl. The term "thiazolinyl" as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl, and 4-thiazolinyl-5-yl. The term "isothiazolinyl" as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl, and 4-isothiazolinyl-5-yl. The term "piperidyl", also known as "piperidinyl", as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl, and piperid-4-yl.As used herein, the term "dihydropyridinyl" includes 1,2-dihydropyridin-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-3-yl, 1,4-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-3-yl, 1,4-dihydropyridin-5-yl, 1,4 ... yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl, and 3,4-dihydropyridin-6-yl. As used herein, the term “tetrahydropyridinyl” includes 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6 ...6-yl, 1,2,3,6-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-6-yl, 1 1,2,3,6-tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, and 2,3,4,5-tetrahydropyridin-6-yl.The term "tetrahydropyranyl", also known as "oxanyl" or "tetrahydro-2H-pyranyl", as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl. The term "2H-pyranyl" as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, and 2H-pyran-6-yl. The term "4H-pyranyl" as used herein includes 4H-pyran-2-yl, 4H-pyran-3-yl, and 4H-pyran-4-yl. The term "3,4-dihydro-2H-pyranyl" as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl, and 3,4-dihydro-2H-pyran-6-yl. The term "3,6-dihydro-2H-pyranyl" as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, and 3,6-dihydro-2H-pyran-5. -yl, and 3,6-dihydro-2H-pyran-6-yl. The term "tetrahydrothiophenyl" as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl-3-yl, and tetrahydrothiophenyl-4-yl. The term "2H-thiopyranyl" as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, and 2H-thiopyran-6-yl. The term "4H-thiopyranyl" as used herein includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, and 4H-thiopyran-4-yl. The term "3,4-dihydro-2H-thiopyranyl" as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl, and 3,4-dihydro-2H-thiopyran-6-yl. The term "3,6-dihydro-2H-thiopyranyl" as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl, and 3,6-dihydro-2H-thiopyran-6-yl. The term "piperazinyl", also known as "piperazidinyl", as used herein includes piperazin-1-yl and piperazin-2-yl. The term "morpholinyl", as used herein, includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term "thiomorpholinyl", as used herein, includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term "dioxanyl", as used herein, includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl.The term "dithianyl" as used herein includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl, and 1,4-dithian-2-yl. The term "oxathianyl" as used herein includes oxathian-2-yl and oxathian-3-yl. The term "trioxanyl" as used herein includes 1,2,3-trioxan-4-yl, 1,2,3-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl, and 1,3,4-trioxan-2-yl. The term "azepanyl" as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl. The term "homopiperazinyl" as used herein includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl, and homopiperazin-4-yl. The term "indolinyl" as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. The term "isoindolinyl" as used herein includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term "3H-indolyl" as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl.The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. The term "tetrahydroquinolinyl" as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl, and tetrahydroquinolin-8-yl. The term "tetrahydroisoquinolinyl" as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, and tetrahydroisoquinolin-8-yl. The term "chromanyl" as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, and chroman-8-yl. The term "1H-pyrrolidine" as used herein includes 1H-pyrrolidin-1-yl, 1H-pyrrolidin-2-yl, 1H-pyrrolidin-3-yl, 1H-pyrrolidin-5-yl, 1H-pyrrolidin-6-yl, and 1H-pyrrolidin-7-yl. The term "3H-pyrrolidine" as used herein includes 3H-pyrrolidin-1-yl, 3H-pyrrolidin-2-yl, 3H-pyrrolidin-3-yl, 3H-pyrrolidin-5-yl, 3H-pyrrolidin-6-yl, and 3H-pyrrolidin-7-yl.

[0067] The term "heteroaryl" refers to an aromatic ring system of 5-18 atoms, containing at least one N, O, S, or P, containing one ring or two rings, which may be fused or covalently bonded together, each ring typically containing 5-6 atoms, at least one of said rings being aromatic, wherein the N and S heteroatoms may be optionally oxidized, the N heteroatoms may be optionally quaternized, and at least one carbon atom of said heteroaryl may be oxidized to form at least one C=O. A fused system of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring is considered heteroaryl, regardless of the ring attached to the core structure. A fused system of a heteroaryl ring with a heterocyclic ring is considered heteroaryl, regardless of the ring attached to the core structure. A fused system of a heteroaryl ring with an aryl ring is considered heteroaryl, regardless of the ring attached to the core structure.Non-limiting examples of such heteroaryls include triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl ... no[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, schizo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridin ...schizo[d]oxazol-2(3H)-one, schizo[d]oxazol-2(3H)-one, schi In some embodiments, the heteroaryl group is selected from the group including pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl, and thiazolyl. In some embodiments, the heteroaryl group is selected from the group including pyridyl, pyrazinyl, pyrimidinyl, indolyl, and benzimidazolyl.

[0068] The term "pyrrolyl" (also known as azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl. The term "furanyl" (also known as furyl) as used herein includes furan-2-yl and furan-3-yl (also known as furan-2-yl and furan-3-yl). The term "thiophenyl" (also known as thienyl) as used herein includes thiophen-2-yl and thiophen-3-yl (also known as thien-2-yl and thien-3-yl). The term "pyrazolyl" (also known as 1H-pyrazolyl and 1,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl, or 1H-pyrazol-5-yl, pyrazol-4-yl, and pyrazol-5-yl. The term "imidazolyl" as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl. The term "oxazolyl" (also known as 1,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl. The term "isoxazolyl" (also known as 1,2-oxazolyl) as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term "thiazolyl" (also known as 1,3-thiazolyl) as used herein includes thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl (also known as 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). As used herein, the term "isothiazolyl" (also known as 1,2-thiazolyl) includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. As used herein, the term "triazolyl" includes triazol-2-yl, 1H-triazolyl, and 4H-1,2,4-triazolyl, and "1H-triazolyl" includes 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, and 1H-1,2,4-triazol-5-yl."4H-1,2,4-triazolyl" includes 4H-1,2,4-triazol-4-yl and 4H-1,2,4-triazol-3-yl. The term "oxadiazolyl" as used herein includes 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, and 1,3,4-oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl (also known as furazan-3-yl), and 1,3,4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl. The term "pyridinyl" (also known as "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also known as 2-pyridyl, 3-pyridyl, and 4-pyridyl). The term "pyrimidyl" as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl, and pyrimid-6-yl. The term "pyrazinyl" as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term "pyridazinyl" as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term "oxazinyl" (also known as "1,4-oxazinyl") as used herein includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl.The term "dioxinyl" (also known as "1,4-dioxinyl") as used herein includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. The term "thiazinyl" (also known as "1,4-thiazinyl") as used herein includes 1,4-thiazin-2-yl, 1,4-thiazin-3-yl, 1,4-thiazin-4-yl, 1,4-thiazin-5-yl, and 1,4-thiazin-6-yl. The term "triazinyl" as used herein includes 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, and 1,2,3-triazin-5-yl. The term "imidazo[2,1-b][1,3]thiazolyl" as used herein includes imidazo[2,1-b][1,3]thiazol-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1-b][1,3]thiazol-5-yl, and imidazo[2,1-b][1,3]thiazol-6-yl. The term "thieno[3,2-b]furanyl" as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. As used herein, the term "thieno[3,2-b]thiophenyl" includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl, and thieno[3,2-b]thien-6-yl. As used herein, the term "thieno[2,3-d][1,3]thiazolyl" includes thieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3-d][1,3]thiazol-5-yl, and thieno[2,3-d][1,3]thiazol-6-yl. As used herein, the term "thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl, and thieno[2,3-d]imidazol-5-yl.The term "tetrazolo[1,5-a]pyridinyl" as used herein includes tetrazolo[1,5-a]pyridin-5-yl, tetrazolo[1,5-a]pyridin-6-yl, tetrazolo[1,5-a]pyridin-7-yl, and tetrazolo[1,5-a]pyridin-8-yl. The term "indolyl" as used herein includes indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term "isoindolyl" as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl, and isoindol-7-yl. The term "benzofuranyl" (also known as benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, and benzofuran-7-yl. The term "isobenzofuranyl" (also known as benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, and isobenzofuran-7-yl. The term "benzothiophenyl" (also known as benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, and -7-benzo[b]thiophenyl (also known as benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl, and benzothien-7-yl).The term "isobenzothiophenyl" (also known as benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl, and isobenzothien-7-yl. The term "indazolyl" (also known as 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term "benzoimidazolyl" as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, and benzimidazol-7-yl. The term "1,3-benzoxazolyl" as used herein includes 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, and 1,3-benzoxazol-7-yl. The term "1,2-benzoisoxazolyl" as used herein includes 1,2-benzoisoxazol-3-yl, 1,2-benzoisoxazol-4-yl, 1,2-benzoisoxazol-5-yl, 1,2-benzoisoxazol-6-yl, and 1,2-benzoisoxazol-7-yl. The term "2,1-benzisoxazolyl" as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl, and 2,1-benzisoxazol-7-yl.The term "1,3-benzothiazolyl" as used herein includes 1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, and 1,3-benzothiazol-7-yl. The term "1,2-benzisothiazolyl" as used herein includes 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, and 1,2-benzisothiazol-7-yl. The term "2,1-benzisothiazolyl" as used herein includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl, and. The term "benzotriazolyl" as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, and benzotriazol-7-yl. The term "1,2,3-benzoxadiazolyl" as used herein includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1,2,3-benzoxadiazol-6-yl, and 1,2,3-benzoxadiazol-7-yl. The term "2,1,3-benzoxadiazolyl" as used herein includes 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl, and 2,1,3-benzoxadiazol-7-yl. The term "1,2,3-benzothiadiazolyl" as used herein includes 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl, and 1,2,3-benzothiadiazol-7-yl. The term "2,1,3-benzothiadiazolyl" as used herein includes 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl, and 2,1,3-benzothiadiazol-7-yl. The term "thienopyridinyl" as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, and thieno[3,2-b]pyridinyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl, and purin-8-yl. The term "imidazo[1,2-a]pyridinyl" as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, and imidazo[1,2-a]pyridin-7-yl.The term "1,3-benzodioxolyl" as used herein includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term "quinolinyl" as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl. The term "cinnolinyl" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl. The term "quinoxalinyl" as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0069] Heteroaryl and heterocycle or heterocyclyl as used herein include, by way of example and without limitation, those groups described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950-present), especially Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, CW, and Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0070] The term “heterocyclyloxy” or “heterocycleoxy” as a group or part of a group refers to a group of the formula —OR i In the formula, R i is heterocyclyl as defined hereinabove.

[0071] The term “heterocyclylalkyloxy” or “heterocycleoxy” as a group or part of a group refers to a group of the formula —OR a -R i In the formula, R i is heterocyclyl as defined hereinabove, and R a is alkyl.

[0072] The term “heteroaryloxy” as a group or part of a group refers to a heteroaryl group of the formula —OR k In the formula, R k is heteroaryl as defined hereinbefore.

[0073] The term “heteroarylalkyloxy” as a group or part of a group refers to a heteroaryl group of the formula —OR a -R i In the formula, R i is heteroaryl as defined hereinabove; R a is alkyl.

[0074] The term "heterocyclyl-alkyl" or "heterocycle-alkyl" as a group or part of a group refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with a heterocyclyl. A non-limiting example of a heterocyclyl-alkyl or heterocycle-alkyl group is 2-piperidinyl-methylene. The heterocyclyl-alkyl or heterocycle-alkyl group can contain 6 to 20 atoms, e.g., the alkyl portion is 1 to 6 carbon atoms and the heterocyclyl portion is 3 to 14 atoms.

[0075] The term "heterocyclyl-alkenyl" or "heterocycle-alkenyl" as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl. The heterocyclyl-alkenyl or heterocycle-alkenyl group can contain 6 to 20 atoms, e.g., the alkenyl portion is 2 to 6 carbon atoms and the heterocyclyl portion is 3 to 14 atoms.

[0076] The term "heterocyclyl-alkynyl" or "heterocycle-alkynyl" as a group or part of a group refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom has been replaced with a heterocyclyl. The heterocyclyl-alkynyl or heterocycle-alkynyl group can contain 6 to 20 atoms, e.g., the alkynyl portion can contain 2 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms.

[0077] The term "heterocyclyl-heteroalkyl" or "heterocycle-heteroalkyl" as a group or part of a group refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) has been replaced with a heterocyclyl. The heterocyclyl-heteroalkyl or heterocycle-heteroalkyl group can contain 6 to 20 atoms, e.g., the heteroalkyl portion can contain 1 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms. In some embodiments, the heterocyclyl-heteroalkyl or heterocycle-heteroalkyl is selected from the group including heterocyclyl-O-alkyl, heterocyclylalkyl-O-alkyl, heterocyclyl-NH-alkyl, heterocyclyl-N(alkyl), heterocyclylalkyl-NH-alkyl, heterocyclylalkyl-N-(alkyl), heterocyclyl-S-alkyl, and heterocyclylalkyl-S-alkyl.

[0078] The term "heterocyclyl-heteroalkenyl" or "heterocycle-heteroalkenyl" as a group or part of a group refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl. The heterocyclyl-heteroalkenyl or heterocycle-heteroalkenyl group can contain 6 to 20 atoms, e.g., the heteroalkenyl portion can contain 2 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms. In some embodiments, the heterocyclyl-heteroalkenyl or heterocycle-heteroalkenyl is selected from the group including heterocyclyl-O-alkenyl, heterocyclylalkyl-O-alkenyl, heterocyclyl-NH-alkenyl, heterocyclyl-N(alkenyl)2, heterocyclylalkyl-NH-alkenyl, heterocyclylalkyl-N-(alkenyl)2, heterocyclyl-S-alkenyl, and heterocyclylalkenyl-S-alkenyl.

[0079] The term "heterocyclyl-heteroalkynyl" or "heterocycle-heteroalkynyl" as a group or part of a group refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl. The heterocyclyl-heteroalkynyl or heterocycle-heteroalkynyl group can contain 6 to 20 atoms, e.g., the heteroalkynyl portion can contain 2 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms. In some embodiments, the heterocyclyl-heteroalkynyl is selected from the group including heterocyclyl-O-alkynyl, heterocyclylalkynyl-O-alkynyl, heterocyclyl-NH-alkynyl, heterocyclyl-N(alkynyl)2, heterocyclylalkynyl-NH-alkynyl, heterocyclylalkynyl-N-(alkynyl)2, heterocyclyl-S-alkynyl, and heterocyclylalkynyl-S-alkynyl.

[0080] The term "heteroaryl-alkyl" as a group or part of a group refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with a heteroaryl. An example of a heteroaryl-alkyl group is 2-pyridyl-methylene. The heteroaryl-alkyl group can contain 6 to 20 atoms, e.g., the alkyl portion of the heteroaryl-alkyl group can contain 1 to 6 carbon atoms and the heteroaryl portion can contain 5 to 14 atoms.

[0081] The term "heteroaryl-alkenyl" as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl. The heteroaryl-alkenyl group can contain 6 to 20 atoms, e.g., the alkenyl portion of the heteroaryl-alkenyl group can contain 2 to 6 carbon atoms and the heteroaryl portion can contain 5 to 14 atoms.

[0082] The term "heteroaryl-alkynyl" as a group or part of a group as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl. The heteroaryl-alkynyl group contains 6 to 20 atoms, e.g., the alkynyl portion of the heteroaryl-alkynyl group is 2 to 6 carbon atoms and the heteroaryl portion is 5 to 14 atoms.

[0083] The term "heteroaryl-heteroalkyl" as a group or part of a group as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with a heteroaryl. The heteroaryl-heteroalkyl group contains 7-20 atoms, e.g., the heteroalkyl portion of the heteroaryl-heteroalkyl group is 2-6 carbon atoms and the heteroaryl portion is 5-14 atoms. In some embodiments, the heteroaryl-heteroalkyl is selected from the group including heteroaryl-O-alkyl, heteroarylalkyl-O-alkyl, heteroaryl-NH-alkyl, heteroaryl-N(alkyl)2, heteroarylalkyl-NH-alkyl, heteroarylalkyl-N-(alkyl)2, heteroaryl-S-alkyl, and heteroarylalkyl-S-alkyl.

[0084] The term "heteroaryl-heteroalkenyl" as a group or part of a group as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl. The heteroaryl-heteroalkenyl group contains 8-20 atoms, e.g., the heteroalkenyl portion of the heteroaryl-heteroalkenyl group is 3-6 carbon atoms and the heteroaryl portion is 5-14 atoms. In some embodiments, the heteroaryl-heteroalkenyl is selected from the group including heteroaryl-O-alkenyl, heteroarylalkenyl-O-alkenyl, heteroaryl-NH-alkenyl, heteroaryl-N(alkenyl)2, heteroarylalkenyl-NH-alkenyl, heteroarylalkenyl-N-(alkenyl)2, heteroaryl-S-alkenyl, and heteroarylalkenyl-S-alkenyl.

[0085] The term "heteroaryl-heteroalkynyl" as a group or part of a group as used herein refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl. The heteroaryl-heteroalkynyl group contains 8-20 atoms, e.g., the heteroalkynyl portion of the heteroaryl-heteroalkynyl group is 2-6 carbon atoms and the heteroaryl portion is 5-14 atoms. In some embodiments, the heteroaryl-heteroalkynyl is selected from the group including heteroaryl-O-alkynyl, heteroarylalkynyl-O-alkynyl, heteroaryl-NH-alkynyl, heteroaryl-N(alkynyl)2, heteroarylalkynyl-NH-alkynyl, heteroarylalkynyl-N-(alkynyl)2, heteroaryl-S-alkynyl, and heteroarylalkynyl-S-alkynyl.

[0086] As examples, a carbon-linked heteroaryl or heterocyclic ring (or heterocycle) may be bonded at the 2-, 3-, 4-, 5-, or 6-position of a pyridine, the 3-, 4-, 5-, or 6-position of a pyridazine, the 2-, 4-, 5-, or 6-position of a pyrimidine, the 2-, 3-, 5-, or 6-position of a pyrazine, the 2-, 3-, 4-, or 5-position of a furan, tetrahydrofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of an oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of an isoxazole, pyrazole, or isothiazole, the 2- or 3-position of an aziridine, the 2-, 3-, or 4-position of an azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of a quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of an isoquinoline. Even more typically, carbon-linked heteroaryls and heterocyclyls include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen-linked heterocyclic rings are attached at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, nitrogen-linked heteroaryls or heterocyclyls include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0087] As used herein, and unless otherwise stated, the terms "alkoxy", "cyclo-alkoxy", "aryloxy", "arylalkyloxy", "heteroaryloxy", "heterocyclyloxy", "alkylthio", "cycloalkylthio", "arylthio", "arylalkylthio", "heteroarylthio", and "heterocyclylthio" refer to a substituent in which an alkyl group, a cycloalkyl, an aryl, an arylalkylheteroaryl, or a heterocyclyl, respectively, as defined herein, is attached to an oxygen or sulfur atom through a single bond, such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl, etc. The same definitions apply to alkenyl and alkynyl instead of alkyl.

[0088] The term “alkylthio” as a group or part of a group refers to a group of the formula —SR b In the formula, R b is alkyl, as defined hereinabove. Non-limiting examples of alkylthio groups include methylthio (-SCH3), ethylthio (-SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.

[0089] The term “alkenylthio” as a group or part of a group means a group of the formula —SR d In the formula, R d is alkenyl as defined hereinabove.

[0090] The term "alkynylthio" as a group or part of a group refers to a group of the formula -SR e In the formula, R e is alkynyl as defined hereinabove.

[0091] The term “arylthio” as a group or part of a group refers to a group of the formula —SR g In the formula, Rg is aryl as defined hereinbefore.

[0092] The term “arylalkylthio” as a group or part of a group refers to a group of the formula —SR a -R g In the formula, R a is alkylene as defined hereinabove; R g is aryl.

[0093] The term “heterocyclylthio” as a group or part of a group means a heterocyclyl group of the formula —SR i In the formula, R i is heterocyclyl as defined hereinabove.

[0094] The term “heteroarylthio” as a group or part of a group refers to a heteroaryl group of the formula —SR k In the formula, R k is heteroaryl as defined hereinabove.

[0095] The term "heterocyclylalkylthio" as a group or part of a group means a heterocyclylalkylthio group of the formula -SR a -R i In the formula, R a is alkylene as defined hereinabove; R i is heterocyclyl.

[0096] The term “heteroarylalkylthio” as a group or part of a group refers to a heteroaryl group of the formula —SR a -R k In the formula, R a is alkylene as defined hereinabove; R k is heteroaryl.

[0097] The term “mono- or di-alkylamino” as a group or part of a group refers to a group of the formula —N(R o )(R b ) group, wherein R ois hydrogen or alkyl, and R b is alkyl. Thus, alkylamino includes mono-alkylamino groups (e.g., mono-alkylamino groups such as methylamino and ethylamino) and di-alkylamino groups (e.g., di-alkylamino groups such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, i-butylamino, sec-butylamino, t-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-i-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-i-propylamino, n-butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n-propylamino, ethyl-i-propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di-n-butylamino, di-i-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

[0098] The term “mono- or di-arylamino” as a group or part of a group refers to a group of the formula —N(R q )(R r ) group, wherein R q and R r are each independently selected from hydrogen, aryl, or alkyl; R q or R r At least one of is aryl.

[0099] The term “mono- or di-heteroarylamino” as a group or part of a group refers to a group of the formula —N(R u )(R v ) group, wherein R u and R v are each independently selected from hydrogen, heteroaryl, or alkyl; R u or R vAt least one of is heteroaryl, as defined herein.

[0100] The term “mono- or di-heterocyclylamino” as a group or part of a group refers to a group of the formula —N(R w )(R x ) group, wherein R w and R x are each independently selected from hydrogen, heterocyclyl, or alkyl; R w or R x At least one of is heterocyclyl, as defined herein.

[0101] As used herein, and unless otherwise specified, the term halogen means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0102] As used herein, the term "optionally containing one or more heteroatoms, said heteroatoms being selected from the group consisting of O, S, and N" refers to a group in which one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, and thus includes, inter alia, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, heteroarylheteroalkynyl, etc., depending on the group being referred to. Thus, the term includes, by way of example, alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-heteroalkyl, heterocyclyl-heteroalkyl, heteroaryl-alkoxy, heterocyclyl-alkoxy, etc., depending on the group being referred to. As an example, the term "alkyl optionally containing one or more heteroatoms selected from the group consisting of O, S, and N" thus refers to heteroalkyl, i.e., alkyl containing one or more heteroatoms in the hydrocarbon chain, but the heteroatoms may be located at the beginning, middle, or end of the hydrocarbon chain. Examples of heteroalkyl include methoxy, methylthio, ethoxy, propoxy, CH3-O-CH2-, CH3-S-CH2-, CH3-CH2-O-CH2-, CH3-NH-, (CH3)2-N-, (CH3)2-CH2-NH-CH2-CH2-, but there are many more examples. As an example, the term "arylalkylene optionally containing one or more heteroatoms in the alkylene chain, which heteroatoms are selected from the group consisting of O, S, and N" thus refers to arylheteroalkylene, i.e., arylalkylene containing one or more heteroatoms in the hydrocarbon chain, but the heteroatoms may be located at the beginning, middle, or end of the hydrocarbon chain.Thus, "arylheteroalkylene" includes aryloxy, arylalkoxy, aryl-alkyl-NH-, and the like, examples of which are phenyloxy, benzyloxy, aryl-CH2-S-CH2-, aryl-CH2-O-CH2-, aryl-NH-CH2-, among many others. The same applies to terms such as "heteroalkenylene," "heteroalkynylene," and the like, as used herein "optionally containing one or more heteroatoms, the heteroatoms being selected from the group consisting of O, S, and N."

[0103] As used herein, the term relating to a chemical group in which "two or more hydrogen atoms adjacent to a carbon atom or heteroatom of said group are optionally available together to form =O or =S" refers to a group in which two or more hydrogen atoms adjacent to a carbon atom or heteroatom of said group are available together to form =O or =S. By way of example, this term refers to "an alkyl in which two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl may optionally join together to form =O or =S," including, among other examples, CH3-C(O)-CH2-, CH3-C(O)-, CH3-C(S)-CH2-, CH3-S(O)2-CH2-, and (CH3)2-CH2-C(O)-CH2-CH2-.

[0104] The combination of the group "optionally containing one or more heteroatoms, said heteroatoms being selected from the group consisting of O, S, and N" and "optionally two or more hydrogen atoms adjacent to carbon atoms or heteroatoms of said group are available together to form =O or =S" can combine the two aspects described herein above, and when the group refers to alkyl, includes CH3-C(O)O-, CH3-C(O)O-CH2-, CH3-NH-C(O)-, CH3-C(O)-NH-, CH3-NH-C(O)-CH2-, CH3-NH-C(S)-CH2-, CH3-NH-C(S)-NH-CH2-, CH3-NH-S(O)2-, and CH3-NH-S(O)2-NH-CH2-, among other examples.

[0105] The term "single bond" as used herein with respect to a linking group (i.e., in formulas herein where a particular linking group is selected from a single bond, etc.) refers to a molecule in which the linking group is absent, and thus refers to a compound in which the two moieties to be joined by the linking group are directly linked via a single bond.

[0106] As used herein with respect to substituents, and unless otherwise specified, the term "substituted" as in "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted aryl," "substituted heteroaryl," "substituted heterocyclyl," "substituted arylalkyl," "substituted heteroaryl-alkyl," "substituted heterocyclyl-alkyl," etc., refers to a chemical structure as defined herein, wherein said alkyl, alkenyl, alkynyl, group and / or said aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more (preferably 1, 2, 3, 4, 5, or 6) substituents, meaning that one or more hydrogen atoms are each independently replaced with at least one substituent. Exemplary substituents include, but are not limited to, the following, and in certain embodiments the substituents are independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl-alkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl-alkyl, heterocyclyl-alkyl, heteroaryl-alkenyl, heterocyclyl-alkenyl and heteroaryl-alkynyl, heterocyclyl-alkynyl, -X, -Z, -O-, -OZ, =O, -SZ, -S - , =S, -NZ2, -N +Z3, =NZ, =N-OZ, -CX3 (e.g. trifluoromethyl), -CN, -OCN, -SCN, -N=C=O, -N=C=S, -NO, -NO2, =N2, -N3, -NZC(O)Z, -NZC(S)Z, -NZC(O)O - , -NZC(O)OZ, -NZC(S)OZ, -NZC(O)NZZ, NZC(NZ)Z, NZC(NZ)NZZ, -C(O)NZZ, -C(NZ)Z, -S(O)2O-, -S(O)2OZ, -S(O )2Z, -OS(O)2OZ, -OS(O)2Z, -OS(O)2O-, -S(O)2NZZ, -S(O)(NZ)Z, -S(O)Z, -OP(O)(OZ)2, -P(O)(OZ)2, -P(O)(O - )2, -P(O)(OZ)(O - ), -P(O)(OH), -C(O)Z, -C(O)X, -C(S)Z, -C(O)OZ, -C(O)O-, -C(S)OZ, -C(O)SZ, -C(S)SZ, -C(O)NZZ, -C(S)NZZ, -C(NZ)NZZ, -OC(O)Z, -OC(S)Z, -OC(O)O-, -OC(O)OZ, -OC(S)OZ, where each X is independently a halogen selected from F, Cl, Br, or I, and each Z is independently -H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, protecting group, or prodrug moiety, but where two Z's attached to a nitrogen atom may together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl. Alk(ene), alken(en)yl, and alkyn(en)yl groups can also be similarly substituted.

[0107] Any substituent designation that occurs at more than one site in a compound of the present disclosure is intended to be independently selected.

[0108] Substituents are optionally depicted with or without bonds. Regardless of the depiction of a bond, if a substituent is multivalent (based on its position in the referenced structure), any and all possible configurations of the substituent are intended.

[0109] As used herein, and unless otherwise specified, the term "solvate" includes any combination that may be formed with a derivative of the present disclosure and a suitable inorganic solvent (e.g., hydrate) or organic solvent (e.g., but not limited to, alcohols, ketones, esters, ethers, nitriles, etc.).

[0110] The term "heteroatom(s)" as used herein means atoms selected from nitrogen, oxygen, and sulfur, including sulfoxide and sulfone, which may be quaternized.

[0111] The term "hydroxy" as used herein means --OH.

[0112] The term "carbonyl" as used herein means a carbon atom attached with a double bond to oxygen, i.e., C=O.

[0113] As used herein, the term "amino" refers to the group --NH.

[0114] The present disclosure provides novel compounds that have been shown to possess YAP / TAZ-TEAD transcriptional inhibitory activity. The present disclosure further demonstrates that these compounds efficiently inhibit TEAD activation, thereby inhibiting YAP / TAZ-TEAD transcriptional activation. Thus, these compounds constitute a useful class of new, potent compounds that can be used in the treatment and / or prevention of YAP / TAZ-TEAD activation-mediated diseases in subjects, more specifically, for the treatment and / or prevention of cancer and fibrosis, among other diseases.

[0115] The present disclosure further relates to compounds for use as pharmaceuticals and their use in the manufacture of a medicament for treating and / or preventing cancer or fibrosis. The present disclosure relates to compounds for use as pharmaceuticals for treating and / or preventing YAP / TAZ-TEAD activation mediated diseases, such as cancer or fibrosis, in animals, mammals, and more particularly in humans. The present disclosure also relates to methods for the preparation of all such compounds, and pharmaceutical compositions comprising them in effective amounts. The present disclosure also relates to methods for treating or preventing cancer or fibrosis in humans by administering one or more such compounds, optionally in combination with one or more other pharmaceuticals, to a patient in need thereof. The present disclosure also relates to compounds for veterinary use and their use as pharmaceuticals for the prevention or treatment of diseases in non-human mammals, such as cancer and fibrosis in non-human mammals.

[0116] In one embodiment, the compounds of the present disclosure have Formula I: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 , (c) C2-C6 alkynyl, (iii) Unsubstituted or substituted C6-C 10 Aryl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of (v) unsubstituted or substituted C3-C6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 , (vi) An unsubstituted or substituted C3-C6 heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 , (vii) -S(=O)Z 2 , and (viii) -C(=O)Z 2 , R 2 and R 3 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; Y 1 -CR 4a R 4b - and -NR 5 - selected from the group consisting of R 4a -NR 6a R 6b and R 4b is selected from the group consisting of hydrogen and C1-C6 alkyl; R 5 is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) cyano, (b) hydroxy, (c)-OZ1 , (d) -C(=O)OH, (e) -C(=O)Z 2 , (f)-C(=O)OZ 2 , (g) -C(=O)NZ 3 Z 4 , (h)-S(=O)2Z 2 , (i)-S(=O)2NZ 3 Z 4 , (j)-S(=O)(=NZ 5 )Z 2 , (k)-S(=NZ 5 )(=NZ 6 )Z 2 , and (l)-S(=O)(=NZ 5 )NZ 3 Z 4 , (iii) C1-C6 haloalkyl, and (iv) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; R 6a is selected from the group consisting of: (i) -C(=O)Z 2 (ii) -C(=O)OZ 2 , (iii) -C(=O)NZ 3 Z 4 , (iv) -S(=O)Z 2 , (v)-S(=O)2NZ 3 Z 4 , (vi)-S(=O)(=NZ 5 )Z 2 , (vii)-S(=NZ 5 )(=NZ 6 )Z 2 , and (viii)-S(=O)(=NZ 5 )NZ 3 Z 4 , R 6b is selected from the group consisting of hydrogen and C1-C6 alkyl; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl, each Z 2 are independently selected from the group consisting of: (i) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; (ii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, (vi) C1-C6 haloalkyl, (vii) Unsubstituted or substituted C6-C 10Aryl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 and (viii) unsubstituted or substituted C3-C6 cycloalkyl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of each Z 3 and Z 4 are independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 , (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) C2-C6 alkynyl (iii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl, each Z 5 and Z 6 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl, X is -CR 7a = and -N=; X 1 -CR 7b = and -N=; X 2 -CR 7c = and -N=; X 3 -CR 7d = and -N=; R 7a , R 7b , R 7c , and R 7d is hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of:

[0117] In another embodiment, the compound of the present disclosure has formula II: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 1 , R 5 , X, X 1 , X 2 , and X 3 is as defined in relation to formula I.

[0118] In another embodiment, the compound of the present disclosure is a compound of formula I or II, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 5 is an unsubstituted or substituted C1-C6 alkyl, one substituent being hydroxy, -C(=O)OH, and -C(=O)NZ; 3 Z 4 . is selected from the group consisting of.

[0119] In another embodiment, the compound of the present disclosure has formula III: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 1 , R 6a , X, X 1 , X 2 , and X 3 is as defined in relation to formula I.

[0120] In another embodiment, the compound of the disclosure is a compound of Formula I or III, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 6a is -C(=O)Z 2 and unsubstituted or substituted C1-C6 alkyl, and Z 2 is selected from the group consisting of: (i) C1-C6 alkyl, and (ii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , and 4- to 8-membered heterocycles.

[0121] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-III, or a stereoisomer, tautomer, pharma-ceutically acceptable salt, or solvate thereof, wherein R 1 is unsubstituted or substituted C6-C 10 aryl, where one or more of the substituents are halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of:

[0122] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-III, or a stereoisomer, tautomer, pharma-ceutically acceptable salt, or solvate thereof, wherein: X is -CR 7a = X 1 -CR 7b = X 2 -CR 7c = and X 3 -CR 7d =.

[0123] In another embodiment, the compound of the present disclosure is a compound of formula I, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: 1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 3-(3-hydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetic acid, 3-(2-hydroxyethyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide, N-methyl-2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide, and N-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acrylamide.

[0124] Preferred or specific descriptions (features) and embodiments of the compounds of the present disclosure are defined herein below. Each description, aspect, and embodiment of the present disclosure thus defined may be combined with any other description, aspect, and / or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as being preferred, specific, or advantageous may be combined with any other feature or description indicated as being preferred, specific, or advantageous. Here, the present disclosure is captured in detail by any one or any combination of one or more of the following numbered descriptions and embodiments with any other description, aspect, and / or embodiment (not numbered).

[0125] Embodiment 1. A compound of formula I: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 , (c) C2-C6 alkynyl, (iii) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of (v) unsubstituted or substituted C3-C6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 , (vi) An unsubstituted or substituted C3-C6 heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 , (vii) -S(=O)Z 2 , and (viii) -C(=O)Z 2 , R 2 and R 3 is independently selected from the group consisting of hydrogen and C1-C6 alkyl; Y 1 -CR 4a R 4b - and -NR 5 is selected from the group consisting of R 4a -NR 6a R 6band R 4b is selected from the group consisting of hydrogen and C1-C6 alkyl; R 5 is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) cyano, (b) hydroxy, (c)-OZ 1 , (d) -C(=O)OH, (e) -C(=O)Z 2 , (f)-C(=O)OZ 2 , (g) -C(=O)NZ 3 Z 4 , (h)-S(=O)2Z 2 , (i)-S(=O)2NZ 3 Z 4 , (j)-S(=O)(=NZ 5 )Z 2 , (k)-S(=NZ 5 )(=NZ 6 )Z 2 , and (l)-S(=O)(=NZ 5 )NZ 3 Z 4 , (iii) C1-C6 haloalkyl, and (iv) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; R 6a is selected from the group consisting of: (i) -C(=O)Z 2 , (ii) -C(=O)OZ 2 , (iii) -C(=O)NZ 3 Z4 , (iv) -S(=O)Z 2 , (v)-S(=O)2NZ 3 Z 4 , (vi)-S(=O)(=NZ 5 )Z 2 , (vii)-S(=NZ 5 )(=NZ 6 )Z 2 , and (viii)-S(=O)(=NZ 5 )NZ 3 Z 4 , R 6b is selected from the group consisting of hydrogen and C1-C6 alkyl; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl, each Z 2 are independently selected from the group consisting of: (i) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of cyano, and C2-C6 alkynyl; (ii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ3 Z 4 and 4- to 8-membered heterocycles; (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, (vi) C1-C6 haloalkyl, (vii) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 and (viii) unsubstituted or substituted C3-C6 cycloalkyl, where one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of each Z 3 and Z 4 are independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C6-C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 , (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) C2-C6 alkynyl, (iii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl, each Z 5 and Z 6 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl, X is -CR 7a = and -N=; X 1 -CR 7b = and -N=; X 2 -CR 7c = and -N=; X 3-CR 7d = and -N=, and Each R 7a , R 7b , R 7c , and R 7d is hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -OZ 1 are independently selected from the group consisting of:

[0126] Embodiment 2. Formula II: [ka] 2. The compound of claim 1, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0127] Embodiment 3.R 5 is an unsubstituted or substituted C1-C6 alkyl, one or more of the substituents being hydroxy, -C(=O)OH, and -C(=O)NZ. 3 Z 4 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0128] Embodiment 4. Formula III: [ka] 2. The compound of claim 1, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0129] Embodiment 5.R 6a is -C(=O)Z 2 and unsubstituted or substituted C1-C6 alkyl, and Z 2 is selected from the group consisting of: (i) C1-C6 alkyl, and (ii) unsubstituted or substituted C2-C6 alkenyl, where one or more of the substituents is cyano, -S(=O)2Z 2, -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 5. The compound according to embodiment 1-4, wherein each of the rings is independently selected from the group consisting of: , 4-8 membered heterocycles, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0130] Embodiment 6.R 1 is unsubstituted or substituted C6-C 10 aryl, where one or more of the substituents are halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and -OZ 1 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, of any one of embodiments 1-5, independently selected from the group consisting of:

[0131] Embodiment 7.X is -CR 7a = X 1 -CR 7b = X 2 -CR 7c = X 3 -CR 7d 7. The compound of any one of embodiments 1-6, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

[0132] Embodiment 8. 1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 3-(3-hydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetic acid, 3-(2-hydroxyethyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide, N-methyl-2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide, and The compound of embodiment 1, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of N-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acrylamide.

[0133] Embodiment 9. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 8, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

[0134] Embodiment 10. A compound according to any one of embodiments 1 to 8 or a pharmaceutical composition according to claim 9 for use as a medicament.

[0135] Embodiment 11. A compound according to any one of embodiments 1 to 8, or a pharmaceutical composition according to embodiment 9, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human.

[0136] Embodiment 12. The compound of embodiment 11 or the pharmaceutical composition of embodiment 11, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from the group including cancer, fibrosis, and YAP / TAZ-TEAD activation-mediated congenital disorder.

[0137] Embodiment 13. The compound of embodiment 12, or the pharmaceutical composition of embodiment 12, wherein the YAP / TAZ-TEAD activation mediated disorder is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma.

[0138] Embodiment 14. A method for the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human, comprising administering to said animal, mammal or human in need of such prevention or treatment an effective dose of a compound according to any one of embodiments 1 to 8.

[0139] Embodiment 15. A method of treating or preventing a YAP / TAZ-TEAD activation mediated disorder according to embodiment 14 in combination with one or more other medicaments selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor, for a patient in need thereof.

[0140] More broadly, the present disclosure relates to compounds of the formulas described herein, and embodiments, descriptions and aspects thereof that are useful as biologically active agents or as diagnostic agents. Any uses referred to in the present disclosure may be limited to non-medical, non-therapeutic, non-diagnostic, or in vitro only, or in association with cells separate from an animal.

[0141] The compounds of the present disclosure are small molecule YAP / TAZ-TEAD inhibitors. Small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers including, but not limited to, lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers characterized by squamous cell carcinoma of the lung, cervix, ovary, head and neck, esophagus, and / or skin. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers arising from neuroectodermal derived tissues, such as ependymomas, meningiomas, schwannomas, peripheral nerve sheath tumors, and / or neuroblastomas. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating vascular cancers such as epithelioid hemangioendothelioma, or for treating supratentorial ependymoma or polocarcinoma. In some embodiments, the solid tumor has a gain-of-function gene amplification, gene fusion, or activating mutation in the YAP1 or WWTR1 (TAZ) genes. In some embodiments, the solid tumor has a loss-of-function mutation or deletion in the NF2, LATS1 / 2, BAP1, FAT1, SAV1, and / or MST1 / 2 genes. In some embodiments, the solid tumor has a gain-of-function mutation in the GNAQ and / or GNA11 genes, for example in uveal melanoma. In some embodiments, the solid tumor is characterized by constitutive nuclear presence of YAP and / or TAZ. In some embodiments, the solid tumor is characterized by overexpression of YAP / TAZ-TEAD signature genes, including but not limited to CTGF, CYR61, AMOTL2, and / or ANKRD1.

[0142] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating cancers that have developed resistance to previous treatments. This may include, for example, treating cancers that have developed resistance to chemotherapy or targeted therapy. In some embodiments, this may include treatment of cancers that have developed resistance to receptor tyrosine kinase inhibitors, such as those against EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or those against AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), or those against RAS itself. This may include treating cancers that have developed resistance to components of the RAS-MAPK signaling cascade, including inhibitors (e.g., AMG510, MRTX849, BI1701963, ARS1620), inhibitors of B-RAF (sorafenib tosylate, dabrafenib, vemurafenib, regorafenib), or inhibitors of MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0143] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in combination with other agents used in the treatment of cancer, either co-administered or subsequently administered, such as inhibitors or monoclonal antibodies targeting receptor tyrosine kinases, such as those against EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), and those against RA. These may include combination treatment with inhibitors of S itself (e.g., AMG510, MRTX849, BI1701963, ARS1620), inhibitors of B-RAF (sorafenib tosylate, dabrafenib, vemurafenib, regorafenib), or inhibitors of MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0144] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating metastatic cancers. In some cases, the metastatic cancer is selected from metastatic uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma.

[0145] In some embodiments, the cancer being treated may be malignant pleural mesothelioma or lung cancer.

[0146] In some embodiments, the compounds of the present disclosure are useful in treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and ovarian cancer. Intestinal cancer, colon cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia Disease, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, ovariectomy, myeloma, myxoma ...eloma, myxoma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myxoma, myeloma, myeloma, myeloma, myxoma, myeloma, myeloma, myeloma, myxoma, myeloma, myeloma, myeloma, myxoma, myeloma, myeloma, myeloma, myeloma, myeloma, myeloma, myxoma, myeloma, myeloma, myeloma, myeloma, myel It may be used for the treatment of adenoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0147] Malignant pleural mesothelioma Small molecule YAP / TAZ-TEAD inhibitors may also be useful for treating malignant pleural mesothelioma as single agents or in combination with inhibitors such as pemetrexed disodium, raltitrexed, carboplatin, oxaliplatin, gemcitabine, doxorubicin, or monoclonal antibodies such as bevacizumab. Combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. Combination with cell therapy, such as chimeric antigen receptor (CAR) T therapy or CAR NK therapy (which may use mesothelin (MSLN) as an antigen, for example). Combination with monoclonal antibodies that recognize mesothelin as an antigen, such as BMS-986148, BAY 94-9343, amatuximab, and / or LMB-100.

[0148] lung cancer Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating lung cancer as single agents or in combination with inhibitors such as afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, and / or onartuzumab, and in combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. In combination with cisplatin, carboplatin, paclitaxel, protein-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, pemetrexed, afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, necitumumab, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, onartuzumab, pembrolizumab, atezolizumab, and / or nivolumab.

[0149] In some embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful, for example, for the treatment of congenital disorders. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ-binding motifs / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the congenital disease is characterized by a mutant Ga protein. In some embodiments, the mutant Ga protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the congenital disease is characterized by a loss-of-function mutation or deletion in the NF2 gene. Exemplary congenital diseases include, but are not limited to, Sturge-Weber syndrome, port-wine stain, and neurofibromatosis. In some embodiments, the congenital disease is neurofibromatosis, including, but not limited to, neurofibromatosis type 2.

[0150] In some embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating fibrotic disorders, such as, for example, fibrosis of the liver, lung, kidney, heart, or skin. In some embodiments, fibrosis may be treated in the context of non-alcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, chronic kidney disease, and / or myocardial infarction injury.

[0151] The compounds of the present disclosure can inhibit YAP / TAZ-TEAD transcriptional activation. The compounds have been shown to inhibit YAP / TAZ-TEAD transcriptional activity in cell and animal models. The compounds have also been shown to have inhibitory effects on cancer cell lines that depend on YAP / TAZ-TEAD transcriptional activity, as well as on cancer growth in xenograft cancer models.

[0152] The compounds of the present disclosure can optionally be covalently attached to an insoluble matrix and used in affinity chromatography (separation according to the nature of the compound's groups; for example, compounds with pendant aryls are useful for hydrophobic affinity separation).

[0153] When using one or more derivatives of the formula as defined herein: - the active ingredients of the compound(s) may be administered to the animal or mammal (including human) to be treated by any means known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intraarterially, parenterally or by catheterization. A therapeutically effective amount of a preparation of compound(s), particularly for the treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription in humans and other mammals (such as cancer, fibrosis, and certain congenital disorders), is preferably a YAP / TAZ-TEAD transcription-inhibiting amount of a compound of the formulas, descriptions, aspects and embodiments as defined herein, corresponding to an amount ensuring plasma levels capable of inhibiting YAP / TAZ-TEAD activation, between 1 μg / ml and 100 mg / ml.

[0154] The appropriate dosage of the compound or composition of the present disclosure should be used to treat or prevent the target disease in the subject.Depending on the pathology to be treated and the condition of the patient, the effective amount may be divided into several subunits per day or may be administered at intervals of more than one day.

[0155] According to certain embodiments of the present disclosure, the compounds of the present disclosure may be used in combination with other therapeutic agents for the treatment or prevention of diseases mediated by the activity of YAP / TAZ-TEAD transcription in humans and other mammals, such as cancer, fibrosis, and certain congenital disorders. Thus, the present disclosure provides (a) one or more compounds of the formulae and aspects, descriptions, and embodiments herein; (b) as biologically active agents in the form of a combined preparation for simultaneous, separate or sequential use, with one or more further therapeutic or prophylactic agents used for the prevention or treatment of cancer or fibrosis; Use of the composition.

[0156] The compounds or compositions may be administered simultaneously with, prior to, or subsequent to one or more additional therapeutic agents (other than the compounds described herein, e.g., which may be useful as a combination therapy).

[0157] Examples of such additional therapeutic agents for use in combination include agents that are inhibitors of the following: ● EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab, etc.), ● AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib, etc.), • Components of the RAS-MAPK signaling cascade, e.g., inhibitors of RAS itself (AMG510, MRTX849, BI1701963, ARS1620, etc.); - B-RAF (sorafenib tosylate, dabrafenib, vemurafenib, regorafenib, etc.), or • MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0158] The pharmaceutical composition or combination preparation according to the present disclosure may contain the compound of the present disclosure in a wide range of content depending on the intended use and expected effect of the preparation. In general, the content of the derivative of the present disclosure in the combination preparation is within the range of 0.1-99.9% by weight, preferably 1-99% by weight, more preferably 5-95% by weight.

[0159] Those of skill in the art will also recognize that the compounds of the present disclosure can exist in many different protonation states, depending on the pH of their environment, etc. Although the structural formulas provided herein represent the compounds in only one of several possible protonation states, it will be understood that these structures are exemplary only, and that the present disclosure is not limited to any particular protonation state, and that compounds in any and all protonated forms are intended to be within the scope of the present disclosure.

[0160] As used herein, the term "pharmaceutically acceptable salts" refers to the therapeutically active, non-toxic salt forms that the compounds of the formulae herein can form. Thus, the compounds of the present disclosure may optionally be used as salts of the compounds herein, particularly, for example, Na + , Li + , K + , Ca 2+ and Mg 2+ The present disclosure includes pharma- ceutically acceptable non-toxic salts containing the above-mentioned. Such salts may include those derived from the combination of suitable cations, such as alkali metal ions and alkaline earth metal ions, or ammonium ions and quaternary amino ions, with an acidic anion moiety, typically a carboxylic acid. The compounds of the present disclosure may have multiple positive or negative charges. The net charge of the compounds of the present disclosure may be either positive or negative. Any associated counterions are typically determined by the synthesis and / or isolation methods used to obtain the compounds. Exemplary counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, and the like, and mixtures thereof. It will be understood that the identity of any associated counterion is not a critical feature of the present disclosure, and that the present disclosure encompasses compounds associated with any type of counterion. Furthermore, since the compounds may exist in a variety of different forms, the present disclosure encompasses compounds in forms associated with counterions (e.g., dry salts) as well as forms not associated with counterions (e.g., aqueous or organic solutions). Metal salts are typically prepared by reacting the metal hydroxide with a compound of the present disclosure. Examples of metal salts thus prepared are Li + , Na + , and K +The salts containing the metal salts are salts containing the metal salts having a low solubility, which can be precipitated from the solution of a highly soluble salt by the addition of a suitable metal compound. Furthermore, salts can be formed from the acid addition of certain organic and inorganic acids to a basic center, typically an amine, or to an acidic group. Examples of such suitable acids include inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as, e.g., acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, etc. Furthermore, the term also includes solvates that the compounds of the formulae herein and their salts can form, such as, for example, hydrates, alcoholates, etc. Finally, it should be understood that the compositions herein include the compounds of the present disclosure in their non-ionized and zwitterionic forms, as well as in combination with a stoichiometric amount of water as hydrates.

[0161] Also included within the scope of this disclosure are salts of the parent compounds with one or more amino acids, particularly the naturally occurring amino acids found as protein components. The amino acids are typically those with side chains that contain a basic or acidic group, such as lysine, arginine, or glutamic acid, or those with side chains that contain a neutral group, such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0162] The compounds of the present disclosure also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the present disclosure include alkali metal (e.g., sodium), alkaline earth (e.g., magnesium), ammonium, and NX4. +(wherein X is C1-C4 alkyl). Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of compounds containing hydroxy groups include salts of Na + and NX4 + (wherein X is typically independently selected from H or a C1-C4 alkyl group), in combination with a suitable cation such as the anion of the compound. However, salts of acids or bases that are not physiologically acceptable may also be used, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether derived from a physiologically acceptable acid or base, are within the scope of the present disclosure.

[0163] As used herein, and unless otherwise specified, the term "enantiomer" means each individual optically active form of a compound of the present disclosure having an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (e.g., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0164] The term "isomer" as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, but not positional isomers, that the compounds of the formulae herein may have. Typically, the structures shown herein only exemplify one tautomeric or resonance form of the compound, but the corresponding alternative configurations are also envisioned. Unless otherwise specified, the chemical name of the compound represents a mixture of all possible stereochemical isomeric forms, including not only stereochemically pure or enriched compounds, but also all diastereomers and enantiomers of the basic molecular structure (since the compounds of the formulae herein may have at least one chiral center). More specifically, the stereocenters may have either the R or S configuration, and the multiple bonds may have either the cis- or trans-configuration.

[0165] A pure isomeric form of the compound is defined as an isomer that is substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term "stereoisomerically pure" or "chirally pure" refers to a compound having a stereoisomeric excess of at least about 80% (e.g., at least 90% of one isomer and at most 10% of the other possible isomer), preferably at least 90%, more preferably at least 94%, and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in the same way, taking into account the enantiomeric excess and diastereomeric excess, respectively, of the mixture in question.

[0166] Separation of stereoisomers is accomplished by standard methods known to those skilled in the art. One of the enantiomers of the compounds of the present disclosure may be separated substantially free of its opposite enantiomer by methods such as the formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by EL Eliel, McGraw Hill, Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302). Separation of isomers in a mixture may be accomplished by any suitable method, including: (1) formation of ionic diastereomeric salts using chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds using chiral derivatizing agents, separation of diastereomers, and conversion to pure enantiomers; or (3) direct separation of enantiomers under chiral conditions. In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like, with asymmetric compounds having acidic functional groups, such as carboxylic and sulfonic acids. The diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. In the case of separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in the formation of diastereomeric salts. Alternatively, according to method (2), the substrate to be resolved can be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reaction of asymmetric compounds with enantiomerically pure chiral derivatizing agents, such as menthyl derivatives, followed by separation and hydrolysis of the diastereomers to give the free enantiomerically enriched compounds.A method for determining the optical purity involves making chiral esters such as menthyl or Mosher esters of the racemic mixture, i.e., a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal and reverse phase chromatography following methods for the separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96 / 15111). In method (3), a racemic mixture of the two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide-based chiral stationary phases are ChiralCeI™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Suitable eluents or mobile phases for use in combination with the polysaccharide chiral stationary phases include, for example, hexane modified with alcohols such as ethanol, isopropanol, etc. ("Chiral Liquid Chromatography" (1989) WJ Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513: 375-378).

[0167] The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of substituents on a ring moiety. The absolute stereochemical configuration of compounds of the formulae described herein can be readily determined by one skilled in the art using well-known methods such as, for example, X-ray diffraction.

[0168] The present disclosure also includes isotopically labeled compounds that are identical to those recited in the formulas recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as: 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 CI. Compounds of the present disclosure and pharma- ceutically acceptable salts of said compounds, or those that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, e.g. 3 H and 14 Those incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution assays. Tritium-labeled (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for ease of preparation and detectability. Additionally, heavier isotopes such as deuterium, i.e. 2Substitution with H may be preferred in some circumstances as it may confer certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the disclosed formulae can generally be prepared by following the procedures disclosed in the examples and preparations described herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0169] The present disclosure also encompasses modified forms of compounds of formula (I) or other formulae, embodiments, aspects or portions thereof, or metabolites thereof using PROTAC technology (Schapira M. et al, Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, PROTAC technology designs bifunctional small molecules with one end being a compound of general formula (I) or other formulae, embodiments, aspects or portions thereof, or metabolites thereof, and the other end being connected via a connecting chain to a ligand of an E3 ubiquitin ligase to form a target-induced protein degradation complex. This degradation is catalytic, so efficient degradation can be achieved at lower dosages. A compound of general formula (I) or other formulae, an embodiment, aspect or portion thereof, or a metabolite thereof can be connected to a ligand of an E3 ubiquitin ligase, such as a thalidomide analog, via a linker arm (e.g., long chain ethylene glycols of 2-10 in length, long chain propylene glycols of 2-10 in length, and long chain fatty alkanes of 2-10 in length).

[0170] The compounds of the present disclosure can be formulated using conventional carriers and excipients selected according to normal practice. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery by other than oral administration. Formulations optionally contain excipients such as those described in "Handbook of Pharmaceutical Excipients" (1986), including ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0171] As used herein, the term "pharmaceutical acceptable carrier" refers to any material or substance with which an active ingredient is formulated to facilitate its application or penetration into the treatment site, for example by dissolving, dispersing, or diffusing the composition, and / or to facilitate its storage, transportation, or handling without compromising its effectiveness. A pharmaceutical acceptable carrier can be a solid, or a liquid, or a gas compressed to form a liquid, for example, the compositions of the present disclosure may be suitably used as a concentrate, emulsion, solution, granule, dust, spray, aerosol, suspension, ointment, cream, tablet, pellet, or powder.

[0172] Suitable pharmaceutical carriers for use in the pharmaceutical compositions and their formulations are well known to those skilled in the art, and the present disclosure does not place any particular restriction on their selection. They may contain additives such as wetting agents, dispersants, adhesives, glues, emulsifiers, solvents, coatings, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (e.g., sugars or sodium chloride), etc., provided that they are in accordance with pharmaceutical practice, e.g., carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present disclosure may be prepared in any known manner, e.g., by intimately mixing, coating, and / or grinding the active ingredient with the selected carrier material and, where appropriate, other additives such as surfactants, in a one-step or multi-step procedure. They may also be prepared by micronization, e.g., for the purpose of obtaining them in the form of microspheres, usually having a diameter of about 1 to 10 gm, i.e., for the manufacture of microcapsules for controlled or sustained release of the active ingredient.

[0173] Surfactants, also known as emulsifiers or emulsifiers, suitable for use in the pharmaceutical compositions of the present disclosure are nonionic, cationic and / or anionic materials with good emulsifying, dispersing and / or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surfactants. Suitable soaps include alkali metal or alkaline earth metal salts, higher fatty acids (C 10 -C 22) unsubstituted or substituted ammonium salts, for example the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable from coconut oil or tallow. Synthetic surfactants include sodium or calcium salts of polyacrylic acid, fatty sulfonates and sulfates, sulfonated benzimidazole derivatives and alkylarylsulfonates. The fatty sulfonates or sulfates are usually in the form of alkali metal or alkaline earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with alkyl or acyl groups having 8 to 22 carbon atoms, for example the sodium or calcium salts of lignosulfonic acid or dodecylsulfonic acid, or mixtures of fatty alcohol sulfates obtained from natural fatty acids, alkali metal or alkaline earth metal salts of sulfate or sulfonate esters (such as sodium lauryl sulfate), and fatty alcohol / ethylene oxide adducts of sulfonic acids. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or alcoholamine salts of dodecylbenzenesulfonic acid or dibutyl-naphthalenesulfonic acid or naphthalene-sulfonic acid / formaldehyde condensation products.The corresponding phosphates, such as the salts of phosphoric acid esters and the ethylene and / or propylene oxide adducts of p-nonylphenol, or phospholipids are also suitable.Suitable phospholipids for this purpose are natural (from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphosphatidyl-choline, and mixtures thereof.

[0174] Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, aliphatic alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkyl arenesulfonates and dialkyl sulfosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, which preferably contain 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon portion and 6 to 18 carbon atoms in the alkyl portion of the alkylphenol. Further suitable nonionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylene diamino polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, these adducts containing 20 to 250 ethylene glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic acid ether, polypropylene / polyethylene oxide adduct, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable nonionic surfactants.

[0175] Suitable cationic surfactants include quaternary ammonium salts, particularly halides having four hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl or hydroxy, e.g., at least one C as an N-substituent. 8-22Quaternary ammonium salts containing alkyl (eg cetyl, lauryl, palmityl, myristyl, oleyl, etc.) and further substituents containing unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy-lower alkyl.

[0176] A more detailed description of suitable surfactants for this purpose can be found, for example, in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw", 2d ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants" (Chemical Publishing Co., New York, 1981).

[0177] The compounds of the present disclosure and their pharma- ceutically acceptable salts (hereinafter collectively referred to as active ingredients) can be administered by any route appropriate to the condition to be treated, suitable routes include oral, rectal, nasal, topical (including ophthalmic, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).The preferred route of administration can vary, for example, depending on the condition of the recipient.

[0178] While it is possible for the active ingredients to be administered alone, it is preferable to provide them as pharmaceutical formulations. The formulations of the present disclosure include at least one active ingredient as described above, together with one or more pharma- ceutically acceptable carriers, for both veterinary and human use, and therefore, optionally, other therapeutic ingredients. The carrier(s) are optimally "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0179] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0180] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or stamped, and can be formulated to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are optionally applied as a topical ointment or cream containing, for example, the active ingredient(s) in an amount of 0.075-20 w / w% (including active ingredient(s) within the range of 0.1%-20% in 0.1 w / w% increments, e.g., 0.6 w / w% increments, 0.7 w / w% increments, etc.), preferably 0.2-15 w / w%, most preferably 0.5-10 w / w%. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least 30 w / w% of a polyhydric alcohol, such as an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.

[0181] The oily phase of the emulsion of the present disclosure can be composed of known ingredients in a known manner. This phase may comprise only an emulsifier (also known as emulgent), but desirably comprises a mixture of at least one emulsifier with fat or oil, or with both fat and oil. Optionally, a hydrophilic emulsifier is included, together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and fat. Taken together, the emulsifier(s), with or without stabilizer(s), constitutes the so-called emulsifying wax, and the wax, together with oil and fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations.

[0182] The solubility of the active compounds in most oils that can be used in pharmaceutical emulsion formulations is very low, so the choice of oils or fats suitable for the formulation is based on achieving the desired cosmetic properties. The cream must therefore be a non-greasy, non-staining and washable product, optionally with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters can be used, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, the last three being the preferred esters. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0183] Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5 w / w%. Formulations suitable for topical administration to the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, pastilles containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia, and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0184] Formulations for rectal administration may be provided as a suppository with a suitable base including, for example, cocoa butter or a salicylate. Formulations suitable for nasal administration, where the carrier is a solid, include coarse powders, for example having a particle size in the range of 20-500 microns (including particle sizes in the range of 20-500 microns with 5 micron increments, for example 30 microns, 35 microns, etc.), administered in a nasal sniffing manner, for example by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Suitable formulations, where the carrier is a liquid, for example for administration as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.

[0185] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0186] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.The preparations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0187] Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0188] It will be understood that the formulations of the present disclosure may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0189] The compounds of the present disclosure can be used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the present disclosure as active ingredients, the release of which can be controlled and regulated to allow for reduced dosing frequency or improved pharmacokinetic or toxicity profile of a given compound of the present disclosure. Controlled release formulations adapted for oral administration, in which discrete units contain one or more compounds of the present disclosure, can be prepared according to conventional methods.

[0190] Additional components may be included to control the duration of action of the active ingredient in the composition. Thus, controlled release compositions can be achieved by selecting appropriate polymeric carriers, such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate, etc. The rate of drug release and duration of action can also be controlled by incorporating the active ingredient into particles, e.g., microcapsules, of polymeric materials, such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate, and other polymers mentioned above. Such methods include colloidal drug delivery systems, such as liposomes, microspheres, microemulsions, nanoparticles, nanocapsules, etc. Depending on the route of administration, the pharmaceutical composition may require a protective coating. Suitable pharmaceutical forms for injection use include sterile aqueous solutions or suspensions and sterile powders for their extemporaneous preparation. Thus, typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, etc., and mixtures thereof.

[0191] Considering that when several active ingredients are used in combination, they do not necessarily directly produce a combined therapeutic effect at the same time in the treated mammal, the corresponding composition may be in the form of a medical kit or package containing the two ingredients in separate but adjacent containers or compartments. In the latter context, each active ingredient may therefore be formulated in a form suitable for a route of administration different from that of the other ingredient, for example one of them may be in the form of an oral or parenteral preparation, whereas the other may be in the form of an ampoule or an aerosol for intravenous injection.

[0192] Another embodiment of the present disclosure relates to various precursor or "prodrug" forms of the compounds of the present disclosure. It may be desirable to formulate the compounds of the present disclosure in the form of chemical species that do not have biologically significant activity themselves, but when delivered to an animal, mammal, or human, undergo a chemical reaction catalyzed by the normal functions of the body of the fish, particularly enzymes present in the stomach or serum, where said chemical reaction has the effect of releasing the compound as defined herein. The term "prodrug" therefore relates to these species that are converted in vivo into the active pharmaceutical ingredient.

[0193] The prodrug of the compound of the present disclosure can have any form suitable for the formulator, for example, ester is a non-limiting common prodrug form.However, in the present case, the prodrug may necessarily be in a form in which the covalent bond is cleaved by the action of the enzyme present at the target site.For example, the CC covalent bond may be selectively cleaved by one or more enzymes at the target site, and therefore, prodrugs in forms other than easily hydrolyzable precursors, especially esters, amides, etc., may be used.The counterpart of the active pharmaceutical ingredient in the prodrug may have different structures, such as amino acid or peptide structures, alkyl chains, sugar moieties, and others known in the art.

[0194] For purposes of this disclosure, the term "therapeutically suitable prodrug" is defined herein as "a compound that, upon contact with the tissue of an animal, mammal or human to which the prodrug is administered, is modified such that it is converted in vivo, whether by a single biotransformation or by multiple biotransformations, into a form that is therapeutically active and that achieves an intended therapeutic result without undue toxicity, irritation, or allergic response."

[0195] More specifically, the term "prodrug" as used herein refers to an inactive or less active derivative of a compound as represented by the structural formula described herein, which undergoes spontaneous or enzymatic conversion in the body to release a pharmacologically active form of the compound. For a comprehensive review, see Rautio J. et al. ("Prodrugs: design and clinical applications" Nature Reviews Drug Discovery, 2008, doi:10.1038 / nrd2468).

[0196] The compounds of the present disclosure can be prepared using a series of chemical reactions well known to those skilled in the art, which together constitute a process for preparing the compounds and are hereinafter exemplified. The processes described hereinafter are intended as examples only and are not intended to limit the scope of the present disclosure in any way. EXAMPLES

[0197] general synthesis Compounds of the present invention can be prepared according to the general procedures outlined in Scheme 1. [ka] Scheme 1: R 1 , R 5 , X 1 , X 2 , and X 3 are all as described for the compounds of the invention and their embodiments and formulas, LG=leaving group, R'=H, alkyl, PFA=paraformaldehyde.

[0198] Substituted 2-aminobenzamides 1, either commercially available or synthesized by procedures known to one skilled in the art, can be reacted with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, boronic acid, and boronic ester in combination with the corresponding Pd or Cu catalyst to provide intermediates of general formula 2. Intermediates of general formula 3 can be obtained from intermediate 2 by acid-catalyzed ring closure reaction utilizing PFA. Furthermore, intermediates of general formula 4 can be obtained by N-alkylation of intermediates of general formula 3 using procedures known to one skilled in the art.

[0199] In another embodiment, compounds of the present invention may be synthesized according to the general procedures outlined in Scheme 2. [ka] Scheme 2: R 1 , R 6a , X, X 1 , X 2 , and X 3 are all as described for the compounds of the invention and their embodiments and formulas.

[0200] Substituted anilines of general formula 1, either commercially available or synthesized by procedures known to those skilled in the art, can be reacted in a suitable solvent (e.g., DCM, DCE, etc.) and with a suitable catalyst (e.g., CuI, Tf2O, etc.) to provide intermediates of general formula 2. Intermediates of general formula 3 can be obtained from intermediate 2 by ester hydrolysis followed by ring closure reaction using procedures known to those skilled in the art. Intermediates of general formula 3 can be converted to the corresponding O-tosyl oximes of general formula 4 using procedures known to those skilled in the art. Intermediate 4 can undergo Neber rearrangement upon treatment with base (e.g., NaOH, KOEt, etc.) in a suitable solvent (e.g., EtOH, etc.) to provide intermediates of general formula 5. More information can be found in Comprehensive Organic Name Reactions and Reagents, Ed. Z.Wang (2010). N-alkylation and N-acylation of intermediates of general formula 5 using procedures known to those skilled in the art can provide intermediates of general formula 6.

[0201] The above general schemes should be considered as non-limiting examples, and it will be understood that the compounds of the invention may be obtained via other methods known to those skilled in the art. [Table 1-1] [Table 1-2]

[0202] These examples are provided for the purpose of illustrating the disclosure and should not be construed in any way as limiting the scope of the disclosure.

[0203] Part A: Experimental Chemistry Procedures Abbreviations used herein, particularly in the schemes and examples, are as follows: aq - aqueous solution, ACN - acetonitrile, CDCl3 - deuterated chloroform, Conc - concentrated, CuI - copper iodide, Cs2CO3 - cesium carbonate, DCM - dichloromethane, DCE - 1,2-dichloroethane, DMF - N,N-dimethylformamide, DMSO - dimethylsulfoxide, DMSO-d6 - deuterated dimethylsulfoxide, EtOH - ethanol, EtOAc - ethyl acetate, Eq. - equivalents, FA - formic acid, h - hours, HCl - hydrogen chloride, K2CO3 - potassium carbonate, KOEt - potassium ethoxide, LiOH.H2O - lithium hydroxide monohydrate, M eOH-methanol, min-minutes, NaBH4-sodium borohydride, NaOAc-sodium acetate, NaHCO3-sodium bicarbonate, Na2SO4-sodium sulfate, NH3-ammonia, Pet ether-petroleum ether, PFA-paraformaldehyde, P2O5-phosphorus(V) oxide, iPrMgCl.LiCl-isopropyl magnesium chloride lithium chloride complex, RT-room temperature, sat-saturated, TEA-triethylamine, TfOH-trifluoromethanesulfonic acid, Tf2O-trifluoromethanesulfonic anhydride, THF-tetrahydrofuran, pTSA-p-toluenesulfonic acid, TsCl-p-toluenesulfonyl chloride.

[0204] All starting materials not explicitly mentioned are either commercially available (details of suppliers such as, for example, Acros, Avocado, Aldrich, Fluka, FluoroChem, MatrixScientific, Maybridge, Merck, Sigma can be found, for example, in the SciFinder® database) or their synthesis has already been precisely described in the specialist literature (experimental guidelines can be found, for example, in the Reaxys® database or the SciFinder® database, respectively) or can be prepared using conventional methods known to the person skilled in the art.

[0205] Reactions were carried out under an inert atmosphere (mostly argon and N2) if necessary. The number of equivalents of reagents and the amount of solvent used, as well as reaction temperature and time, may vary slightly between different reactions carried out by similar methods. Workup and purification methods are adapted according to the unique properties of each compound and may vary slightly for similar methods. The yields of the prepared compounds are not optimized.

[0206] The designation "equivalent" ("eq." or "eq" or "equiv.") means molar equivalent, "RT" or "rt" means room temperature T (23±7°C), "M" is the designation of concentration in mol / l, "sol." means solution, and "conc." means concentrated. Solvent mixture ratios are usually described as volume / volume ratios.

[0207] To carry out reactions under microwave irradiation, a CEM microwave (Discover SP) was used (heating rate: 2-6 °C / s, temperature: 30-300 °C volume independent infrared (IR) and 80-300 °C fiber optic (FO) temperature measurement, pressure: 0-435 psi, ActiVent™ technology, power: 0-300 W, magnetron frequency: 2450 MHz, reaction stirring: magnetic stirring, air cooling: ≥ 25 psi (flow rate 20 L / min), system control: Synergy™ software).

[0208] Key analytical characterizations were performed for all example compounds and selected intermediate products. 1 H-NMR spectroscopy and / or mass spectrometry (MS, [M+H] + and / or [MH] - In certain cases, e.g., when regioisomers and / or diastereomers were or could be formed during the reaction, the 13 Additional analyses, including C NMR and NOE (nuclear Overhauser effect) NMR experiments, were performed.

[0209] The analytical instruments used were, for example, BRUKER AVANCE 400MHz (software Topspin) for NMR analysis or VARIAN MR 400MHz (VNMRJ software) machines. For LC / MS analysis, for example, Acquity UPLC H-Class, mass: Acquity SQD2 Detector (ESI), Acquity UPLC, mass: Quatro premier XE Detector (ESI), Acquity UPLC, mass: Waters Xevo TQ-S Detector (ESI / ESCI), or Alliance Waters 2695, mass: Quattromicro™ (ESCI) multimode ionization were used. Analytical HPLC was measured, for example, on an Alliance Waters 2695. Analytical SFC was performed, for example, on PIC solution (software: SFC PIC Lab Online), WATERS-X5 (software MASSLYNX), or WATERS-UPC2 (Empower).

[0210] The structures of exemplary compounds containing stereocenters are depicted and named with absolute stereochemistry if known. When the absolute stereochemistry is unknown, the compound may be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia1 and Dia2 mean that diastereiosomers were isolated but the stereochemistry is unknown. En1 and En2 mean that both enantiomers were isolated but the absolute configuration is unknown. If no suffix is ​​given after the compound code, it means that the compound containing a stereocenter was obtained as a racemic mixture or a mixture of diastereomers, respectively, unless the chemical name of the compound specifies the exact stereochemistry.

[0211] The LC / MS analyses mentioned in the experimental part were also carried out on an Alliance Waters 2695 HPLC (equipped with a PDA detector) connected to a mass spectrometer Waters Quattromicro (ESCI, multimode, ionization) (Method L in the table below).

[0212] Conditions used for HPLC analysis in the experimental part. The LC / MS analysis mentioned in the experimental part was carried out on an Alliance Waters 2695 HPLC (equipped with a PDA detector) connected to a mass spectrometer Waters Quattromicro (ESCI, multimode, ionization). Separation was carried out on an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) column thermostatted at 30-35 °C and the PDA acquisition wavelength was set in the range of 210-400 nm (Acuisition Software: MassLynx) (Method L in the table below). Elution was carried out as described in the table below. For methods L1 and L2, solvent A: 0.05% LC-MS grade FA in milliQ water. Solvent B: 0.05% LC-MS grade FA in LC-MS grade ACN. [Table 2]

[0213] The preparative HPLC purifications mentioned in this experimental part were carried out using the following systems: Waters 2545 (Empower software, 2996 PDA detector, 2707 autosampler), Gilson (software Trilution, 171 DAD detector, GX-271 autosampler), or Shimadzu (software LC Solution, CMB-20A detector, SIL-10AP autosampler). Separations were carried out on X-Bridge C18 (5 μm, 19×150 mm), X-Select C18 (5 μm, 19×250 mm or 10 μm, 25×150 mm), X-Select CSH Phenyl-Hexyl (5 μm, 19×250 mm), or Kromasil C18 (5 μm, 19×150 mm) columns. Elution was carried out using the columns and solvents listed in the table below. A gradient system for each compound was used using the solvents listed in the table. The detection wavelengths were fixed at 210 and 254 nm. [Table 3]

[0214] Example 1-2: Synthesis of 1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound No. 1) and 3-(3-hydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound No. 2) [ka]

[0215] Step 1: A solution of 2-aminobenzamide (10 g, 73.4 mmol), TEA (24.5 g, 242.6 mmol), (4-trifluoromethyl)phenyl)boronic acid (35 g, 184.2 mmol) and CuI (35 g, 184.2 mmol) in MeOH (150 mL) was stirred at room temperature under oxygen atmosphere (balloon pressure) for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.5, TLC detection: UV. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product (35 g, LC / MS 69%), which was purified by normal phase flash column chromatography using an 80 g column (silica) and a gradient of 0-2% MeOH in DCM as eluent to give 2-((4-(trifluoromethyl)phenyl)amino)benzamide as an off-white solid (5.5 g, 25%, LC / MS 94%). (LC / MS, m / z 281.2 [M+H] + ).

[0216] Step 2: A solution of 2-((4-(trifluoromethyl)phenyl)amino)benzamide (500 mg, 1.78 mmol), PFA (107 mg, 3.58 mmol) and pTSA (31 mg, 0.18 mmol) in EtOH (5 mL) was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.3, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give the crude product (600 mg, LC / MS 76%), which was purified by normal phase flash column chromatography using an 80 g column (silica) and a gradient of 0-2% MeOH in DCM as eluent to give 1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound No. 1) as an off-white solid (120 mg, 23%, LC / MS 95%). (LC / MS, m / z 293.1 [M+H] + ).

[0217] Step 3: A solution of compound No. 1 (300 mg, 1.03 mmol), Cs2CO3 (668 mg, 2.05 mmol) and 3-bromopropanol (214 mg, 1.54 mmol) in DMF (3 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.25, TLC detection: UV. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (60 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (300 mg, LC / MS 59%), which was purified by preparative HPLC method H1. The collected fractions were lyophilized to give 3-(3-hydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (compound No. 2) as a gum (31 mg, 9%, LC / MS 99%). (LC / MS, m / z 351.2 [M+H] + ).

[0218] Step 4: A solution of compound No. 1 (500 mg, 1.71 mmol), K2CO3 (473 mg, 3.42 mmol) and ethyl bromoacetate (428 mg, 2.56 mmol) in DMF (4 mL) was stirred at 100 °C for 16 h (sealed vessel). The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.71, TLC detection: UV. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (80 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (750 mg, LC / MS 28%), which was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 0-2% MeOH in DCM as eluent to give ethyl 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetate (Intermediate-1) as a white solid (250 mg, 31%, LC / MS 76%). (LC / MS, m / z 379.2 [M+H] + ).

[0219] Examples 3-4: Synthesis of 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetic acid (Compound No. 3) and 3-(2-hydroxyethyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (Compound No. 4) [ka]

[0220] Step 1: A solution of intermediate-1 (150 mg, 0.39 mmol) and LiOH·H2O (29 mg, 1.19 mmol) in MeOH (4 mL) and H2O (1 mL) was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.15, TLC detection: UV. The reaction was concentrated under reduced pressure, dissolved in H2O (5 mL), cooled to 0 °C, acidified with 2 Maq HCl (2 mL), and extracted with EtOAc (30 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (130 mg, LC / MS 87%), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetic acid (compound No. 3) as a white solid (26 mg, 19%, LC / MS 99%). (LC / MS, m / z 351.2 [M+H] + ).

[0221] Step 2: A solution of intermediate-1 (200 mg, 0.53 mmol) in EtOH (4 mL) was treated with NaBH4 (117 mg, 3.17 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.3, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, diluted with H2O (10 mL) and extracted with EtOAc (40 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (160 mg, LC / MS 79%), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give 3-(2-hydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one (compound No. 4) as an off-white solid (52 mg, 29%, LC / MS 99%). (LC / MS, m / z 337.4 [M+H] + ).

[0222] Examples 5-6: Synthesis of 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide (Compound No. 5) and N-methyl-2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide (Compound No. 6) [ka]

[0223] Step 1: Intermediate-1 (100 mg, 0.26 mmol) was treated with NH3 (7.0 M in MeOH, 4 mL) and the solution was stirred at 120 °C for 16 h (sealed vessel). The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.17, TLC detection: UV. The reaction mixture was evaporated under reduced pressure to give the crude product (100 mg, LC / MS 61%), which was purified by preparative HPLC method H4. The collected fractions were lyophilized to give 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide (compound No. 5) as a white solid (21 mg, 24%, LC / MS 99%). (LC / MS, m / z 350.3 [M+H] + ).

[0224] Step 2: A solution of intermediate-1 (80 mg, 0.21 mmol) in THF (2 mL) was cooled to 0° C. and treated with MeNH2 (2.0 M in THF, 0.5 mL) and iPrMgCl.LiCl (1.3 M in THF, 0.3 mL) and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.1, TLC detection: UV. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product (90 mg, LC / MS 77%), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give N-methyl-2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinazolin-3(4H)-yl)acetamide (compound No. 6) as an off-white solid (35 mg, 44%, LC / MS 97%). (LC / MS, m / z 364.2 [M+H] + ).

[0225] Example 7: Synthesis of N-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acrylamide (Compound No. 7) [ka]

[0226] Step 1: A solution of diphenylamine (15 g, 88.7 mmol), methyl acrylate (9.2 g, 106.5 mmol), TfOH (13.3 g, 88.7 mmol), Tf2O (25 g, 88.7 mmol) and CuI (843 mg, 4.44 mmol) in DCE (200 mL) was stirred at 120 °C for 24 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.39, TLC detection: UV. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (500 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (19 g), which was purified by normal phase flash column chromatography using an 80 g column (silica) and a gradient of 0-12% EtOAc in petroleum ether as eluent to give methyl 3-(diphenylamino)propanoate as a pale yellow liquid (13 g, 54%, LC / MS 94%). (LC / MS, m / z 256.1 [M+H] + ).

[0227] Step 2: A solution of methyl 3-(diphenylamino)propanoate (3.0 g, 11.8 mmol) and LiOH.H2O (991 mg, 23.5 mmol) in THF (10 mL), MeOH (10 mL) and H2O (5 mL) was stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, dissolved in H2O (20 mL) and acidified with 2 Maq HCl (10 mL). The precipitated solid was filtered, washed with H2O (2 x 10 mL) and dried under reduced pressure to give 3-(diphenylamino)propanoic acid as an off-white solid (1.7 g, 63%, LC / MS 99%). (LC / MS, m / z 242.2 [M+H] + ).

[0228] Step 3: A solution of 3-(diphenylamino)propanoic acid (1.4 g, 5.80 mmol) and P2O5 (3.3 g, 23.2 mmol) in xylene (30 mL) was stirred at 120 °C for 6 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 20% EtOAc in petroleum ether, RF: 0.64, TLC detection: UV. The reaction mixture was cooled to room temperature, quenched with ice-cold H2O (20 mL), basified with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (1.2 g, LC / MS 79%), which was purified by normal phase flash column chromatography using a 24 g column (silica) and a gradient of 0-13% EtOAc in petroleum ether as eluent to give 1-phenyl-2,3-dihydroquinolin-4(1H)-one as a pale yellow solid (700 mg, 54%, LC / MS 99%). (LC / MS, m / z 224.2 [M+H] + ).

[0229] Step 4: A solution of 1-phenyl-2,3-dihydroquinolin-4(1H)-one (700 mg, 3.14 mmol), NaOAc (386 mg, 4.70 mmol) and hydroxylamine hydrochloride (327 mg, 4.70 mmol) in EtOH (10 mL) was stirred at 90 °C for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.45, TLC detection: UV. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (20 mL) and H2O (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give (Z)-1-phenyl-2,3-dihydroquinolin-4(1H)-one oxime as a pale yellow solid (700 mg, 92%, LC / MS 97%). (LC / MS, m / z 239.1 [M+H] + ).

[0230] Step 5: A solution of (Z)-1-phenyl-2,3-dihydroquinolin-4(1H)-one oxime (700 mg, 2.94 mmol) and TsCl (847 mg, 4.41 mmol) in pyridine (10 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 20% EtOAc in petroleum ether, RF: 0.56, TLC detection: UV. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (900 mg, LC / MS 75%), which was purified by normal phase flash column chromatography using a 24 g column (silica) and a gradient of 0-10% EtOAc in petroleum ether as eluent to give (Z)-1-phenyl-2,3-dihydroquinolin-4(1H)-one O-tosyloxime as a pale yellow solid (650 mg, 54%, LC / MS 93%). (LC / MS, m / z 393.2 [M+H] + ).

[0231] Step 6: A solution of (Z)-1-phenyl-2,3-dihydroquinolin-4(1H)-one O-tosyloxime (500 mg, 1.27 mmol) and KOEt (128 mg, 1.53 mmol) in EtOH (1 mL) and benzene (10 mL) was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 20% EtOAc in petroleum ether, RF: 0.08, TLC detection: UV. The reaction mixture was quenched with HCl (4.0 M in 1,4-dioxane, 2.5 mL) at 0° C., stirred for 10 min, and concentrated under reduced pressure to give 3-amino-1-phenyl-2,3-dihydroquinolin-4(1H)-one hydrochloride as a brown gum (650 mg, LC / MS 74%). (LC / MS, m / z 239.2 [M+H] + ). The product was used directly without further purification.

[0232] Step 7: A solution of 3-amino-1-phenyl-2,3-dihydroquinolin-4(1H)-one hydrochloride (200 mg, 0.73 mmol, LC / MS 74%) and NaHCO3 (212 mg, 2.52 mmol) in 1,4-dioxane (10 mL) and H2O (3 mL) was treated with a solution of acryloyl chloride (38 mg, 0.42 mmol) in 1,4-dioxane (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The progress of the reaction was monitored by TLC. TLC mobile phase: 30% EtOAc in petroleum ether, RF: 0.37, TLC detection: UV. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (220 mg, LC / MS 68%), which was purified by preparative HPLC method H5. The collected fractions were lyophilized to give N-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acrylamide (compound No. 7) as a yellow solid (56 mg, 35%, LC / MS 98%). (LC / MS, m / z 293.2 [M+H] + ). [Table 4-1] [Table 4-2]

[0233] Part B: Experimental Biology Procedures Example 8: Activity of compounds of the present disclosure in a reporter gene assay to measure inhibition of YAP / TAZ-TEAD transcription Hek293T cells are cultured in DMEM supplemented with 10% fetal bovine serum, sodium pyruvate, sodium bicarbonate, and L-glutamine. Cells are harvested and transiently transfected with a TEAD-responsive element luciferase reporter. Transfected cells are plated in 384-well plates containing pre-diluted compounds. After 24 h incubation at 37°C / 5% CO2, assay plates are cooled to RT and leveled to equal volumes per well, after which 25 uL of luciferase substrate SteadyLite (Perkin Elmer) / well is added. Plates are shaken at 600 rpm for 10 min, centrifuged at 500 rpm for 1 min, and measured on an Envision reader (PerkinElmer). The amount of relative light units produced by the TEAD reporter is used to calculate percent inhibition.

[0234] Percent reporter inhibition was calculated in the presence of a positive control inhibitor (100% inhibition) versus vehicle basal activity of the reporter (0% inhibition). The ability of test compounds to inhibit this activity was determined as follows: Percentage of inhibition = [1 - ((RLU determined in the presence of vehicle - RLU determined for samples with test compound present) ÷ (RLU determined in the presence of vehicle - RLU determined for samples with positive control inhibitor present)) × 100

[0235] The activities of exemplary compounds tested are shown in Table 3. Activity ranges A, B, and C are determined by IC 50 "A" refers to the value of IC 50 <1μM, "B": 1μM ≤ IC 50 ≦20 μM, and "C": IC 50 >20 μM, NT=not tested. [Table 5]

[0236] Example 9: Activity of compounds of the present disclosure in mesothelioma cell line proliferation assays Mesothelioma cell lines NCI-H226 and NCI-H2052 (all sourced from ATCC cell culture collection) are plated in 96-well plates (Corning® 96 Well White Polystyrene Microplates, clear flat bottom, white polystyrene (TC treated)) at 1500 cells / well in complete medium (RPMI 1640 ATCC modification with L-glutamine, HEPES, phenol red, sodium pyruvate, high glucose, low sodium bicarbonate and 10% fetal bovine serum). Cells are incubated overnight at 37° C. in an incubator with 5% CO2. Compounds dissolved in DMSO are then added in dose response. Cells are incubated with compound dilutions for an additional 6 days at 37° C. in an incubator with 5% CO2. Cell viability is quantified using an ATPlite kit (Perkin-Elmer) and luminescence is read using an Envision instrument (Perkin-Elmer). The amount of relative light units generated using the ATPlite kit is used to calculate the percentage of inhibition.

[0237] The activity of some exemplary compounds is shown in Table 4. Activity ranges A, B, and C refer to EC50 values ​​in the mesothelioma cell line proliferation assay as described, with "A": EC 50 <1μM, "B": 1μM≦EC 50 ≦10 μM, and "C": EC 50 >10 μM, NT=not tested. [Table 6]

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R １ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ -C ６ Alkyl, (4) C ３ -C ６ Cycloalkyl, (5) C １ -C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ -C ６ Alkenyl, and (8) C ２ -C ６ Alkynyl, (b) Unsubstituted or substituted C ３ -C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ -C ６ Alkyl, (4) C ３ -C ６ Cycloalkyl, (5) C １ -C ６ Haloalkyl, and (6)-OZ １ 、 (c) C ２ -C ６ Alkynyl, (iii) unsubstituted or substituted C ６ -C １０ aryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ -C ６ Alkyl, (d) C ３ -C ６ Cycloalkyl, (e) C １ -C ６ Haloalkyl, (f) -OZ １ , and (g) Unsubstituted or substituted C ６ ~C １０ Aryl, where one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ -C ６ Alkyl, (d) C ３ -C ６ Cycloalkyl, (e) C １ -C ６ Haloalkyl, (f) -OZ １ , and (g) Unsubstituted or substituted C ６ -C １０ Aryl, where one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of: (v) unsubstituted or substituted C ３ -C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ -C ６ Alkyl, (d) C ３ -C ６ Cycloalkyl, (e) C １ -C ６ Haloalkyl, and (f)-OZ １ 、 (vi) unsubstituted or substituted C ３ -C ６ A heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ -C ６ Alkyl, (d) C ３ -C ６ Cycloalkyl, (e) C １ -C ６ Haloalkyl, and (f)-OZ １ 、 (vii)-S(=O) ２ Z ２ , and ()) ()) ２ 、 R ２ and R ３ is hydrogen and C １ -C ６ independently selected from the group consisting of alkyl, Y １ is -CR ４ａ R ４ｂ - and -NR ５ - selected from the group consisting of R ４ａ is -NR ６ａ R ６ｂ and R ４ｂ is hydrogen and C １ -C ６ is selected from the group consisting of alkyl, R ５ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ -C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) cyano, (b) hydroxy, (c)-OZ １ 、 (d) -C(=O)OH, (e)-C(=O)Z ２ 、 (f)-C(=O)OZ ２ 、 (g)-C(=O)NZ ３ Z ４ 、 (h)-S(=O) ２ Z ２ 、 (i)-S(=O) ２ NZ ３ Z ４ 、 (j)-S(=O)(=NZ ５ )Z ２ 、 (k) -S (=NZ ５ ) (=N.Z. ６ ) Z ２ , and (l)-S(=O)(=NZ ５ )NZ ３ Z ４ 、 (viii) C １ -C ６ Haloalkyl, and (iv) unsubstituted or substituted C ２ -C ６ alkenyl, where one or more of the substituents are halogen, -NZ ３ Z ４ , 4-8 membered heterocycle; R ６ａ is selected from the group consisting of: (i)-C(=O)Z ２ 、 (ii)-C(=O)OZ ２ 、 (iii)-C(=O)NZ ３ Z ４ 、 (iv)-S(=O) ２ Z ２ 、 (v)-S(=O) ２ NZ ３ Z ４ 、 (vi)-S(=O)(=NZ ５ )Z ２ 、 (vii)-S(=NZ ５ ) (=N.Z. ６ ) Z ２ , and ( ) ( ) ( ) ( ) ( ) ５ )!: ３ : ４ 、 R ６ｂ is hydrogen and C １ ~C ６ is selected from the group consisting of alkyl, Each Z １ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ -C ６ Alkyl, (iii) unsubstituted or substituted C ２ -C ６ alkenyl, where one or more of the substituents are cyano, -S(=O) ２ Z ２ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4-8 membered heterocycle; (iv) C ２ -C ６ Alkynyl, (v) C ３ -C ６ Cycloalkyl, (vi) C ３ -C ６ Cycloalkenyl, and (vii) C １ -C ６ Haloalkyl, Each Z ２ are independently selected from the group consisting of: (i) Unsubstituted or substituted C １ -C ６ alkyl, where one or more of the substituents are cyano, and C ２ -C ６ alkynyl, (ii) unsubstituted or substituted C ２ -C ６ alkenyl, where one or more of the substituents are cyano, -S(=O) ２ Z ２ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4-8 membered heterocycle; (iii) C ２ -C ６ Alkynyl, (iv) C ３ -C ６ Cycloalkyl, (v) C ３ -C ６ Cycloalkenyl, (vi) C １ -C ６ Haloalkyl, (vii) unsubstituted or substituted C ６ -C １０ Aryl, where one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ and (viii) unsubstituted or substituted C ３ -C ６ Cycloalkyl, where one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of Each Z ３ and Z ４ are independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ -C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ -C ６ Alkyl, (4) C ３ -C ６ Cycloalkyl, (5) C １ -C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ -C ６ Alkenyl, and (8) C ２ -C ６ Alkynyl, (b) Unsubstituted or substituted C ３ -C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ -C ６ Alkyl, (4) C ３ -C ６ Cycloalkyl, (5) C １ -C ６ Haloalkyl, and (6)-OZ １ 、 (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ -C ６ Alkyl, (4) C ３ -C ６ Cycloalkyl, (5) C １ -C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ -C ６ Alkenyl, and (8) C ２ -C ６ Alkynyl, (iii) unsubstituted or substituted C ２ -C ６ alkenyl, where one or more of the substituents are cyano, -S(=O) ２ Z ２ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4-8 membered heterocycle; (iv) C ２ -C ６ Alkynyl, (v) C ３ -C ６ Cycloalkyl, (vi) C ３ -C ６ Cycloalkenyl, and (vii) C １ -C ６ Haloalkyl, Each Z ５ and Z ６ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ -C ６ Alkyl, and (iii) C ３ -C ６ Cycloalkyl, X is -CR ７ａ = and -N=; X １ is -CR ７ｂ = and -N=; X ２ is -CR ７ｃ = and -N=; X ３ is -CR ７ｄ is selected from the group consisting of = and -N=, and Each R ７ａ , R ７ｂ , R ７ｃ , and R ７ｄ is hydrogen, halogen, hydroxy, cyano, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, and -OZ １ or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

2. Formula II: 【Chemistry 2】 2. The compound of claim 1, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

3. R ５ is unsubstituted or substituted C １ -C ６ alkyl, one substituent being hydroxy, -C(=O)OH, and -C(=O)NZ ３ Z ４ 3. The compound of claim 1 or 2, selected from the group consisting of:

4. Formula III: 【Chemistry 3】 2. The compound of claim 1, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

5. R ６ａ is -C(=O)Z ２ , and unsubstituted or substituted C １ -C ６ is selected from the group consisting of alkyl, and Z ２ is selected from the group consisting of: (i) C １ -C ６ Alkyl, and (ii) unsubstituted or substituted C ２ -C ６ alkenyl, where one or more of the substituents are cyano, -S(=O) ２ Z ２ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ 5. The compound of claim 1 or 4, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein each of the rings is independently selected from the group consisting of: , 4-8 membered heterocycle.

6. R １ is unsubstituted or substituted C ６ -C １０ aryl, where one or more of the substituents are halogen, hydroxy, cyano, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, and -OZ １ 6. The compound of any one of claims 1 to 5, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

7. X is -CR ７ａ = X １ is -CR ７ｂ = X ２ is -CR ７ｃ = and X ３ is -CR ７ｄ 7. The compound of any one of claims 1 to 6, wherein: = or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

8. 1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 3-(3-hydroxypropyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetic acid, 3-(2-hydroxyethyl)-1-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide, N-methyl-2-(4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide, and 2. The compound of claim 1, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of N-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acrylamide.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

10. A compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for use as a medicament.

11. A compound according to any one of claims 1 to 8, or a pharmaceutical composition according to claim 9, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human.

12. The compound of claim 11, or the pharmaceutical composition of claim 11, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from the group including cancer, fibrosis, and YAP / TAZ-TEAD activation-mediated congenital disorder.

13. 13. The compound of claim 12, or the pharmaceutical composition of claim 12, wherein the YAP / TAZ-TEAD activation mediated disorder is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma.

14. The YAP / TAZ-TEAD activation mediated disorders include acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, craniopharyngioma, sac Alveolar adenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphatic duct Endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteomyeloma 13. The compound of claim 12 or the pharmaceutical composition of claim 12, wherein the compound is selected from the group consisting of ovarian tumors, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung carcinoma, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid carcinoma, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

15. A method for the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human, comprising administering to said animal, mammal or human in need thereof an effective dose of a compound according to any one of claims 1 to 8.

16. 15. The method of treating or preventing a YAP / TAZ-TEAD activation mediated disorder according to claim 14 in combination with one or more other medicaments selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor, for a patient in need thereof.

Images