2-Pyrazoleanilines and related analogues for inhibiting YAP / TAZ-TEAD

Abstract

The present disclosure relates to novel compounds, more particularly to said compounds for use as medicaments 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.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 293,531, filed December 23, 2022. The entire contents of the above-referenced provisional patent application are incorporated herein by reference.

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

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

[0004] Hippo signaling is important for limiting organ size through inactivation of the YAP / TAZ-TEAD transcriptional complex. In some aggressive solid tumors, Hippo signaling is inactivated by loss-of-function mutations or deletions in genes encoding upstream regulators (e.g., NF2, MST1 / 2, or LATS1 / 2), unleashing constitutive YAP / TAZ-TEAD transcriptional activity and leading to unrestrained tumor growth and metastasis. Knockout, knockdown, or pharmacological inactivation of YAP / TAZ-TEAD is sufficient to impair 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 within TEAD.

[0005] The primary physiological function of the Hippo pathway is to restrict tissue growth in adult tissues and 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, Ste20-like kinases, MST1 / 2 (Drosophila homologs), phosphorylate and activate large tumor suppressor 1 / 2 (LATS1 / 2). NF2, a core Hippo kinase scaffold, promotes LATS1 / 2 activation by tethering 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 motif (TAZ) through 14-3-3-mediated cytoplasmic sequestration and ubiquitin-mediated degradation induced by β-TRCP E3 ligase. When the Hippo pathway is inactive, YAP and TAZ translocate to the nucleus and bind to the TEAD transcription factor family, inducing the expression of specific signatures that promote matrix remodeling, cell proliferation, survival, and migration. TEAD1-4 also bind to VGLL4 in the nucleus and can act as a transcriptional repressor. VGLL4 is not structurally related to YAP / TAZ but competes with them based on partially overlapping binding sites on TEADs (Johnson and Halder, 2014, Nat Rev Drug Discov 13, 63-79).

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

[0007] In honeybees, 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 cuticle overgrowth and increased organ size as a result of dysregulated cell proliferation and resistance to apoptosis. 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 progenitor cell expansion, resulting in liver and heart overgrowth and ultimately cancer formation in the liver, small intestine, and skin. In contrast, a serine-to-alanine mutation at position 94 of YAP, which is unable to bind TEAD, is not oncogenic (Zhao et al., 2008, Genes Dev 22, 1962-1971). Similarly, a dominant-negative TEAD mutant unable to bind DNA overcomes YAP-driven liver tumorigenesis. Additionally, NF2 mutant hepatocellular carcinomas were significantly suppressed by heterologous loss 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] Gene 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. YAP / TAZ promotes the acquisition of several important cancer cell phenotypes, such as proliferation, resistance to apoptosis, invasion, and immunosuppression (e.g., by attracting myeloid-derived suppressor cells (Wang et al., 2016, Cancer Discov 6, 80-95)). In addition, gene fusions with YAP1 have been identified in several cancer types, including ependymoma, vascular carcinoma, cervical carcinoma, and ovariectomy carcinoma, which result in constitutive activation of YAP-TEAD and are carcinogenic in mice (Szulzewsky et al., 2020, Genes Dev 34:1-14). Additionally, several germline or somatic mutations in components of the Hippo pathway associated with various cancer types have been discovered in targeted and whole-genome sequencing studies. The most well-studied example is the NF2 gene locus, which is frequently mutated in neurofibromatosis. Deficiencies of NF2 and LATS2 are also frequently observed in schwannomas. Another tumor type commonly associated (in approximately 70% of cases) with constitutive YAP-TEAD activation due to 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 some mesothelioma cell lines harboring NF2 loss-of-function mutations exhibit decreased YAP phosphorylation and increased YAP-TEAD reporter activity. YAP-TEAD transcription and viability of NF2 mutant mesothelioma cell lines (but not WT mesothelioma) are sensitive to treatment with YAP siRNA (an effect that can be rescued by overexpression of siRNA-resistant YAP) and 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 beta-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 promote tumorigenesis, and YAP / TAZ is hyperactivated in many different human cancer types (often due to loss-of-function mutations in upstream negative regulators). Genetic deletion or pharmacological inhibition of YAP / TAZ has been shown to suppress tumor development and progression in different cancer types. Therefore, 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 by inhibiting YAP, TAZ, TEAD, and / or YAP / TAZ-TEAD protein-protein interactions may be a valuable approach for treating cancers with functional alterations of this pathway.

[0011] YAP / TAZ-TEAD activation has also been shown to play an important role in other diseases besides cancer, namely fibrosis and certain congenital disorders. Fibrosis is characterized by excessive deposition of extracellular matrix (ECM) containing cross-linked collagen fibers, which leads to tissue stiffening and ultimately to the dysfunction of affected organs. ECM reinforcement 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 involved 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 YAP / TAZ as contributing factors to fibrotic disease in vivo. These include reports of elevated YAP / TAZ levels and transcriptional activity in fibroblasts and alveolar and respiratory epithelia 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 drives fibrosis progression parallel to that 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 (NF2) is characterized by nervous system tumors, including schwannomas, meningiomas, and ependymomas. It is a genetic disorder caused by inactivation of NF2 (Striedinger et al., 2008, Neoplasia 10, 1204–1210). Loss of NF2 leads to constitutive activation of YAP / TAZ-TEAD. Sturge-Weber syndrome (STS) is a congenital neurocutaneous disorder characterized by port-wine staining affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vasculature in the brain and choroidal thin meninges, glaucoma, seizures, stroke, and intellectual disability. Sturge-Weber syndrome and port-wine staining are caused by somatic activating mutations in GNAQ, which lead to activation of YAP / TAZ-TEAD transcription (Shirley et al., 2013, NEJM, 368, 1971–1979). Therefore, several congenital disorders characterized by constitutive YAP / TAZ-TEAD activation can be treated with inhibitors of YAP / TAZ-TEAD.

[0013] Several publications describe inhibitors of YAP-TEAD transcriptional activation. Inventiva highlighted YAP-TEAD protein-protein interaction inhibitors in WO2020 / 070181, WO2018 / 185266, and WO2017 / 064277. General Hospital Corporation, Boston, described autopalmitoylation in WO2017 / 053706. Vivace Therapeutics, Inc. disclosed non-fused tricyclic (WO2018 / 204532), benzosulfonyl (WO2019 / 040380), benzocarbonyl (WO2019 / 113236), oxadiazole (WO2019 / 222431), and bicyclic (WO2020 / 097389) compounds that modulate the interaction between YAP / TAZ and TEAD. The 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. revealed alpha, beta unsaturated amide compounds that exhibit anticancer activity in WO2018 / 235926 and US2019 / 0010136. Genentech, Inc. disclosed carboxamide and sulfonamide derivatives useful as inhibitors of YAP-TEAD protein-protein interactions in WO2019 / 232216 and WO2020 / 051099. Dana-Farber Cancer Institute, Inc. highlighted 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 inhibitors of TEAD autopalmitoylation (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 great need for new, alternative, or better therapies for the prevention or treatment of diseases mediated by YAP / TAZ-TEAD activation, such as cancer and fibrosis, among other potential indications. Therapies with better efficacy, fewer side effects, greater activity, lower toxicity, or better pharmacokinetic or dynamic properties, or a combination thereof, would be highly welcome.

[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 discovery that at least one of the above-mentioned problems can be solved by the class of compounds described below.

[0017] The present disclosure provides new compounds that have been shown to have inhibitory activity against YAP / TAZ-TEAD transcription. The disclosure further demonstrates that these compounds efficiently inhibit the activity of YAP / TAZ-TEAD transcription. Accordingly, these compounds constitute a useful class of new, potent compounds that can be used to treat and / or prevent Hippo-mediated disorders in animals, mammals, and humans, more specifically, (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, mesothelial tumors, and / or sarcoma; (ii) fibrosis; and (iii) congenital disorders associated with YAP / TAZ-TEAD activation.

[0018] In some aspects, the compounds described herein are useful for the treatment and / or prevention of Hippo-mediated disorders in animals, mammals, and humans, more specifically, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, hemangiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, myeloma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, and the like. Hematologic malignancies, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic 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, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma , hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelioma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies 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 nat carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, vera erythrocytosis, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, melloma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial cancer, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular cancer, uterine cancer and Wilms' tumor.

[0019] The present disclosure further relates to the use of such compounds as pharmaceuticals, more particularly their use for the manufacture of a medicament for treating and / or preventing YAP / TAZ-TEAD activation-mediated diseases in animals or mammals, more particularly 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, stomach cancer, brain cancer and prostate cancer, mesothelial tumors, and / or sarcoma, and (ii) fibrosis. The present disclosure also relates to methods for preparing all such compounds, and pharmaceutical compositions comprising them in effective amounts.

[0020] In some embodiments, the present disclosure provides compounds of the present invention for use as a medicament, the use of such compounds as a medicament, more particularly 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, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, Chondrosarcoma, Myeloma, Choriocarcinoma, Chronic Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelocytic (Granulocytic) Leukemia, Chronic Myeloid Leukemia, Colon Cancer, Craniopharyngioma, Cystadenocarcinoma, Diffuse Large B-Cell Lymphoma, Dysplastic Changes (Dysplasia and Metaplasia), Embryonal Carcinoma, Endometrial Cancer, Endothelial Cancer, Ependymoma, Ependymoma, Epithelial Carcinoma, Erythroleukemia, Esophageal Cancer, Estrogen Receptor-Positive Breast Cancer, Essential Thrombocythemia, Ewing's Tumor, Fibrosarcoma, Follicular Lymphoma, Germ Cell Testicular Cancer, Glioma, Glioblastoma, Gliosarcoma, Heavy Chain Diseases, hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelioma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies 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, nat midline and their use for the manufacture of a medicament for the treatment and prevention of adenocarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, vera erythrocytosis, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, melloma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial cancer, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer and Wilms' tumor.

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

[0022] definition The term "YAP / TAZ-TEAD activation-mediated disease" refers to diseases in which hippo signaling is inactivated, thereby causing YAP / TAZ-TEAD activation to contribute to, drive, maintain, or enable such disease. This may be due to loss-of-function mutations or deletions in genes encoding upstream regulators of YAP / TAZ-TEAD (e.g., NF2, MST1 / 2, LATS1 / 2, FAT1, or SAV1), unleashing constitutive YAP-TEAD transcriptional activity and leading to unrestrained tumor growth and metastasis in some cancers. This may also be due to, among other things, YAP1 or WWTR1 (TAZ) gene amplification, gene fusion, or activating mutation, or YAP / TAZ overexpression or hyperactivity. Thus, YAP / TAZ-TEAD activation-mediated diseases also include not only cancer, but also 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, bile duct cancer), skin cancer, pancreatic cancer, gastric cancer, brain tumors, 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, (ii) cancers derived from tissues of neuroectodermal origin, such as epithelioma, meningioma, schwannoma, peripheral nerve sheet tumor, and / or neuroblastoma, or (iii) vascular cancers, 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 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 prior treatment with EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors, and the like.

[0024] As used herein, the terms "treat" or "treating" are intended to refer to the administration of a compound or composition to a subject for the purpose of providing a therapeutic or prophylactic benefit through the inhibition of YAP / TAZ-TEAD transcription. Treating includes reversing, ameliorating, alleviating, inhibiting the progression of, reducing the severity of, or preventing such a disease, disorder, or condition mediated through YAP / TAZ-TEAD transcription, or one or more symptoms of such a disease, disorder, or condition. "Therapeutic benefit" refers to the eradication, amelioration, reversal, alleviation, inhibiting the progression of, or reducing the severity of the underlying disorder being treated. In some embodiments, therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, even if the patient continues to suffer from the underlying disorder. In terms of prophylactic benefit, in some embodiments, a composition is administered to a patient at risk of developing a particular disease or who reports one or more physiological symptoms of a disease, even if the disease has not been diagnosed.

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

[0026] As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician, including the 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 a product containing therapeutically effective amounts of the specified ingredients, and any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0028] As used herein, the terms "antagonist" or "inhibitor," with respect to inhibitors of YAP / TAZ-TEAD activation, refer to compounds that are 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 subsequently listed means; it does not exclude other elements or steps.

[0030] References herein to "one embodiment" or "an embodiment" mean that a particular feature, structure, act, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments. When an infinitive or definite article is used when referring to a singular noun, e.g., "a," "an," or "the," this includes the plural of that noun unless something else is specifically stated.

[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, figure, or description thereof for the purpose of streamlining 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 represents the maximum number of carbon atoms that are generally optimally present in a substituent or linker, and where otherwise indicated in this application, it is understood that the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.

[0033] As used herein, the term "leaving group" or "LG" refers to a chemical group that is susceptible to displacement by a nucleophile or to 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 substructure of protecting groups varies widely. One function of protecting groups is to serve as intermediates in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, "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 and aid in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered, planned manner. Protection of a compound's functional group alters other physical properties beyond the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0035] Protected compounds can also exhibit altered and possibly optimized properties in vitro and in vivo, such as the ability to pass through cell membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with the intended therapeutic effect can be referred to as prodrugs. Another function of a protecting group is to convert a parent drug into a prodrug, whereby the parent drug is released upon conversion of the prodrug in vivo. Because an active prodrug can be absorbed more effectively than the parent drug, the prodrug may have greater efficacy in vivo than the parent drug. Protecting groups are removed in vitro in the case of chemical intermediates and 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 C1-C alkyl groups with no unsaturation. 18 means a normal, secondary or tertiary, linear, branched or straight chain hydrocarbon. Examples are methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-butyl), 2-butyl (s-butyl), 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 n-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 1~12 Alkyl (C 1~12 hydrocarbons), and more specifically, C1~9 Alkyl (C 1~9 and more specifically, C 1~6 Alkyl (C 1~6 refers to hydrocarbons).

[0037] The term "haloalkyl," as a group or part of a group, refers to an alkyl group having the meaning defined above in which one, two, or three hydrogen atoms are each replaced with 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" refers to a group or part of a group of the formula -OR b where R b is C as defined herein above 1~6 Alkyl. 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" refers to a group or part of a group of the formula -OR c where 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] As used herein, "cycloalkyl" or "C 3~18 The term "cycloalkyl" means, unless otherwise specified, any of the C cycloalkyl groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl, etc. 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 refers to a C 3~12 Cycloalkyl (saturated cyclic C 3~12 hydrocarbons), and more specifically, C 3~9 Cycloalkyl (saturated cyclic C 3~9 and more specifically, 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 will be considered heterocyclic regardless of the ring attached to the core structure. A fused system of a cycloalkyl ring with an aryl ring will be considered aryl regardless of the ring attached to the core structure. A fused system of a cycloalkyl ring with a heteroaryl ring will be considered heteroaryl regardless of the ring attached to the core structure.

[0041] As used herein, "alkenyl" or "C 2~18 The term "alkenyl" refers to a C2-C6 alkyl group having at least one site of unsaturation (usually 1-3, preferably 1), i.e., a carbon-carbon, sp2 double bond. 18 It is a normal, secondary or tertiary, straight, branched or linear hydrocarbon. Examples include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), and 5-hexenyl (-CHCHCHCHCH=CH). The double bond can be in the cis or trans configuration. In certain embodiments, the term alkenyl refers to C 2~12Alkenyl (C 2~12 hydrocarbons), and more specifically C 2~9 Alkenyl (C 2~9 and more specifically refers to C as further defined herein above. 2~6 Alkenyl (C 2~6 It refers to a hydrocarbon having at least one site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp2 double bond.

[0042] The term "alkenyloxy" refers to a group or part of a group of the formula -OR d where R d is alkenyl as defined herein above.

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

[0044] As used herein, "alkynyl" or "C 2~18 The term "alkynyl" refers to a C2-C alkyl group having at least one site of unsaturation (usually 1-3, preferably 1), i.e., a carbon-carbon, sp triple bond. 18 It refers to a normal, secondary or tertiary, linear, branched or straight chain hydrocarbon. Examples include, but are not limited to, ethynyl (-C=CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CHC≡CH). In certain embodiments, the term alkynyl refers to C 2~12 Alkynyl (C 2~12 hydrocarbons), and more specifically C 2~9 Alkynyl (C 2~9 hydrocarbons), and more particularly C as further defined herein above. 2~6 Alkynyl (C 2~6 It refers to a hydrocarbon having at least one unsaturated site (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond.

[0045] The term "alkynyloxy" refers to a group or part of a group of the formula -OR e where R e is alkynyl as defined herein above.

[0046] As used herein, the term "cycloalkynyl" refers to a cycloalkynyl group having at least one site of unsaturation (typically 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond, and 5~10 Monocyclic or C 7~18"cycloalkynyl" refers to a non-aromatic hydrocarbon group having 5 to 18 carbon atoms, 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 5~10 Cycloalkynyl (cyclic C 5~10 hydrocarbons), and more specifically, C 5~9 Cycloalkynyl (cyclic C 5~9 refers to a C hydrocarbon, and even more specifically to a C hydrocarbon, as further defined herein above, having at least one site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond. 5~6 Cycloalkynyl (cyclic C 5~6 For the avoidance of doubt, a fused system of a cycloalkynyl ring with a heterocyclic ring will be considered heterocyclic, regardless of the ring attached to the core structure. A fused system of a cycloalkynyl ring with an aryl ring will be considered aryl, regardless of the ring attached to the core structure. A fused system of a cycloalkynyl ring with a heteroaryl ring will be considered heteroaryl, regardless of the ring attached to the core structure.

[0047] As used herein, the term "alkylene" refers to alkylenes containing 1 to 18 carbon atoms (more specifically, C 1~12 , C 1~9 or C 1~6 (carbon atoms) having two monovalent radical centers derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane. Typical alkylenes include, but are not limited to, methylene (-CH-), 1,2-ethyl (-CHCH-), 1,3-propyl (-CHCHCH-), 1,4-butyl (-CHCHCHCH-), and the like.

[0048] As used herein, the term "alkenylene" refers to an alkylene group of 2 to 18 carbon atoms (more specifically C), each having at least one site of unsaturation (usually 1 to 3, preferably 1), 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. 2~12 , C 2~9 or C 2~6 refers to branched or straight chain hydrocarbons of 100 carbon atoms.

[0049] As used herein, the term "alkynylene" refers to an alkyl group of 2 to 18 carbon atoms (more specifically C), each having at least one site of unsaturation (usually 1 to 3, preferably 1), 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 alkene. 2~12 , C 2~9 or C 2~6 refers to branched or straight chain hydrocarbons of 100 carbon atoms.

[0050] As used herein, the term "heteroalkyl" refers to an alkyl in which one or more carbon atoms are replaced with 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 where R a is alkylene and R b is alkyl, and 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] As used herein, the term "heteroalkenyl" 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 where R b is alkyl, and 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] As used herein, the term "heteroalkynyl" refers to an acyclic alkynyl in which one or more carbon atoms are replaced by an oxygen, nitrogen, or sulfur atom. Thus, the term heteroalkynyl includes, but is not limited to, -OR d , -N(R d )2, NHR d , -N(R b )(R e ), -N(R d )(R e ), and -SR d where R b is alkyl, and Re is alkynyl and R d is alkenyl as defined herein. 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] As used herein, the term "heteroalkylene" refers to an alkylene in which one or more carbon atoms has been replaced by one or more oxygen, nitrogen, or sulfur atoms.

[0054] As used herein, the term "heteroalkenylene" refers to an alkenylene in which one or more carbon atoms has been replaced by one or more oxygen, nitrogen, or sulfur atoms.

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

[0056] As used herein, the term "aryl" refers to an aromatic hydrocarbon of 6 to 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 fused rings derived from benzene, naphthalene, anthracene, biphenyl, etc. In certain embodiments, the term aryl refers to an aromatic ring of 6 to 14 carbon atoms, and more specifically, an aromatic ring of 6 to 10 carbon atoms. A fused system of an aryl ring with a cycloalkyl, cycloalkenyl, or cycloalkynyl ring is considered aryl regardless of the ring attached to the core structure. A fused system of an aryl ring with a heterocyclic ring is considered heterocyclic regardless of the ring attached to the core structure. Thus, indoline, dihydrobenzofuran, dihydrobenzothiophene, etc. are considered heterocyclic rings according to the present disclosure. A fused system of an aryl ring with a heteroaryl ring is considered heteroaryl regardless of the ring attached to the core structure.

[0057] The term "aryloxy" refers to a group or part of a group of the formula -OR g where R g is aryl as defined herein above.

[0058] The term "arylalkyl" or "arylalkyl-" 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-phenylethan-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. An arylalkyl group contains 6 to 20 carbon atoms; for example, 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" refers to a group or part of a group of the formula -OR a-R i where R g is aryl and R a is alkyl as defined herein above.

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

[0061] As used herein, the term "arylalkynyl" or "arylalkynyl-" 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 terms "arylheteroalkyl" or "arylheteroalkyl-" refer 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), arylalkyl-NH-alkyl, arylalkyl-N-(alkyl), aryl-S-alkyl, and arylalkyl-S-alkyl.

[0063] As used herein, the term "arylheteroalkenyl" or "arylheteroalkenyl-" 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; for example, 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), arylalkenyl-NH-alkenyl, arylalkenyl-N-(alkenyl), aryl-S-alkenyl, and arylalkenyl-S-alkenyl.

[0064] As used herein, the term "arylheteroalkynyl" or "arylheteroalkynyl-" 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; for example, 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), arylalkynyl-NH-alkynyl, arylalkynyl-N-(alkynyl), aryl-S-alkynyl, and arylalkynyl-S-alkynyl.

[0065] As used herein, the term "heterocycle" or "heterocyclyl" refers to a non-aromatic, fully saturated, or partially unsaturated ring system of 3 to 18 atoms containing at least one N, O, S, or P (e.g., a 3- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or a total of 3 to 10 ring atoms). Each ring of a heterocycle or heterocyclyl may have 1, 2, 3, or 4 heteroatoms selected from N, O, and / or S; the N and S heteroatoms may be optionally oxidized; the N heteroatom may be optionally quaternized; and at least one carbon atom of a heterocyclyl may be oxidized to form at least one C=O. A heterocycle may be bonded at any heteroatom or carbon atom of the ring or ring system, where valency allows. The rings of a polycyclic heterocyclyl or heterocycle may be fused, bridged, and / or joined through one or more spiro atoms. A heterocyclic or heterocyclyl fused system with an aryl ring is considered a heterocyclic or heterocyclyl regardless of which ring is attached to the core structure. A heterocyclic or heterocyclyl fused system with a heteroaryl ring is considered 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, yl, 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-quinolidinyl, 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-oxathianyl, 1,4-dithianyl group, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl. As used herein, the term "aziridinyl" includes aziridin-1-yl and aziridin-2-yl. As used herein, the term "oxiranyl" includes oxiranyl-2-yl. As used herein, the term "thiiranyl" includes thiiran-2-yl. As used herein, the term "azetidinyl" includes azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl. As used herein, the term "oxetanyl" includes oxetan-2-yl and oxetan-3-yl.As used herein, the term "thietanyl" includes thietan-2-yl and thietan-3-yl. As used herein, the term "pyrrolidinyl" includes pyrrolidin-1-yl, pyrrolizidin-2-yl, and pyrrolidin-3-yl. As used herein, the term "tetrahydrofuranyl" includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. As used herein, the term "tetrahydrothiophenyl" includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. As used herein, the term "succinimidyl" includes succinimide-1-yl and succinimide-3-yl. As used herein, the term "dihydropyrrolyl" 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. As used herein, the term "2H-pyrrolyl" includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl, and 2H-pyrrol-5-yl. As used herein, the term "3H-pyrrolyl" includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl, and 3H-pyrrol-5-yl. As used herein, the term "dihydrofuranyl" 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. As used herein, the term "dihydrothiophenyl" 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.As used herein, the term "imidazolidinyl" includes imidazolidin-1-yl, imidazolidin-2-yl, and imidazolidin-4-yl. As used herein, the term "pyrazolidinyl" includes pyrazolidin-1-yl, pyrazolidin-3-yl, and pyrazolidin-4-yl. As used herein, the term "imidazolinyl" includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl, and imidazolin-5-yl. As used herein, the term "pyrazolinyl" 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. As used herein, the term "dioxolanyl," also known as "1,3-dioxolanyl," includes dioxolan-2-yl, dioxolan-4-yl, and dioxolan-5-yl. As used herein, the term "dioxolyl," also known as "1,3-dioxolyl," includes dioxol-2-yl, dioxol-4-yl, and dioxol-5-yl. As used herein, the term "oxazolidinyl" includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, and oxazolidin-5-yl. As used herein, the term "isoxazolidinyl" includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl. As used herein, the term "oxazolinyl" 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.As used herein, the term "isoxazolinyl" 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. As used herein, the term "thiazolidinyl" includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, and thiazolidin-5-yl. As used herein, the term "isothiazolidinyl" includes isothiazolin-2-yl, isothiazolin-3-yl, isothiazolin-4-yl, and isothiazolin-5-yl. As used herein, the term "thiazolinyl" 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. As used herein, the term "isothiazolinyl" 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. As used herein, the term "piperidyl," also known as "piperidinyl," 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, and the like. 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, 1,23,4-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-6 ... 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.As used herein, the term "tetrahydropyranyl," also known as "oxanyl" or "tetrahydro-2H-pyranyl," includes tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl. As used herein, the term "2H-pyranyl" includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, and 2H-pyran-6-yl. As used herein, the term "4H-pyranyl" includes 4H-pyran-2-yl, 4H-pyran-3-yl, and 4H-pyran-4-yl. As used herein, the term "3,4-dihydro-2H-pyranyl" 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. As used herein, the term "3,6-dihydro-2H-pyranyl" includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-6-yl.

[0023] As used herein, the term "tetrahydrothiophenyl" includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl-3-yl, and tetrahydrothiophenyl-4-yl. As used herein, the term "2H-thiopyranyl" includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, and 2H-thiopyran-6-yl. As used herein, the term "4H-thiopyranyl" includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, and 4H-thiopyran-4-yl. As used herein, the term "3,4-dihydro-2H-thiopyranyl" 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. As used herein, the term "3,6-dihydro-2H-thiopyranyl" 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. As used herein, the term "piperazinyl," also known as "piperazidinyl," includes piperazin-1-yl and piperazin-2-yl. As used herein, the term "morpholinyl" includes morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl. As used herein, the term "thiomorpholinyl" includes thiomorpholin-2-yl, thiomorpholin-3-yl, and thiomorpholin-4-yl. As used herein, the term "dioxanyl" 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.As used herein, the term "dithianyl" 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. As used herein, the term "oxathianyl" includes oxathian-2-yl and oxathian-3-yl. As used herein, the term "trioxanyl" 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. As used herein, the term "azepanyl" includes azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl. As used herein, the term "homopiperazinyl" includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl, and homopiperazin-4-yl. As used herein, the term "indolinyl" includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. As used herein, the term "quinolizinyl" includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. As used herein, the term "isoindolinyl" includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. As used herein, the term "3H-indolyl" 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. As used herein, the term "quinolizinyl" includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl.As used herein, the term "quinolizinyl" includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. As used herein, the term "tetrahydroquinolinyl" 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. As used herein, the term "tetrahydroisoquinolinyl" 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. As used herein, the term "chromanyl" includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, and chroman-8-yl. As used herein, the term "1H-pyrrolidine" 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. As used herein, the term "3H-pyrrolidine" 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 atom, comprising one or two rings (each ring typically containing 5-6 atoms) that may be fused or covalently linked together, wherein at least one of the rings is aromatic, the N and S heteroatoms may be optionally oxidized, the N heteroatom may be optionally quaternized, and at least one carbon atom of the 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 heterocycle 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, and thieno[3,2-b]furanyl. group, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl group, 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, benzothiazolyl, Triazolyl, 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, isoquino 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] As used herein, the term "pyrrolyl" (also known as azolyl) includes pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl. As used herein, the term "furanyl" (also known as "furyl") includes furan-2-yl and furan-3-yl (also known as furan-2-yl and furan-3-yl). As used herein, the term "thiophenyl" (also known as "thienyl") includes thiophen-2-yl and thiophen-3-yl (also known as thien-2-yl and thien-3-yl). As used herein, the term "pyrazolyl" (also known as 1H-pyrazolyl and 1,2-diazolyl) includes pyrazol-1-yl, pyrazol-3-yl or 1H-pyrazol-5-yl, pyrazol-4-yl, and pyrazol-5-yl. As used herein, the term "imidazolyl" includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl. As used herein, the term "oxazolyl" (also called 1,3-oxazolyl) includes oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl. As used herein, the term "isoxazolyl" (also called 1,2-oxazolyl) includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. As used herein, the term "thiazolyl" (also called 1,3-thiazolyl) includes thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). As used herein, the term "isothiazolyl" (also called 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. As used herein, the term "oxadiazolyl" 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. As used herein, the term "thiadiazolyl" 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 (also known as furazan-3-yl), and 1,3,4-oxadiazol-2-yl. As used herein, the term "tetrazolyl" includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. As used herein, the term "oxatriazolyl" includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. As used herein, the term "thiatriazolyl" includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl. As used herein, the term "pyridinyl" (also called "pyridyl") includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also called 2-pyridyl, 3-pyridyl, and 4-pyridyl).As used herein, the term "pyrimidyl" includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl, and pyrimid-6-yl. As used herein, the term "pyrazinyl" includes pyrazin-2-yl and pyrazin-3-yl. As used herein, the term "pyridazinyl" includes pyridazin-3-yl and pyridazin-4-yl. As used herein, the term "oxazinyl" (also referred to as "1,4-oxazinyl") includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl. As used herein, the term "dioxinyl" (also referred to as "1,4-dioxinyl") includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. As used herein, the term "thiazinyl" (also referred to as "1,4-thiazinyl") 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. As used herein, the term "triazinyl" 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. As used herein, the term "imidazo[2,1-b][1,3]thiazolyl" 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. As used herein, the term "thieno[3,2-b]furanyl" 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]imidazolyl" includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl, and thieno[2,3-d]imidazol-5-yl. As used herein, the term "tetrazolo[1,5-a]pyridinyl" 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. As used herein, the term "indolyl" includes indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, and indol-7-yl. As used herein, the term "indolizinyl" includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. As used herein, the term "isoindolyl" includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl, and isoindol-7-yl. As used herein, the term "benzofuranyl" (also called benzo[b]furanyl) includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, and benzofuran-7-yl. As used herein, the term "isobenzofuranyl" (also called benzo[c]furanyl) includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, and isobenzofuran-7-yl.As used herein, the term "benzothiophenyl" (also known as benzo[b]thienyl) 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). As used herein, the term "isobenzothiophenyl" (also known as benzo[c]thienyl) includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl, and isobenzothien-7-yl. As used herein, the term "indazolyl" (also known as 1H-indazolyl or 2-azandyl) 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. As used herein, the term "benzimidazolyl" includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, and benzimidazol-7-yl. As used herein, the term "1,3-benzoxazolyl" 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. As used herein, the term "1,2-benzisoxazolyl" includes 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl, and 1,2-benzisoxazol-7-yl.As used herein, the term "2,1-benzisoxazolyl" 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. As used herein, the term "1,3-benzothiazolyl" 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. As used herein, the term "1,2-benzisothiazolyl" 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 "1,2,3-benzoxadiazolyl" 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. As used herein, the term "benzothiazolyl" 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. As used herein, the term "2,1,3-benzoxadiazolyl" 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. As used herein, the term "1,2,3-benzothiadiazolyl" 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. As used herein, the term "2,1,3-benzothiadiazolyl" 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. As used herein, the term "thienopyridinyl" includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, and thieno[3,2-b]pyridinyl. As used herein, the term "purinyl" includes purin-2-yl, purin-6-yl, purin-7-yl, and purin-8-yl.As used herein, the term "imidazo[1,2-a]pyridinyl" 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. As used herein, the term "1,3-benzodioxolyl" includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. As used herein, the term "quinolinyl" includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, and quinolin-8-yl. As used herein, the term "isoquinolinyl" includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl. As used herein, the term "cinnolinyl" includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, and cinnolin-8-yl. As used herein, the term "quinazolinyl" includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl. As used herein, the term "quinoxalinyl" includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0069] As used herein, heteroaryl and heterocycle or heterocyclyl include, by way of example only, groups described in Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950-present), particularly 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, by way of example only, but not limited to.

[0070] The term "heterocyclyloxy" or "heterocycloxy" refers to a group or part of a group of the formula -OR i where R i is heterocyclyl as defined herein above.

[0071] The term "heterocyclylalkyloxy" or "heterocycloxy" refers to a group or part of a group of the formula -OR a -R i (In the formula, R i is heterocyclyl and R a refers to a group having a , which is alkyl as defined herein above.

[0072] The term "heteroaryloxy" refers to a group or part of a group of the formula -OR k where R k is heteroaryl as defined herein above.

[0073] The term "heteroarylalkyloxy" refers to a group or part of a group of the formula -ORa -R i where R i is heteroaryl, and R a is alkyl as defined herein above.

[0074] The term "heterocyclyl-alkyl" or "heterocyclyl-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 heterocyclyl-alkyl group is 2-piperidinyl-methylene. The heterocyclyl-alkyl or heterocyclyl-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 terms "heterocyclyl-alkenyl" or "heterocyclyl-alkenyl," as a group or part of a group, refer to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom has been replaced with a heterocyclyl. The heterocyclyl-alkenyl or heterocyclyl-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 terms "heterocyclyl-alkynyl" or "heterocyclyl-alkynyl," as a group or part of a group, refer 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 heterocyclyl-alkynyl group can contain 6 to 20 atoms; for example, the alkynyl portion can contain 2 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms.

[0077] The terms "heterocyclyl-heteroalkyl" or "heterocyclyl-heteroalkyl," as a group or part of a group, refer 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 heterocyclyl. The heterocyclyl-heteroalkyl or heterocyclyl-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 heterocyclyl-heteroalkyl is selected from the group consisting of 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 terms "heterocyclyl-heteroalkenyl" or "heterocyclyl-heteroalkenyl," as a group or part of a group, refer to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom has been replaced with a heterocyclyl. The heterocyclyl-heteroalkenyl or heterocyclyl-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 heterocyclyl-heteroalkenyl is selected from the group including heterocyclyl-O-alkenyl, heterocyclylalkyl-O-alkenyl, heterocyclyl-NH-alkenyl, heterocyclyl-N(alkenyl), heterocyclylalkyl-NH-alkenyl, heterocyclylalkyl-N-(alkenyl), heterocyclyl-S-alkenyl, and heterocyclylalkenyl-S-alkenyl.

[0079] The terms "heterocyclyl-heteroalkynyl" or "heterocyclyl-heteroalkynyl," as a group or part of a group, refer to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom has been replaced with a heterocyclyl. The heterocyclyl-heteroalkynyl or heterocyclyl-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), heterocyclylalkynyl-NH-alkynyl, heterocyclylalkynyl-N-(alkynyl), 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; for example, 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 has been replaced with a heteroaryl. A heteroaryl-alkenyl group can contain 6 to 20 atoms; for example, 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] As used herein, the term "heteroaryl-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 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] As used herein, the term "heteroaryl-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, is replaced with a heteroaryl. The heteroaryl-heteroalkyl group contains 7 to 20 atoms; e.g., the heteroalkyl portion of the heteroaryl-heteroalkyl group is 2 to 6 carbon atoms and the heteroaryl portion is 5 to 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), heteroarylalkyl-NH-alkyl, heteroarylalkyl-N-(alkyl), heteroaryl-S-alkyl, and heteroarylalkyl-S-alkyl.

[0084] As used herein, the term "heteroaryl-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 heteroaryl. The heteroaryl-heteroalkenyl group contains 8 to 20 atoms; for example, the heteroalkenyl portion of the heteroaryl-heteroalkenyl group is 3 to 6 carbon atoms and the heteroaryl portion is 5 to 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), heteroarylalkenyl-NH-alkenyl, heteroarylalkenyl-N-(alkenyl), heteroaryl-S-alkenyl, and heteroarylalkenyl-S-alkenyl.

[0085] As used herein, the term "heteroaryl-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 heteroaryl. The heteroaryl-heteroalkynyl group contains 8 to 20 atoms, e.g., the heteroalkynyl portion of the heteroaryl-heteroalkynyl group is 2 to 6 carbon atoms and the heteroaryl portion is 5 to 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), heteroarylalkynyl-NH-alkynyl, heteroarylalkynyl-N-(alkynyl), heteroaryl-S-alkynyl, and heteroarylalkynyl-S-alkynyl.

[0086] As examples, a carbon-linked heteroaryl or heterocyclic ring (or heterocycle) can 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, thiofuran, 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 linked at the 2-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, isoindole or isoindoline, the 4-position of morpholine, and the 9-position of carbazole or β-carboline. Even more typically, nitrogen-linked heteroaryl or heterocyclyl groups include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

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

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

[0089] The term "alkenylthio" refers to a group or part of a group of the formula -SR d where R d is alkenyl as defined herein above.

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

[0091] The term "arylthio" refers to a group or part of a group of the formula -SR g where R gis aryl as defined herein above.

[0092] The term "arylalkylthio" refers to a group or part of a group of the formula -SR a -R g where R a is alkylene and R g is aryl as defined herein above.

[0093] The term "heterocyclylthio" refers to a group or part of a group of the formula -SR i where R i is heterocyclyl as defined herein above.

[0094] The term "heteroarylthio" refers to a group or part of a group of the formula -SR k where R k is heteroaryl as defined herein above.

[0095] The term "heterocyclylalkylthio" refers to a group or part of a group of the formula -SR a -R i where R a is alkylene and R i is heterocyclyl as defined herein above.

[0096] The term "heteroarylalkylthio" refers to a group or part of a group of the formula -SR a -R k where R a is alkylene and R k is heteroaryl as defined herein above.

[0097] The term “mono- or di-alkylamino” refers to a group or part of a group of the formula —N(R o )(R b ) group, wherein R o is hydrogen or alkyl, and R bis alkyl. Thus, alkylamino includes monoalkylamino groups (e.g., monoalkylamino groups such as methylamino and ethylamino) and dialkylamino groups (e.g., dialkylamino 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 diarylamino” refers to a group or part of 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, q or R r At least one of is aryl.

[0099] The term “mono- or di-heteroarylamino” refers to a group or part of 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, u or R v At least one of is heteroaryl as defined herein.

[0100] The term “mono- or diheterocyclylamino” as a group or part of a group has the formula —N(R W )(R X ) group, wherein R w and R x are each independently selected from hydrogen, heterocyclyl, or alkyl, 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, wherein the heteroatoms are selected from the group consisting of O, S, and N" in reference to a chemical 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, among others, depending on the group being referenced. Thus, the term includes, for example, alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-heteroalkyl, heterocyclyl-heteroalkyl, heteroaryl-alkoxy, heterocyclyl-alkoxy, among others. As an example, the term "alkyl optionally containing one or more heteroatoms, wherein the heteroatoms are selected from the group consisting of O, S, and N" therefore refers to heteroalkyl and means an alkyl containing one or more heteroatoms in the hydrocarbon chain, which may be positioned at the beginning, within, 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-, among many other examples. As an example, the term "arylalkylene optionally comprising one or more heteroatoms in the alkylene chain, wherein the heteroatoms are selected from the group consisting of O, S, and N" therefore refers to an arylheteroalkylene, and means an arylalkylene comprising one or more heteroatoms in the hydrocarbon chain, which heteroatoms may be positioned at the beginning of the hydrocarbon chain, within the hydrocarbon chain, or at the termini 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. When it is said to "optionally contain one or more heteroatoms, the heteroatoms being selected from the group consisting of O, S, and N," the same applies to "heteroalkenylene," "heteroalkynylene," and other terms used herein.

[0103] As used herein, the term with respect to a chemical group "wherein two or more hydrogen atoms on a carbon atom or heteroatom of the group may optionally join together to form =O or =S" refers to a group where two or more hydrogen atoms on a carbon atom or heteroatom of the group may join together to form =O or =S. As an example, the term refers to "an alkyl where two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl may optionally join together to form =O or =S," and includes, 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 a group "optionally containing one or more heteroatoms, said heteroatoms being selected from the group consisting of O, S, and N" and the combination of a group "optionally two or more hydrogen atoms on the carbon atoms or heteroatoms of said group may together form =O or =S" can combine the two aspects described herein above and, when the group referred to is alkyl, includes inter alia 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-.

[0105] As used herein with respect to a linking group, i.e., in a manner in which a particular linking group in a formula herein is selected from a single bond, etc., the term "single bond" refers to a molecule in which a linking group is absent, and thus refers to a compound having a direct connection via a single bond between the two moieties joined by the linking group.

[0106] As used herein with respect to substituents, and unless otherwise specified, the terms "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted aryl," "substituted heteroaryl," "substituted heterocyclyl," "substituted arylalkyl," "substituted heteroaryl-alkyl," "substituted heterocyclyl-alkyl," and the like refer to a chemical structure, as defined herein, wherein the alkyl, alkenyl, alkynyl group and / or the aryl, heteroaryl, or heterocyclyl group may be optionally substituted with one or more substituents (preferably 1, 2, 3, 4, 5, or 6), 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 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, heteroarylalkenyl, 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)2, -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, wherein 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, and wherein the Zs attached to the two nitrogen atoms can be combined with the nitrogen atoms to which they are attached to form a heteroaryl or heterocyclyl. Alkyl(ene), alkenyl(ene), and alkynyl(ene) groups can also be similarly substituted.

[0107] Any substituent designation found at more than one site in a compound of this disclosure must be independently selected.

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

[0109] As used herein, and unless otherwise specified, the term "solvate" includes any combination that may be formed by the derivatives of the present disclosure with suitable inorganic solvents (e.g., hydrates) or organic solvents, such as, but not limited to, alcohols, ketones, esters, ethers, nitriles, and the like.

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

[0111] As used herein, the term "hydroxy" means --OH.

[0112] As used herein, the term "carbonyl" means a carbon atom attached to an oxygen with a double bond, ie, C=O.

[0113] As used herein, the term "amino" refers to the group --NH.sub.2.

[0114] The present disclosure provides novel compounds that have been shown to have 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 particularly in the treatment and / or prevention of cancer and fibrosis, among others.

[0115] The present disclosure further relates to compounds for use as drugs and their use for the manufacture of a medicament for treating and / or preventing cancer or fibrosis. The present disclosure relates to compounds for use as drugs for treating and / or preventing YAP / TAZ-TEAD activation-mediated diseases, such as cancer or fibrosis, in animals, mammals, and more particularly humans. The present disclosure also relates to methods for preparing 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 agents, to a patient in need of such treatment or prevention. The present disclosure also relates to compounds for veterinary use and their use as drugs 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 present disclosure provides a compound of formula (I): [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: [ka] is selected from the group consisting of: [ka] In the formula, the bond marked with "*" is R 2 is bound to X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, CR 1 or X is CR 1 and X 1 But, -CR 10b = and -N=, or X is -CR10a X is selected from the group consisting of = and -N=; 1 But, -CR 10b = and -N=; X 2 But, -CR 10c = and -N=; X 3 But, -CR 10d = and -N=; L 1 -NH- and -(CH2) p - selected from the group consisting of p is 0 or 1, R 1 is selected from the group consisting of: (i) hydrogen, (ii)-L 2 -NR 4a R 4b (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2 , (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 8 , (f)-S(=O)2NZ 3 Z 4 , (g) cyano; (h)-OZ 1 , and (i) halogens, (iv) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently selected from -OZ 1 , -C(=O)Z 2 , halogen, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), [ka] L 2 is -(CH2) n- and C3-C6 cycloalkylenyl n is 0 or 1, R 2 is selected from the group consisting of: [ka] [ka] R 3a but, (i) hydrogen, (ii) halogens, (iii) cyano, (iv)-OZ 1 , (v)-C(=O)NZ 3 Z 4 , (vi)-NZ 3 Z 4 , (vii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of: (a) cyano, (b)-C(=O)NZ 3 Z 4 , (c)-OZ 1 , (d)-NZ 3 Z 4 (e) Unsubstituted or substituted C6-C 10 aryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 , and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, (14)-NZ 5 C(=O)Z 2 , (15)-NZ 5 S(=O)2Z 2 , and (16)-NZ 5 S(=O)2NZ 3 Z 4 , (f) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of: (1) C1-C6 alkyl, and (2) C1-C6 haloalkyl, (g) unsubstituted or substituted 5-10 membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 , and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C 1~ C6 alkyl, hydroxy, and -NZ 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 selected from the group consisting of (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, and (14)-NZ 5 C(=O)Z 2 , (viii) C1-C6 haloalkyl, (ix) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C1-C6 alkyl; (x) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 , and (c)-S(=O)2Z 8 , (xi) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (d) C1-C6 haloalkyl, (e) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (f)-C(=O)NZ 3 Z 4 , (g)-NZ 3 Z 4 , (h) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (j) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (k)-OZ 1 , (l) -C(=O)OH, (m) hydroxy, and (n)-NZ 5 C(=O)Z 2 , R 3b , R 3c , and R 3d are independently selected from the group consisting of: (i) hydrogen, (ii) halogens, (iii) cyano, (iv) -C(=O)NZ 3 Z 4 , (v) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (vi) C1-C6 haloalkyl, (vii) C3-C6 cycloalkyl, and (viii) OZ 1 , q is 0, 1, or 2; R 4a but, (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z4 、 (g)-C(=O)Z 2 、 (h)-C(=O)OH, (i)-C(=O)OZ 2 、 (j)-C(=O)NZ 3 With 4 、 (k)-NZ 5 C(=O)Z 2 、 (l)-NZ 5 C(=O)OZ 2 、 (m)-NZ 5 C(=O)NZ 3 With 4 、 (n)-S(=O)2Z 8 、 (o)-S(=O)2NZ 3 With 4 、 (p)-S(=O)(=NZ) 6 )Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ) 6 )NZ 3 With 4 、 (s)-NZ 5 S(=O)2Z 2 、 (t)-NZ 5 S(=O)2NZ 3 With 4 、 (u)-NZ 5 S(=O)(=NZ) 6 )Z 2 、 (in)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、2. (w)-NZ 5 S(=O)(=NZ) 6 )NZ 3 With 4 、 (iii) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 (h)C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O)2Z 8 , (o)-S(=O)2NZ 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 , (r)-S(=O)(=NZ 6 )NZ 3 Z 4 , (s)-NZ 5 S(=O)2Z 2 , (t)-NZ 5 S(=O)2NZ 3 Z 4 , (u)-NZ 5 S(=O)(=NZ6 )Z 2 , (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (x) C1-C6 alkyl, (y) C1-C6 haloalkyl, and (z) C3-C6 cycloalkyl, (iv) unsubstituted or substituted C2-C6 alkenyl (wherein one or more substituents are independently —C(═O)OZ 2 , halogen, and unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (v)-C(=O)Z 2 (vi)-C(=O)OZ 2 , (vii)-C(=O)NZ 3 Z 4 , (viii)-S(=O)Z 8 , (ix)-S(=O)2NZ 3 Z 4 , (x)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (xii)-S(=O)(=NZ 6 )NZ 3 Z 4 , R 4b is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, each Z1 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, (vii) C1-C6 haloalkyl, (viii) cyano, and (ix)-C(=O)Z 2 , each Z 4 , Z 5 , Z 6 and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl, each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (iv) a halogen; (v) hydroxy, R 3b and R 3c are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) C1-C6 haloalkyl, and (iv) C3-C6 cycloalkyl, [ka] is selected from the group consisting of: (i) C3-C6 cycloalkyl, (ii) a 4- to 10-membered heterocycle, (iii) C6 to C 10 aryl, and (iv) 5- to 10-membered heteroaryl, Each R 5 are independently selected from the group consisting of: (i) halogens, (ii) hydroxy, (iii) cyano, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii)-C(=O)Z 2 (viii) -C(=O)OH, (ix)-C(=O)OZ 2 , (x)-C(=O)NZ 3 Z 4 , (xi)-NZ 5 C(=O)Z 2 , (xii)-NZ 5 C(=O)OZ 2 , (xiii)-NZ 5 C(=O)NZ 3 Z 4 , (xiv)-S(=O)Z 8 , (xv)-S(=O)2NZ 3 Z 4 , (xvi)-S(=O)(=NZ 6 )Z 2 , (xvii)-S(=Z 6 )(=NZ 7 )Z 2 , (xviii)-S(=O)(=NZ 6 )NZ 3 Z 4 , (xix)-NZ 5 S(=O)2Z 2 , (xx)-NZ 5 S(=O)2NZ 3 Z4 , (xxi)-NZ 5 S(=O)(=NZ 6 )Z 2 , (xxii)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , (xxiii)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (xxiv) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (xxv) C1-C6 haloalkyl, (xxvi) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (xxvii) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (xxviii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (xxix) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; R 6a but, (i) hydrogen, and (ii) C1-C6 alkyl, R 6b is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, The compound or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4. R 10a , R 10b , R 10c , and R 10d But independently, (i) hydrogen, (ii) cyano, (iii) hydroxy, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii) C1-C6 alkyl, and (viii) is selected from the group consisting of C1-C6 haloalkyl.

[0117] In one embodiment, the present disclosure provides a compound of formula II: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: [ka] is selected from the group consisting of: [ka] In the formula, the bond marked with "*" is R 2 is bound to X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, CR 1 or X is CR 1 and X 1 But, -CR 10b= and -N=, or X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, -CR 10b = and -N=; X 2 But, -CR 10c = and -N=; X 3 But, -CR 10d = and -N=; L 1 -NH- and -(CH2) p - selected from the group consisting of p is 0 or 1, R 1 is selected from the group consisting of: (i) hydrogen, (ii)-L 2 -NR 4a R 4b (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2 , (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 8 , and (f)-S(=O)2NZ 3 Z 4 ; L 2 is selected from the group consisting of -(CH2)n- and C3-C6 cycloalkylenyl n is 0 or 1, R 2 is selected from the group consisting of: [ka] R 3a but, (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) hydroxy, (b)-OZ 1 、 (c) Unsubstituted or substituted C6-C 10 aryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl (wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles), (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, (14)-NZ 5 C(=O)Z 2 , (15)-NZ 5 S(=O)2Z 2 , and (16)-NZ 5 S(=O)2NZ 3 Z 4 , (d) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of: (1) C1-C6 alkyl, and (2) C1-C6 haloalkyl, (e) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 selected from the group consisting of (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, and (14)-NZ 5 C(=O)Z 2 , (iii) C1-C6 haloalkyl, (iv) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C1-C6 alkyl; (v) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 , and (c)-S(=O)2Z 8 , (vi) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from hydroxy, -OZ 1 and -NZ 3 Z4 selected from the group consisting of (d) C1-C6 haloalkyl, (e) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (f)-C(=O)NZ 3 Z 4 , (g)-NZ 3 Z 4 , (h) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (j) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (k)-OZ 1 , (l) -C(=O)OH, (m) hydroxy, and (n)-NZ 5 C(=O)Z 2 , R 3b , R 3c , and R 3d are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) C1-C6 haloalkyl, and (iv) C3-C6 cycloalkyl, q is 0, 1, or 2; R 4a but, (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 (h)C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O)2Z 8 , (o)-S(=O)2NZ 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 , (r)-S(=O)(=NZ 6 )NZ 3 Z 4 , (s)-NZ 5 S(=O)2Z 2 , (t)-NZ 5 S(=O)2NZ3 Z 4 , (u)-NZ 5 S(=O)(=NZ 6 )Z 2 , (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (iii) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 (h)C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O)2Z 8 , (o)-S(=O)2NZ 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ 6 )NZ 3 Z 4 、 (s)-NZ 5 S(=O)2Z 2 、 (t)-NZ 5 S(=O)2NZ 3 Z 4 、 (u)-NZ 5 S(=O)(=NZ 6 )Z 2 、 (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、 (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 、 (x)C1 - C6 alkyl, (y)C1 - C6 haloalkyl, and (z)C3 - C6 cycloalkyl, (iv)-C(=O)Z 2 (v)-C(=O)OZ 2 、 (vi)-C(=O)NZ 3 Z 4 、 (vii)-S(=O)2Z 8 、 (viii)-S(=O)2NZ 3 Z 4 、 (ix)-S(=O)(=NZ 6 )Z 2 、 (x)-S(=Z 6 )(=NZ 7 )Z 2 、and (xi)-S(=O)(=NZ 6 )NZ 3 Z 4 、 R 4b is selected from the group consisting of: (i) hydrogen, and (ii) 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, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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) C1-C6 alkyl, (ii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, and (vi) C1-C6 haloalkyl, each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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 4 , Z 5 , Z 6 and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl, each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (iv) a halogen; (v) hydroxy, R 3b and R 3c are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) C1-C6 haloalkyl, and (iv) C3-C6 cycloalkyl, [ka] is selected from the group consisting of: (i) C3-C6 cycloalkyl, (ii) a 4- to 10-membered heterocycle, (iii) C6 to C 10 aryl, and (iv) 5- to 10-membered heteroaryl, Each R 5 are independently selected from the group consisting of: (i) halogens, (ii) hydroxy, (iii) cyano, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii)-C(=O)Z 2 (viii) C(=O)OH, (ix)-C(=O)OZ 2 , (x)-C(=O)NZ 3 Z 4 , (xi)-NZ 5 C(=O)Z 2 , (xii)-NZ 5 C(=O)OZ 2 , (xiii)-NZ 5 C(=O)NZ 3 Z 4 , (xiv)-S(=O)Z 8 , (xv)-S(=O)2NZ 3 Z 4 , (xvi)-S(=O)(=NZ 6 )Z 2 , (xvii)-S(=Z 6 )(=NZ 7 )Z 2 , (xviii)-S(=O)(=NZ 6 )NZ 3 Z 4 , (xix)-NZ 5 S(=O)2Z 2 , (xx)-NZ 5 S(=O)2NZ 3 Z 4 , (xxi)-NZ 5 S(=O)(=NZ 6 )Z 2 , (xxii)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , (xxiii)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (xxiv) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (xxv) C1-C6 haloalkyl, (xxvi) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (xxvii) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (xxviii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (xxix) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; R 6a but, (i) hydrogen, and (ii) C1-C6 alkyl, R 6b is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, m is 0, 1, 2, or 3; R 10a , R 10b , R 10c , and R 10d But independently, (i) hydrogen, (ii) cyano, (iii) hydroxy, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii) C1-C6 alkyl, and (viii) is selected from the group consisting of C1-C6 haloalkyl.

[0118] In another embodiment, the present disclosure provides a compound of formula III: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 , R 5 , X, X 1 , X 2 , X 3 , L 1 , m, and [ka] is as defined in relation to formula I or II.

[0119] In another embodiment, the present disclosure provides a compound of formula IV: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 2 , R 5 , X, X 2 , X 3 , m, and [ka] is as defined in relation to formula I or II.

[0120] In another embodiment, the present disclosure provides a compound of any one of Formulas I-IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X, X 2 , and X 3 is -CH=.

[0121] In another embodiment, the present disclosure provides a compound of any one of Formulas I-IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X is -N= and X 2 and X 3 is -CH=.

[0122] In another embodiment, the present disclosure provides a compound of any one of Formulas I-IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X is -N= and X 2 and X 3 is -CH=.

[0123] In another embodiment, the present disclosure provides a compound of any one of Formulas I-IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X and X 3 is -CH=, and X 2 is N=.

[0124] In another embodiment, the present disclosure provides a compound of any one of Formulas I-IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X and X 2 is -CH=, and X 3 is N=.

[0125] In another aspect, the present disclosure provides a compound of formula (V): [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 , R 5 , X 1 , X 2 , X 3 , m, and [ka] is as defined in relation to formula I or II.

[0126] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 , X 2 , and X 3 is -CH=.

[0127] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 -N = X 2 and X 3 is -CH=.

[0128] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 and X3 is -CH=, and X 2 is N=.

[0129] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 and X 2 is -CH=, and X 3 is N=.

[0130] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 -L 2 -NR 4a R 4b is.

[0131] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein L 2 is -(CH2) n -It is.

[0132] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein L 2 is -(CH2) n - and n is 0.

[0133] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein L 2 is -(CH2) n - and n is 1.

[0134] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4a is -C(=O)Z 2 , -C(=O)OZ 2 , -C(=O)NZ 3 Z 4 , -S(=O)2Z 8 , and -S(=O)2NZ 3 Z 4 is selected from the group consisting of:

[0135] In another embodiment, the disclosure provides a compound of any one of Formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: Z 2 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; Z 3 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; Z 4 is hydrogen.

[0136] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is an unsubstituted or substituted 4- to 8-membered heterocycle.

[0137] In another embodiment, the disclosure provides a compound of any one of formula I, II, or V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is as follows: [ka]

[0138] In another embodiment, the present disclosure provides a compound of formula VI: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: X is -CR 10a = and -N=; X 1 -CR 10b = and -N=; R 2 , R 5 , X 2 , X 3 , m, and [ka] is as defined in relation to formula I or II.

[0139] In another embodiment, the disclosure provides a compound of any one of formula I, II, or VI, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X, X 1 , X 2 , and X 3 is -CH=.

[0140] In another embodiment, the present disclosure provides a compound of formula VII: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 2 , R 5 , m, and [ka] is as defined in relation to formula I or II.

[0141] In another embodiment, the present disclosure provides a compound of formula VIII: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 2 , R 5 , R 6a , m, and [ka] is as defined in relation to formula I or II.

[0142] In another embodiment, the disclosure provides a compound of any one of formula I, II, VII or VIII, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 6a is selected from the group consisting of hydrogen and C1-C4 alkyl.

[0143] In another embodiment, the present disclosure provides a compound of formula IX: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 2 , R 5 , R 6b , m, and [ka] is as defined in relation to formula I or II.

[0144] In another embodiment, the disclosure provides a compound of any one of formula I, II, or IX, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 6b is selected from the group consisting of hydrogen and C1-C4 alkyl.

[0145] In another embodiment, the disclosure provides a compound of any one of formulas I-IX, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2is R 2 It is -1.

[0146] In another embodiment, the disclosure provides compounds of Formulas I-IX, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: [ka] is C6~C 10 It is aryl.

[0147] In another embodiment, the disclosure provides compounds of Formulas I-IX, wherein: [ka] is phenyl and R 5 is halo and m is 1 or 2.

[0148] In another embodiment, the disclosure provides a compound selected from any one or more of the compounds in Table 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0149] In another embodiment, the present disclosure provides a compound selected from the group consisting of: 1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one, (S)-1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one, and (R)-1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one.

[0150] Preferred or specific descriptions (features) and embodiments of the compounds of the present disclosure are set forth herein below. Each description, aspect, and embodiment of the present disclosure as defined above may be combined with any other description, aspect, and / or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as preferred, specific, or advantageous may be combined with any other feature or description indicated as preferred, specific, or advantageous. The present disclosure is herein specifically incorporated by any one or any combination of one or more of the following numbered descriptions and embodiments, together with any other (unnumbered) descriptions, aspects, and / or embodiments.

[0151] Embodiment 1. A compound of Formula I: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: [ka] is selected from the group consisting of: [ka] In the formula, the bond marked with "*" is R 2 is bound to X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, CR 1 or X is CR 1 and X 1 But, -CR 10b = and -N=, or X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, -CR 10b = and -N=; X 2 But, -CR 10c= and -N=; X 3 But, -CR 10d = and -N=; L 1 -NH- and -(CH2) p - selected from the group consisting of p is 0 or 1, R 1 is selected from the group consisting of: (i) hydrogen, (ii)-L 2 -NR 4a R 4b (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2 , (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 8 , (f)-S(=O)2NZ 3 Z 4 , (g) cyano; (h)-OZ 1 , and (i) halogens, (iv) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently selected from -OZ 1 , -C(=O)Z 2 , halogen, C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), [ka] L 2 But -(CH2) n - and C3-C6 cycloalkylenyl, n is 0 or 1, R 2 is selected from the group consisting of: [ka] [ka] R 3a is selected from the group consisting of: (i) hydrogen, (ii) halogens, (iii) cyano, (iv)-OZ 1 , (v)-C(=O)NZ 3 Z 4 , (vi)-NZ 3 Z 4 , (vii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of: (a) cyano, (b)-C(=O)NZ 3 Z 4 , (c)-OZ 1 , (d)-NZ 3 Z 4 (e) Unsubstituted or substituted C6-C 10 aryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, (14)-NZ 5 C(=O)Z 2 , (15)-NZ 5 S(=O)2Z 2 , and (16)-NZ 5 S(=O)2NZ 3 Z 4 , (f) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of: (1) C1-C6 alkyl, and (2) C1-C6 haloalkyl, (g) unsubstituted or substituted 5-10 membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 selected from the group consisting of (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) hydroxy, and (14)-NZ 5 C(=O)Z 2 , (viii) C1-C6 haloalkyl, (ix) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C1-C6 alkyl; (x) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 , and (c)-S(=O)2Z 8 , (xi) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (d) C1-C6 haloalkyl, (e) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (f)-C(=O)NZ 3 Z 4 , (g)-NZ 3 Z 4 , (h) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (j) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (k)-OZ 1 , (l) -C(=O)OH, (m) hydroxy, and (n)-NZ 5 C(=O)Z 2 , R 3b , R 3c , and R 3d are independently selected from the group consisting of: (i) hydrogen, (ii) halogens, (iii) cyano, (iv) -C(=O)NZ 3 Z 4 , (v) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (vi) C1-C6 haloalkyl, (vii) C3-C6 cycloalkyl, and (viii) OZ 1 , q is 0, 1, or 2; R 4a but, (i) hydrogen, (ii) unsubstituted or substituted C1-C6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 , (h) -C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O)2Z 8 , (o)-S(=O)2NZ 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 , (r)-S(=O)(=NZ 6 )NZ 3 Z 4 , (s)-NZ 5 S(=O)2Z 2 , (t)-NZ 5 S(=O)2NZ 3 Z 4 , (u)-NZ 5 S(=O)(=NZ 6 )Z 2 , (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (iii) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a)ハロゲン、 (b)ヒドロキシ、 (c)シアノ、 (d)-OZ 1 、 (e)-SZ 1 、 (f)-NZ 3 WITH 4 、 (g)-C(=O)Z 2 (h)C(=O)OH、 (i)-C(=O)OZ 2 、 (j)-C(=O)NZ 3 WITH 4 、 (k)-NZ 5 C(=O)Z 2 、 (l)-NZ 5 C(=O)OZ 2 、 (m)-NZ 5 C(=O)NZ 3 WITH 4 、 (n)-S(=O)2Z 8 、 (o)-S(=O)2NZ 3 WITH 4 、 (p)-S(=O)(=NZ 6 )WITH 2 、 (q)-S(=Z 6 )(=NZ 7 )WITH 2 、 (r)-S(=O)(=NZ 6 )NZ 3 WITH 4 、 (s)-NZ 5 S(=O)2Z 2 、 (t)-NZ 5 S(=O)2NZ 3 WITH 4 、 (u)-NZ 5 S(=O)(=NZ 6 )WITH 2 、 (v)-NZ 5 S(=NZ6 )(=NZ 7 )Z 2 , (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (x) C1-C6 alkyl, (y) C1-C6 haloalkyl, and (z) C3-C6 cycloalkyl, (iv) unsubstituted or substituted C2-C6 alkenyl (wherein one or more substituents are independently —C(═O)OZ 2 , halogen, and unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (v)-C(=O)Z 2 (vi)-C(=O)OZ 2 , (vii)-C(=O)NZ 3 Z 4 , (viii)-S(=O)Z 8 , (ix)-S(=O)2NZ 3 Z 4 , (x)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (xii)-S(=O)(=NZ 6 )NZ 3 Z 4 , R 4b is selected from the group consisting of: (i) hydrogen, and (ii) 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, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, (vii) C1-C6 haloalkyl, (viii) cyano, and (ix)-C(=O)Z 2 , each Z 4 , Z 5 , Z 6 and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl, each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) a halogen; (v) hydroxy, R 3b and R 3c are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) C1-C6 haloalkyl, and (iv) C3-C6 cycloalkyl, [ka] is selected from the group consisting of: (i) C3-C6 cycloalkyl, (ii) a 4- to 10-membered heterocycle, (iii) C6 to C 10 aryl, and (iv) 5- to 10-membered heteroaryl, Each R 5are independently selected from the group consisting of: (i) halogens, (ii) hydroxy, (iii) cyano, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii)-C(=O)Z 2 (viii) -C(=O)OH, (ix)-C(=O)OZ 2 , (x)-C(=O)NZ 3 Z 4 , (xi)-NZ 5 C(=O)Z 2 , (xii)-NZ 5 C(=O)OZ 2 , (xiii)-NZ 5 C(=O)NZ 3 Z 4 , (xiv)-S(=O)Z 8 , (xv)-S(=O)2NZ 3 Z 4 , (xvi)-S(=O)(=NZ 6 )Z 2 , (xvii)-S(=Z 6 )(=NZ 7 )Z 2 , (xviii)-S(=O)(=NZ 6 )NZ 3 Z 4 , (xix)-NZ 5 S(=O)2Z 2 , (xx)-NZ 5 S(=O)2NZ 3 Z 4 , (xxi)-NZ 5 S(=O)(=NZ6 )Z 2 , (xxii)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , (xxiii)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (xxiv) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (xxv) C1-C6 haloalkyl, (xxvi) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (xxvii) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (xxviii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (xxix) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; R 6a is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, R 6b is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, m is 0, 1, 2, 3, or 4; R 10a , R 10b , R 10c , and R 10d But independently, (i) hydrogen, (ii) cyano, (iii) hydroxy, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii) C1-C6 alkyl, and (viii) A compound of formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of C1-C6 haloalkyl.

[0152] Embodiment 2. A compound of Formula II: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: [ka] is selected from the group consisting of: [ka] In the formula, the bond marked with "*" is R 2 is bound to X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, CR 1 or X is CR 1 and X 1 But, -CR 10b = and -N=, or X is -CR 10a X is selected from the group consisting of = and -N=; 1 But, -CR 10b = and -N=; X 2 But, -CR 10c = and -N=; X 3 But, -CR 10d = and -N=; L 1 -NH- and -(CH2) p - selected from the group consisting of p is 0 or 1, R 1 is selected from the group consisting of: (i) hydrogen, (ii)-L 2 -NR 4a R 4b (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more substituents are selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2 , (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 8 , and (f)-S(=O)2NZ 3 Z 4 ; L 2 But -(CH2) n - and C3-C6 cycloalkylenyl, n is 0 or 1, R 2 is selected from the group consisting of: [ka] R 3a 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) hydroxy, (b)-OZ 1 、 (c) Unsubstituted or substituted C6-C 10 aryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl (wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles), (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, (14)-NZ 5 C(=O)Z 2 , (15)-NZ 5 S(=O)2Z 2 , and (16)-NZ 5 S(=O)2NZ 3 Z 4 , (d) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of: (1) C1-C6 alkyl, and (2) C1-C6 haloalkyl, (e) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (1) halogen, (2) Cyano, (3) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 , and -NZ 3 Z 4 selected from the group consisting of (4) C1-C6 haloalkyl, (5) C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and - New Zealand 3 Z 4 selected from the group consisting of (6)-C(=O)NZ 3 Z 4 , (7)-NZ 3 Z 4 , (8) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 selected from the group consisting of (9) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (11)-OZ 1 , (12)-C(=O)OH, (13) Hydroxy, and (14)-NZ 5 C(=O)Z 2 , (iii) C1-C6 haloalkyl, (iv) unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of halogen and C1-C6 alkyl; (v) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) C1-C6 alkyl, (b)-C(=O)Z 2 , and (c)-S(=O)2Z 8 , (vi) unsubstituted or substituted 5- to 10-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from hydroxy, -OZ 1 , and -NZ 3 Z4 selected from the group consisting of (d) C1-C6 haloalkyl, (e) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more substituents are independently selected from C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (f)-C(=O)NZ 3 Z 4 , (g)-NZ 3 Z 4 , (h) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (j) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; (k)-OZ 1 , (l) -C(=O)OH, (m) hydroxy, and (n)-NZ 5 C(=O)Z 2 , R 3b , R 3c , and R 3d are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) C1-C6 haloalkyl, and (iv) C3-C6 cycloalkyl, q is 0, 1, or 2; R 4a 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) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 (h)C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O)2Z 8 , (o)-S(=O)2NZ 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 , (r)-S(=O)(=NZ 6 )NZ 3 Z 4 , (s)-NZ 5 S(=O)2Z 2 , (t)-NZ 5S(=O)2NZ 3 Z 4 , (u)-NZ 5 S(=O)(=NZ 6 )Z 2 , (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (iii) an unsubstituted or substituted 4- to 10-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 (h)C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O)2Z 8 , (o)-S(=O)2NZ 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ 6 )NZ 3 Z 4 、 (s)-NZ 5 S(=O)2Z 2 、 (t)-NZ 5 S(=O)2NZ 3 Z 4 、 (u)-NZ 5 S(=O)(=NZ 6 )Z 2 、 (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、 (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 、 (x)C1 - C6 alkyl, (y)C1 - C6 haloalkyl, and (z)C3 - C6 cycloalkyl, (iv)-C(=O)Z 2 (v)-C(=O)OZ 2 、 (vi)-C(=O)NZ 3 Z 4 、 (vii)-S(=O)2Z 8 、 (viii)-S(=O)2NZ 3 Z 4 、 (ix)-S(=O)(=NZ 6 )Z 2 、 (xi)-S(=Z 6 )(=NZ 7 )Z 2 、and (x)-S(=O)(=NZ 6 )NZ 3 Z 4, R 4b is selected from the group consisting of: (i) hydrogen, and (ii) 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, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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) C1-C6 alkyl, (ii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, and (vi) C1-C6 haloalkyl, each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -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 4 , Z 5 , Z 6 and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl, each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles; (iv) a halogen; (v) hydroxy, R 3b and R 3c are independently selected from the group consisting of: (i) hydrogen, (ii) C1-C6 alkyl, (ii) C1-C6 haloalkyl, and (iii) C3-C6 cycloalkyl, [ka] is selected from the group consisting of: (i) C3-C6 cycloalkyl, (ii) a 4- to 10-membered heterocycle, (iii) C6 to C 10 aryl, and (iv) 5- to 10-membered heteroaryl, Each R 5 are independently selected from the group consisting of: (i) halogens, (ii) hydroxy, (iii) cyano, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii)-C(=O)Z 2 (viii) C(=O)OH, (ix)-C(=O)OZ 2 , (x)-C(=O)NZ 3 Z 4 , (xi)-NZ 5 C(=O)Z 2 , (xii)-NZ 5 C(=O)OZ 2 , (xiii)-NZ 5 C(=O)NZ 3 Z 4 , (xiv)-S(=O)Z 8 , (xv)-S(=O)2NZ 3 Z 4 , (xvi)-S(=O)(=NZ 6 )Z 2 , (xvii)-S(=Z 6 )(=NZ 7 )Z 2 , (xviii)-S(=O)(=NZ 6 )NZ 3 Z 4 , (xix)-NZ 5 S(=O)2Z 2 , (xx)-NZ 5 S(=O)2NZ 3 Z 4 , (xxi)-NZ 5 S(=O)(=NZ 6 )Z 2 , (xxii)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , (xxiii)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (xxiv) Unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently hydroxy, -OZ 1 , and -NZ 3 Z 4 selected from the group consisting of (xxv) C1-C6 haloalkyl, (xxvi) C3-C6 cycloalkyl (wherein one or more substituents are independently C1-C6 alkyl, hydroxy, and -NZ) 3 Z 4 selected from the group consisting of (xxvii) Unsubstituted or substituted C2-C6 alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6 alkyl, and one or more substituents are independently selected from the group consisting of -NZ 3 Z 4 and 4- to 8-membered heterocycles), (xxviii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are independently halo, -OZ 1 , C1-C6 alkyl, cyano, hydroxy, and C1-C6 haloalkyl), (xxix) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; R 6a is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, R 6b is selected from the group consisting of: (i) hydrogen, and (ii) C1-C6 alkyl, m is 0, 1, 2, or 3; R 10a , R 10b , R 10c , and R 10d But independently, (i) hydrogen, (ii) cyano, (iii) hydroxy, (iv)-OZ 1 , (v)-SZ 1 (vi)-NZ 3 Z 4 , (vii) C1-C6 alkyl, and (viii) A compound of formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of C1-C6 haloalkyl.

[0153] Embodiment 3. A compound according to embodiment 1 or 2 of formula III, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0154] Embodiment 4. A compound according to embodiment 1 or 2 of formula IV, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0155] Embodiment 5.X, X 2 , and X 3 is -CH=, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0156] Embodiment 6. X is -N= and X 2 and X 3 is -CH=, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0157] Embodiment 7.X and X 3 is -CH= and X 2 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0158] Embodiment 8.X and X 2 is -CH= and X 3 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0159] Embodiment 9. A compound according to embodiment 1 or 2 of formula V, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0160] Embodiment 10.X 1 , X 2 , and X 3 is -CH=, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0161] Embodiment 11.X 1 But -N=X 2 and X 3 is -CH=, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0162] Embodiment 12.X 1 and X 3 is -CH= and X 2 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0163] Embodiment 13.X 1 and X 2 is -CH= and X 3 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0164] Embodiment 14.R 1 But -L 2 -NR 4a R 4b 14. The compound of any one of embodiments 1-13, wherein:

[0165] Embodiment 15.L 2 But -(CH2) n or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0166] Embodiment 16. A compound according to embodiment 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein n is 0.

[0167] Embodiment 17. A compound according to embodiment 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein n is 1.

[0168] Embodiment 18.R 4a But -C(=O)Z 2 , -C(=O)OZ 2 , -C(=O)NZ 3 Z 4 , -S(=O)2Z 8 , and -S(=O)2NZ 3 Z 4 18. The compound of any one of embodiments 1-17, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

[0169] Embodiment 19. Z 2 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; Z 3 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl; Z 4 The compound of any one of embodiments 1-18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein is hydrogen.

[0170] Embodiment 20.R 1 is an unsubstituted or substituted 4-8 membered heterocycle, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0171] Embodiment 21.R 1 21. The compound of embodiment 20, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: [ka]

[0172] Embodiment 22. A compound according to embodiment 1 or 2 of formula VI, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: X is -CR 10a = and -N=; X 1 But, -CR 10b = and -N=, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0173] Embodiment 23.X, X 1 , X 2 , and X 3 23. The compound of embodiment 1, 2, or 22, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0174] Embodiment 24. A compound according to embodiment 1 or 2 of formula VII, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0175] Embodiment 25. A compound according to embodiment 1 or 2 of formula VII, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0176] Embodiment 26.R 6a is selected from the group consisting of hydrogen and C1-C4 alkyl, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0177] Embodiment 27. A compound according to embodiment 1 or 2 of formula VII, [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0178] Embodiment 28.R 6b is selected from the group consisting of hydrogen and C1-C4 alkyl, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0179] Embodiment 29.R 2 But R 2 29. The compound of any one of embodiments 1-28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R is -1.

[0180] Embodiment 30. [ka] But C6~C 10 The compound of any one of embodiments 1-29, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0181] Embodiment 31. [ka] is phenyl, and R 5 The compound of any one of embodiments 1-30, wherein is halo and m is 1 or 2.

[0182] Embodiment 32. A compound selected from any one or more of the compounds in Table 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0183] Embodiment 33. A compound of embodiment 1 or 2, or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: 1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one, (S)-1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one, and (R)-1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one.

[0184] Embodiment 34. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 33, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.

[0185] Embodiment 35. A compound according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use as a medicament.

[0186] Embodiment 36. A compound according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder in an animal, mammal, or human.

[0187] Embodiment 37. A compound according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder selected from the group consisting of cancer, fibrosis, and a YAP / TAZ-TEAD activation-mediated congenital disorder.

[0188] Embodiment 38. A compound according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder 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, mesothelial tumors, and / or sarcoma.

[0189] Embodiment 39. Acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, myeloma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes (dysplastic changes). Breast cancer, esophageal ... and non-Hodgkin's), malignancies 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 natal carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythrocytosis vera, rectal cancer, renal cell carcinoma, retinoblastoma , rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, melloma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial carcinoma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0190] Embodiment 40. A method for preventing or treating 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 of any one of embodiments 1 to 33.

[0191] Embodiment 41. A method for treating or preventing a YAP / TAZ-TEAD activation-mediated disorder according to embodiment 40 in a patient in need thereof, in combination with one or more other agents selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor.

[0192] More generally, the present disclosure relates to compounds of the formulae described herein, and embodiments, descriptions and aspects thereof, that are useful as biologically active agents or as diagnostic agents. Any of the uses referred to in connection with the present disclosure may be limited to non-medical, non-therapeutic, non-diagnostic uses, or exclusively in vitro uses, or uses involving cells away from an animal.

[0193] 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, mesothelial tumors, and / or sarcomas. 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 derived from tissues of neuroectodermal origin, such as ependymomas, meningiomas, schwannomas, peripheral nerve sheet tumors, and / or neuroblastomas. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating vascular cancers such as epithelioid hemangioendotheliomas, or for treating epithelioma or pore cancer. In some embodiments, the solid tumor has a gain-of-function gene amplification, gene duplication, or activating mutation in the YAP1 or WWTR1 (TAZ) gene. 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 gene, e.g., in uveal melanoma. In some embodiments, the solid cancer 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.

[0194] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating cancers that have developed resistance to previous treatments, including, for example, treating cancers that have developed resistance to chemotherapy or targeted therapy. In some embodiments, this may include treating cancers that have developed resistance to components of the RAS-MAPK signaling cascade, including inhibitors of receptor tyrosine kinases such as EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, vemtinib, duvelmatinib), inhibitors of RAS itself (AMG510, MRTX849, BI1701963, ARS1620, etc.), inhibitors of B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib), or MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0195] Small molecule YAP / TAZ-TEAD inhibitors may also be useful when combined with, administered simultaneously with, or subsequently to other drugs used in the treatment of cancer. This may include, for example, inhibitors of receptor tyrosine kinases such as EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, vemtinib, duvelmatinib), inhibitors of RAS itself (AMG510, MRTX849, BI1701963, ARS1620, etc.), inhibitors of B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib), or monoclonal inhibitors targeting receptor tyrosine kinases such as MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0196] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating metastatic cancers, in some cases 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.

[0197] In some embodiments, the cancer being treated may be malignant pleural mesothelioma or lung cancer.

[0198] In some embodiments, compounds of the present disclosure are useful in treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, myeloma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, thyroid cancer ... Intestinal cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic 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, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma , leukemia, liposarcoma, lung cancer, lymphangioendothelioma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies 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, Nat midline carcinoma (NMC), non-small cell lung cancer , oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, erythrocytosis vera, prostate, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, melloma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial cancer, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0199] Malignant pleural mesothelioma Small molecule YAP / TAZ-TEAD inhibitors may also be useful for treating malignant pleural mesothelioma, either as single agents or in combination with inhibitors such as pemetrexed disodium, raltitrexed, carboplatin, oxaliplatin, gemcitabine, doxorubicin, or monoclonal antibodies such as bevacizumab. They may also be combined with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. They may also be combined with cell therapy, such as chimeric antigen receptor (CAR) T therapy or CAR NK therapy, which may use mesothelin (MSLN) as the antigen. For example, they may be combined with monoclonal antibodies that recognize mesothelin as an antigen, such as BMS-986148, BAY94-9343, amatuximab, and / or LMB-100.

[0200] 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 onaltuzumab, or in combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. Combinations with cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, 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, onaltuzumab, pemlolizumab, atezolizumab, and / or nivolumab

[0201] In some embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful, for example, for the treatment of congenital disorders. In some embodiments, the congenital disorder is mediated by activation of a transcriptional coactivator with a PDZ-binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the congenital disorder 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 disorder is characterized by a loss-of-function mutation or deletion in the NF2 gene. Exemplary congenital disorders include, but are not limited to, Sturge-Weber syndrome, port-wine staining syndrome, and neurofibromatosis. In some embodiments, the congenital disorder is neurofibromatosis, including, but not limited to, neurofibromatosis type 2.

[0202] 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 can be treated in the context of nonalcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, chronic kidney disease, and / or myocardial infarction injury.

[0203] 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 the growth of cancer cell lines and cancers that depend on YAP / TAZ-TEAD transcriptional activity in xenograft cancer models.

[0204] The compounds of the present disclosure can optionally be covalently attached to an insoluble matrix and used for affinity chromatography (separation will depend on the nature of the compound's groups; for example, compounds with pendant aryls are useful for hydrophobic affinity separations).

[0205] When one or more derivatives of the formulae defined herein are used, The active ingredients of the compound(s) may be administered to the animal or mammal (including humans) to be treated by any means well known in the art, i.e., orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intraarterially, parenterally, or by catheterization. A therapeutically effective amount of a compound(s) preparation, in particular for the treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription (such as cancer, fibrosis, and certain congenital disorders) in humans and other mammals, is preferably a YAP / TAZ-TEAD transcription-inhibiting amount of a compound of the formulas, statements, aspects, and embodiments defined herein, capable of inhibiting YAP / TAZ-TEAD activity, corresponding to an amount ensuring plasma levels between 1 μg / ml and 100 mg / ml.

[0206] A suitable dosage of the compound or composition of the present disclosure should be used to treat or prevent the target disease in a subject. Depending on the pathological condition 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 one or more days.

[0207] 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. Accordingly, the present disclosure relates to the use of a composition comprising: (a) one or more compounds of the formulae and aspects, statements and embodiments herein; and (b) One or more additional therapeutic or prophylactic agents used as biologically active agents in the prevention or treatment of cancer or fibrosis in the form of a combined preparation for simultaneous, separate, or sequential use.

[0208] The compounds or compositions may be administered simultaneously with, before, or after one or more additional therapeutic agents that are different from the compounds described herein and that may be useful, for example, as a combination therapy.

[0209] Examples of such additional therapeutic agents for use in combination include agents that are inhibitors of: 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, including inhibitors of RAS itself (e.g., AMG510, MRTX849, BI1701963, ARS1620), B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib, etc.), or · MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0210] The pharmaceutical compositions or combined preparations according to the present disclosure may contain the compounds of the present disclosure over a wide range of contents depending on the intended use and the expected effect of the preparation. Generally, the content of the derivatives of the present disclosure in the combined preparation is within the range of 0.1 to 99.9% by weight, preferably 1 to 99% by weight, and more preferably 5 to 95% by weight.

[0211] Those skilled in the art will also recognize that the compounds of the present disclosure can exist in many different protonation states, depending, inter alia, on the pH of their environment. Although the structural formulas provided herein show the compounds in only one of several possible protonation states, it will be understood that these structures are merely exemplary, and the present disclosure is not limited to any particular protonation state. Any and all protonation forms of the compounds are intended to fall within the scope of the present disclosure.

[0212] The term "pharmaceutically acceptable salts" as used herein refers to therapeutically active, non-toxic salts that the compounds of the formulae herein can form. Thus, the compounds of the present disclosure may optionally be salts of the compounds herein, particularly salts of, for example, Na + , Li + , K. + , Ca 2+ and Mg 2+ These salts include pharmaceutically acceptable, non-toxic salts containing the compound. Such salts may include salts derived from the combination of suitable cations, such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions, with an acid anion moiety, typically a carboxylic acid. The compounds of the present disclosure may bear multiple positive or negative charges. The net charge of the compounds of the present disclosure may be either positive or negative. Any associated counterion is typically determined by the synthesis and / or isolation method by which the compound is obtained. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetates, trifluoroacetates, etc., and mixtures thereof. It will be understood that the identity of any associated counterion is not a critical feature of the present disclosure, and the present disclosure encompasses compounds associated with any type of counterion. Furthermore, because compounds can exist in a variety of different forms, the present disclosure is intended to encompass not only forms of compounds associated with a counterion (e.g., dry salts) but also forms not associated with a counterion (e.g., aqueous or organic solutions). Metal salts are typically prepared by reacting a metal hydroxide with a compound of the present disclosure. Examples of metal salts prepared in this way are Li + , Na + , and K +(Illegible) . Less soluble metal salts can be precipitated from the solution of a more soluble salt by adding a suitable metal compound. In addition, salts can be formed from the acid addition of certain organic and inorganic acids to basic centers, typically amines, or acidic groups. Examples of suitable acids include inorganic acids such as hydrohalogen acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as 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, cyclohexanesulfonic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, and the like. Furthermore, the term also includes solvates that the compounds of the formulae herein, as well as their salts, are able to form, such as hydrates, alcoholate salts, etc. Finally, it should be understood that the compositions herein include the compounds of the present disclosure in non-ionized as well as zwitterionic form, and combinations with a stoichiometric amount of water similar to a hydrate.

[0213] 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. Amino acids typically have side chains with basic or acidic groups, such as lysine, arginine, or glutamic acid, or neutral groups, such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0214] 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. +(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 a hydroxy group include salts of Na + and NX4 + (where X is typically independently selected from H or a C1-C4 alkyl group). 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.

[0215] 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%.

[0216] As used herein, the term "isomer" refers to all possible isomeric forms, including tautomeric and stereochemical forms, that a compound of the formula herein may possess, but does not include positional isomers. Typically, a structure depicted herein illustrates only one tautomeric or resonance form of a compound, but the corresponding alternative configurations are also contemplated. Unless otherwise specified, the chemical name of a compound denotes a mixture of all possible stereochemically isomeric forms, which mixtures contain all diastereomers and enantiomers of the basic molecular structure (since compounds of the formula herein may have at least one chiral center), as well as stereochemically pure or enriched compounds. More specifically, stereogenic centers may have either the R or S configuration, and multiple bonds may have either the cis or trans configuration.

[0217] 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 "chiral pure" relates to compounds 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 a similar manner, taking into account the enantiomeric excess, respectively diastereomeric excess, of the mixture in question.

[0218] Separation of stereoisomers can be achieved by standard methods known to those skilled in the art. One enantiomer of a compound of the present disclosure can 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 can be achieved by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure enantiomers; or (3) enantiomers can be separated directly under chiral conditions. In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, and a-methyl-b-phenylethylamine (amphetamine), with asymmetric compounds containing acidic functional groups, such as carboxylic and sulfonic acids. Diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. For the 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, in 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 reacting the asymmetric compound with an enantiomerically pure chiral derivatizing reagent, such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to give the free enantiomerically enriched compound.A method for determining optical purity involves preparing chiral esters, such as menthyl or Mosher esters, a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture and analyzing the NMR spectrum for the presence of two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal-phase and reverse-phase chromatography, following the separation method for atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96 / 15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, particularly cellulose or amylose derivatives. Commercially available polysaccharide chiral stationary phases include 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 these polysaccharide chiral stationary phases include hexane modified with alcohols such as ethanol and isopropanol. ("Chiral Liquid Chromatography" (1989) W. J. 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).

[0219] The terms cis and trans are used herein in accordance with chemical abstract 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.

[0220] The present disclosure also encompasses isotopically labeled compounds that are identical to the compounds listed herein except for the fact that one or more atoms have been replaced with 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, respectively: 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 Included within the scope of the present disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as CI. Compounds of the present disclosure and pharmaceutically acceptable salts of such compounds, or salts containing the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds, for example, 3 H and 14 Compounds into which radioactive isotopes such as 3C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced required dosage, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the disclosed formulae may generally be prepared by the procedures disclosed in the examples and preparations described herein, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0221] The present disclosure relates to the modification of compounds of formula (I) or other formulae, or embodiments, aspects, or portions thereof, using PROTAC technology (Schapira M. et al., Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, PROTAC technology designs bifunctional small molecules, one end of which is a compound of general formula (I) or other formulae, or an embodiment, aspect, or portion thereof, or a metabolite thereof, and the other end of which is connected via a connecting chain to a ligand of an E3 ubiquitin ligase, to form a targeted protein degradation complex. This degradation is catalytic, allowing for efficient degradation 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).

[0222] The compounds of the present disclosure can be formulated using conventional carriers and excipients selected according to ordinary practice. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic if intended for delivery by other than oral administration. Formulations optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986), including ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid.

[0223] As used herein, the term "pharmaceutically acceptable carrier" refers to any material or substance in which an active ingredient is formulated to facilitate its application or dissemination to the locus to be treated, for example, by dissolving, dispersing, or diffusing the composition, and / or by facilitating its storage, transportation, or handling without compromising its efficacy. A pharmaceutically acceptable carrier may be a solid or liquid, or a gas compressed to form a liquid; for example, the compositions of the present disclosure may be suitable for use as a concentrate, emulsion, solution, granule, dust, spray, aerosol, suspension, ointment, cream, tablet, pellet, or powder.

[0224] Suitable pharmaceutical carriers for use in the pharmaceutical compositions and their formulations are well known to those skilled in the art, and their selection within the present disclosure is not particularly limited. They may also contain additives such as wetting agents, dispersants, stickers, adhesives, emulsifiers, solvents, coatings, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (e.g., sugars or sodium chloride), etc., consistent with pharmaceutical practice, e.g., carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present disclosure can be prepared by any known method, for example, by uniformly mixing, coating, and / or grinding the active ingredient with the selected carrier material and, if appropriate, other additives such as surfactants, in one or more steps. They can also be prepared by micronization, for example, to obtain the form of fine particles, typically having a diameter of about 1 to 10 gm, i.e., for the production of microcapsules for controlled or sustained release of the active ingredient.

[0225] Suitable surfactants, also known as opacifiers or emulsifiers, 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 or alkaline earth metal salts, higher fatty acids (C 10 ~C22 Examples of suitable surfactants include unsubstituted or substituted ammonium salts of fatty acids such as sodium or potassium salts of oleic acid or stearic acid, or mixtures of natural fatty acids obtained from coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acid, fatty acid sulfonates and sulfates, sulfonated benzimidazole derivatives, and alkylaryl sulfonates. The fatty acid sulfonates or sulfates are usually in the form of alkali or alkaline earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with alkyl or acyl groups having 8 to 22 carbon atoms, such as sodium or calcium salts of lignosulfonic acid or dodecylsulfonic acid, or mixtures of fatty alcohol sulfates obtained from the sulfonic acids of alkali or alkaline earth metal salts of natural fatty acids, sulfates or sulfonate esters (e.g., sodium lauryl sulfate), and fatty alcohol sulfates obtained from the sulfonic acids of fatty alcohol / ethylene oxide adducts. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulfonates are sodium, calcium, or alcoholamine salts of dodecylbenzenesulfonic acid or dibutylnaphthalenesulfonic acid, or naphthalenesulfonic acid / formaldehyde condensation products. Also suitable are the corresponding phosphates, such as salts of phosphoric acid ester and p-nonylphenol adducts with ethylene and / or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are natural (animal or plant cell-derived) or synthetic phospholipids of the cephalin or lecithin type, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerin, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphosphatidylcholine, and mixtures thereof.

[0226] Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines, or amides containing at least 12 carbon atoms in the molecule; polyglycol ether derivatives of aliphatic and alicyclic alcohols; saturated and unsaturated fatty acids; and alkylphenols, such as alkylarethsulfonates and dialkylsulfosuccinates, preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable nonionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol and ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain; these adducts contain 20 to 250 ethylene glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds typically contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycol 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.

[0227] Suitable cationic surfactants include quaternary ammonium salts, especially halides, having four hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl, or hydroxy; e.g., quaternary ammonium salts having at least one C as an N-substituent; 8~22 Quaternary ammonium salts containing alkyl (eg, cetyl, lauryl, palmityl, myristyl, oleyl, etc.) and further substituents include unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy-lower alkyl.

[0228] A more detailed description of surfactants suitable for this purpose can be found, for example, in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw", 2nd ed. (Hanser Verlag, Vienna, 1981), and "Encyclopaedia of Surfactants," (Chemical Publishing Co., New York, 1981).

[0229] The compounds of the present disclosure and their pharmaceutically acceptable salts (hereinafter collectively referred to as the active ingredients) may be administered by any suitable route appropriate to the condition to be treated, including 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 may vary, for example, depending on the condition of the recipient.

[0230] While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Both veterinary and human formulations of the present disclosure comprise at least one active ingredient, as described above, one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic ingredients. The carrier(s) are optionally "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 presented 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 the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0231] 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 emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0232] Tablets can be produced 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 as powder or granules, optionally mixed with binders, lubricants, inert diluents, preservatives, surfactants, or dispersants, etc., in a suitable machine.Molded tablets can be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.Tablets can optionally be coated or divided, and can be formulated to provide a slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues, for example mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount, for example, 0.075 to 20% w / w (including 0.1% to 20% of the active ingredient(s), in increments of 0.1% w / w, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a 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, e.g., 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 optionally 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 dimethyl sulfoxide and related analogues.

[0233] The oily phase of the emulsion of the present disclosure can be composed of known ingredients in a known manner. The phase can simply comprise an emulsifier (otherwise known as an emulsion), but preferably comprises a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier(s) with or without the stabilizer(s) constitute the so-called emulsifying wax, and the wax together with the oil and fat constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0234] The selection of an appropriate oil or fat for a formulation is based on achieving the desired cosmetic properties, since the solubility of active compounds in most oils likely to be used in pharmaceutical emulsion formulations is very low. Therefore, creams must be non-greasy, non-staining, and washable, optionally with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched mono- or dibasic alkyl esters, 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, may also be used, with the last three being preferred. These may be used alone or in combination depending on the desired properties. Alternatively, high-melting-point lipids such as white petrolatum and / or liquid paraffin, or other mineral oils, may be used.

[0235] 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 in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia, and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0236] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for nasal administration, where the carrier is a solid, include, for example, a coarse powder having a particle size in the range of 20 to 500 microns (including particle sizes in the range of 20 to 500 microns in 5 micron increments, such as 30 microns, 35 microns, etc.), which is administered in the manner in which nasal inhalation is taken, e.g., 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 administration, for example, as a nasal spray or as 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.

[0237] 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.

[0238] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The formulations 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) state requiring only the addition of a sterile liquid carrier, such as water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind described above.

[0239] Preferred unit dosage formulations are those containing a daily dose or daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0240] It will be understood that in addition to the ingredients particularly mentioned above, the formulations of the present disclosure may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0241] 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, where release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given disclosed compound. Controlled-release formulations suitable for oral administration can be prepared according to conventional methods, where discrete units containing one or more compounds of the present disclosure.

[0242] Additional ingredients may be included to control the duration of action of the active ingredient in the composition. 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, such as microcapsules, of polymeric substances, such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate, and other polymers mentioned above. Such methods include colloid drug delivery systems, such as liposomes, microspheres, microemulsions, nanoparticles, and nanocapsules. Depending on the route of administration, pharmaceutical compositions may require protective coatings. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions, and sterile powders for their extemporaneous preparation. Typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, etc., and mixtures thereof.

[0243] When several active ingredients are used in combination, taking into account the fact that they do not necessarily simultaneously exert their joint therapeutic effect in the treated mammal, the corresponding composition may be in the form of a medical kit or package containing the two components in separate but adjacent compartments or repositories. In the latter context, each active ingredient may therefore be formulated in a way suitable for a different administration route than the other components, for example, one of them may be in the form of an oral or parenteral preparation, while the other is in the form of an ampoule or aerosol for intravenous injection.

[0244] 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 are not themselves significantly biologically active, but that, when delivered to an animal, mammal, or human, undergo chemical reactions catalyzed by the normal functioning of the body, particularly enzymes present in the stomach or serum, which have the effect of releasing the compounds defined herein. The term "prodrug" therefore relates to these species that are converted in vivo into the active pharmaceutical ingredient.

[0245] Prodrugs of the compounds of the present disclosure can have any form suitable for formulation, for example, esters are a non-limiting example of a common prodrug form. However, in this case, the prodrug may necessarily exist in a form in which the covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a CC covalent bond may be selectively cleaved by one or more enzymes at the target locus, and therefore prodrugs in forms other than readily hydrolyzable precursors, particularly esters, amides, etc., may be used. The counterpart of the active pharmaceutical ingredient in the prodrug may have a different structure, such as an amino acid or peptide structure, an alkyl chain, a sugar moiety, and others known in the art.

[0246] For purposes of this disclosure, the term "therapeutically suitable prodrug" is defined herein as "a compound that is modified in such a way that it is transformed in vivo, by either single or multiple biological transformations, into a therapeutically active form without undue toxicity, irritation, or allergic response upon contact with the tissues of an animal, mammal, or human to which the prodrug is administered, and that achieves an intended therapeutic result."

[0247] More specifically, as used herein, the term "prodrug" refers to an inactive or significantly less active derivative of a compound as represented by the structural formulas set forth herein, which undergoes spontaneous or enzymatic transformation in the body to release the 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).

[0248] The compounds of the present disclosure can be prepared using a series of chemical reactions well known to those skilled in the art, which, taken together, constitute a process for preparing said compounds. The processes further described are intended as examples only and are not intended to limit the scope of the present disclosure in any way. [Example]

[0249] General Synthesis Representative compounds of the present disclosure can be synthesized according to the general synthetic methods described below and illustrated in the following schemes. Because the schemes are illustrative, the present disclosure should not be construed as limited by the specific chemical reactions and specific conditions described in the schemes and examples. The various starting materials used in the schemes are commercially available or can be prepared by methods well within the skill of one of ordinary skill in the art. The variables, as defined herein, are within the skill of one of ordinary skill in the art.

[0250] The compounds of the present disclosure can be prepared using a series of chemical reactions well known to those skilled in the art, which, taken together, constitute a process for preparing said compounds. The processes further described are intended as examples only and are not intended to limit the scope of the present disclosure in any way.

[0251] The present invention relates to a method for the preparation of a compound -dihalo-nitro(hetero)arenes or dihalo(hetero)arenenitriles successively reacted with suitable coupling agents to give azolyl-(hetero)aryl-nitro(hetero)arenes or azolyl-(hetero)aryl-(hetero)arenenitriles, respectively; - azole alkylation of the previously obtained azolyl-(hetero)aryl-nitro(hetero)arenes or azolyl-(hetero)aryl-(hetero)arenenitriles to obtain N-functionalized azolyl-(hetero)aryl-nitro(hetero)arenes or azolyl-(hetero)aryl-(hetero)arenenitriles, respectively; - reduction of the previously obtained azolyl-(hetero)aryl-nitro(hetero)arene or azolyl-(hetero)aryl-(hetero)arenenitrile, followed by derivatization of the resulting amine or aniline moiety, respectively, to obtain the desired compound of the invention.

[0252] Compounds of the present invention may be prepared according to the general procedures outlined in Scheme 1. [ka] Scheme 1: All R 3a , R 4a , R 4b , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas.

[0253] 1-(5-bromo-2-nitrophenyl)ethan-1-one 2, which is commercially available or synthesized from 1-(2-nitrophenyl)ethan-1-one 1 by procedures known to those skilled in the art, may be reacted with N,N-dimethylformamide dimethyl acetal in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.) at an elevated temperature of 100° C. to 120° C., followed by reaction with hydrazine in a suitable solvent (e.g., EtOH, 1,4-dioxane, etc.) at an elevated temperature of 80° C. to 120° C. to provide intermediates of general formula 3. Intermediates of general formula 5 can be obtained from intermediate 3 by pyrazole N-alkylation using procedures known to those skilled in the art, followed by a coupling reaction applying an appropriate coupling agent selected from, but not limited to, halo(hetero)aryls, (hetero)anilines, boronic acids, and boronic esters in combination with the corresponding Pd or Cu catalyst. Alternatively, intermediates of general formula 4 can be obtained by reacting intermediate 2 with a suitable coupling agent selected from, but not limited to, halo(hetero)aryls, (hetero)anilines, boronic acids, and boronic acid esters in combination with the corresponding Pd or Cu catalyst. Intermediates of general formula 4 can then be reacted with N,N-dimethylformamide dimethyl acetal in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.) at an elevated temperature of 100 to 120° C., followed by reaction with hydrazine in a suitable solvent (e.g., EtOH, 1,4-dioxane, etc.) at an elevated temperature of 80 to 120° C. Finally, pyrazole N-alkylation using procedures known to those skilled in the art can provide intermediates of general formula 5. Intermediates of general formula 6 may be obtained from intermediate 5 by reduction of the nitro moiety of intermediates of general formula 5 in a suitable solvent (e.g., EtOH, etc.) at temperatures increasing from 80° C. to 100° C., followed by reaction with an alkyl halide or an electron-deficient polar double bond in the presence of a base (e.g., KCO, TEA, DIPEA, etc.) in a suitable solvent (e.g., AcOH, ACN, MeOH, etc.). Further information can be found in Journal of Medicinal Chemistry 1999, 2831.Alternatively, reduction of the nitro moiety of the intermediate of general formula 5 may be followed by coupling with a carboxylic acid derivative under standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar, inorganic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Additionally, reduction of the nitro moiety of the intermediate of general formula 5 may be followed by reaction with a ketone or aldehyde derivative in the presence of a reducing agent (e.g., NaCNBH3, Pic-BH3, etc.) in a suitable solvent (e.g., MeOH, AcOH, etc.).

[0254] Compounds of the present invention may be prepared according to the general procedure outlined in Scheme 2. [ka] Scheme 2: All R 3a , R 4a , R 4b , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas.

[0255] 1-(3-bromo-5-nitrophenyl)ethan-1-one 7, commercially available or synthesized from 3-bromobenzaldehyde by procedures known to those skilled in the art, can be reacted with an appropriate coupling agent, such as, but not limited to, halo(hetero)aryl, (hetero)aniline, boronic acid, and boronic acid ester, in combination with the corresponding Pd or Cu catalyst to provide compounds of general formula 8. Intermediates of general formula 8 can be reacted with N,N-dimethylformamide dimethyl acetal in a suitable solvent (e.g., toluene, 1,4-dioxane, etc.) at an elevated temperature of 100 to 120°C, followed by reaction with hydrazine in a suitable solvent (e.g., EtOH, 1,4-dioxane, etc.) at an elevated temperature of 80 to 120°C. Finally, pyrazole N-alkylation using procedures known to those skilled in the art can provide intermediates of general formula 9. Intermediates of general formula 10 may be obtained from intermediate 9 by reduction of the nitro moiety of intermediates of general formula 9 in a suitable solvent (e.g., EtOH, etc.) at temperatures increasing from 80° C. to 100° C., followed by reaction with an alkyl halide or an electron-deficient polar double bond in the presence of a base (e.g., KCO, TEA, DIPEA, etc.) in a suitable solvent (e.g., AcOH, ACN, MeOH, etc.). Further information can be found in Journal of Medicinal Chemistry 1999, 2831. Alternatively, reduction of the nitro moiety of the intermediate of general formula 9 may be followed by coupling with a carboxylic acid derivative under standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar, inorganic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Additionally, reduction of the nitro moiety of the intermediate of general formula 9 may be followed by reaction with a ketone or aldehyde derivative in the presence of a reducing agent (e.g., NaCNBH3, Pic-BH3, etc.) in a suitable solvent (e.g., MeOH, AcOH, etc.).

[0256] In another embodiment, compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 3. [ka] Scheme 3: All R 3a , R 4a , R 4b , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas.

[0257] Intermediates of general formula 6 can be reacted with sodium nitrite in water at 0° C., followed by reaction with a mixture of potassium cyanide and copper(I) cyanide at temperatures increasing from 0° C. to 50° C. to provide intermediates of general formula 11. Further information can be found in Journal of the American Chemical Society 2000, 8376. Intermediates of general formula 12 can be obtained from intermediate 11 by reduction of the nitrile moiety using procedures known to those skilled in the art, followed by reaction with an alkyl halide or an electron-deficient polar double bond in the presence of a base (e.g., KCO, TEA, DIPEA, etc.) in a suitable solvent (e.g., AcOH, ACN, MeOH, etc.). Alternatively, reduction of the nitrile moiety of the intermediate of general formula 11 may be followed by coupling with a carboxylic acid derivative under standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar, non-molecular solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.).

[0258] Alternatively, compounds of the present invention can also be synthesized according to the general procedures outlined in Scheme 4. [ka] Scheme 4: All R 3a , R 3b , R4a , X, X 2 , X 3 , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas. 1 , Hal 2 = Cl, Br, X 4 , X 5 , X 6 =CH,N.

[0259] Commercially available halogenated (hetero)aryl nitrile 13 can be reacted with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, (hetero)aniline, boronic acid, and boronic ester in combination with the corresponding Pd or Cu catalyst, followed by coupling with azole boronic acids and esters in combination with the corresponding Pd catalyst to provide compounds of general formula 14. Further information can be found in Journal of Medicinal Chemistry 2011, 1914. Intermediates of general formula 15 can be obtained by reacting halogenated (hetero)aryl nitrile 13 with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, (hetero)aniline, boronic acid, and boronic ester in combination with the corresponding Pd or Cu catalyst, followed by nucleophilic addition-elimination reaction (Z-A) using procedures known to those skilled in the art. 2 (which substitutes) with an azole. Further information can be found in WO2013 / 048214 and WO2018 / 209030. Compounds of general formula 16 and 17 may be obtained from intermediates 14 and 15, respectively, via the procedure described in Scheme 3.

[0260] Compounds of the present invention can also be synthesized according to the general procedures outlined in Scheme 5. [ka] Scheme 5: All R 3a , R 4a , X 1 , X 2 , X 3 , L1 and B are as described for the compounds of the invention, and their embodiments and formulas. 1 , Hal 2 = Cl, Br, X 4 , X 5 , X 6 =CH,N.

[0261] Commercially available halogenated (hetero)arylnitrile 18 can be reacted with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, (hetero)aniline, boronic acid, and boronic acid ester in combination with the corresponding Pd or Cu catalyst, followed by coupling with azole boronic acids and esters in combination with the corresponding Pd catalyst to give compounds of general formula 19. Further information can be found in Journal of Medicinal Chemistry 2011, 1914. Compounds of general formula 20 can be obtained from intermediate 19 via the procedure described in Scheme 3.

[0262] Compounds of the present invention can also be synthesized according to the general procedures outlined in Scheme 6. [ka] Scheme 6: All R 3a , R 4a , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas.

[0263] 2-Bromo-4-chlorobenzonitrile 21 can be reacted with ethynyltrimethylsilane in combination with the corresponding Pd or Cu catalyst to give compound 22. Further information can be found in Chemical Communications 2012, 6052. Intermediates of general formula 23 can be obtained by reacting compound 2 with sodium azide (further information can be found in Organometallics 2018, 4224), followed by triazole N-alkylation using procedures known to those skilled in the art. Compounds of general formula 24 can be obtained by reacting intermediate 23 with a suitable coupling agent selected from, but not limited to, halo(hetero)aryls, (hetero)anilines, boronic acids, and boronate esters in combination with the corresponding Pd or Cu catalyst, followed by reduction and acylation according to the procedure described in Scheme 3.

[0264] In another embodiment, compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 7. [ka] Scheme 7: All R 3a , R 4a , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas.

[0265] 2-Bromo-5-chlorobenzonitrile 25 can be reacted with sodium azide in a suitable solvent (e.g., DMF) at an elevated temperature of 100-120°C, followed by tetrazole N-alkylation using procedures known to those skilled in the art to provide intermediates of general formula 26. Intermediates of general formula 27 can be obtained by reaction with copper(I) cyanide, followed by a coupling reaction applying a suitable coupling agent selected from, but not limited to, halo(hetero)aryls, (hetero)anilines, boronic acids, and boronic acid esters in combination with the corresponding Pd or Cu catalyst. Compounds of general formula 28 can be obtained from intermediate 27 via the procedure described in Scheme 3.

[0266] Compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 8. [ka] Scheme 8: All R 3a , R 3b , R 4a , X, X 2 , X 3 , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas. 4 , X 5 , X 6 =CH or N.

[0267] Intermediates of general formula 29 synthesized according to Scheme 4 can be reacted with appropriate reagents, such as alkyl halides and alkyl sulfonates, in the presence of a base (e.g., TEA, DIPEA, KCO, etc.) and a suitable solvent (e.g., ACN, MeOH, DCM, DMF, etc.) to provide intermediates of general formula 30. In some cases, intermediates of general formula 30 are generated by initial alkylation followed by functional group transformation (e.g., hydrolysis, amidation, deprotection, etc.). Deprotection of intermediates of general formula 30 by treatment with an acid, such as TFA or HCl, in a suitable solvent (e.g., DCM or 1,4-dioxane), followed by an acylation reaction, according to the procedure described in Scheme 3, provides compounds of general formula 31.

[0268] Alternatively, compounds of the present invention can also be synthesized according to the general procedures outlined in Scheme 9. [ka] Scheme 9: All R 3a , R 3b , R 4a , X, X 2 , X 3 , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas. 1, Hal 2 =Cl or Br;X 4 , X 5 , X 6 =CH or N.

[0269] Intermediates of general formula 13 can be coupled with an appropriate reagent selected from, but not limited to, a halo(hetero)aryl, a (hetero)aniline, a boronic acid, and a boronic acid ester in combination with a corresponding Pd or Cu catalyst, followed by reduction and protection to provide intermediates of general formula 32. Intermediates of general formula 32 can be coupled with boronic acids and boronic acid esters according to the method described in Scheme 8, followed by deprotection and acylation to provide compounds of general formula 33. Alternatively, intermediates of general formula 32 can be converted to intermediates of general formula 34 by coupling with B2Pin2. Intermediates of general formula 34 can be reacted with an appropriate reagent, such as a halo(hetero)aryl, in combination with a corresponding Pd or Cu catalyst, followed by deprotection and acylation to provide compounds of general formula 33.

[0270] Compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 10. [ka] Scheme 10: All R 3a , R 3b , R 4a , X, X 2 , X 3 , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas. 1 , Hal 2 = Cl, Br, or I, X 4 , X 5 , X 6 =CH or N. FGT = functional group transformation.

[0271] Intermediates of general formula 13 can be coupled with a suitable reagent selected from, but not limited to, halo(hetero)aryls, (hetero)anilines, boronic acids, and boronic esters in combination with the corresponding Pd or Cu catalyst, followed by coupling with an azole boronic acid or ester, reduction, and diazotization to provide intermediates of general formula 35. Intermediates of general formula 35 can be coupled with amines in the presence of a base and a Pd or Cu catalyst, followed by acylation, alkylation, or functional group transformation to provide compounds of general formula 36. Alternatively, intermediates of general formula 35 can be subjected to halogen-metal exchange using alkyllithium, alkyl Grignard, or similar reagents, reacted with cyclic ketones, followed by acylation, alkylation, or functional group transformation to provide compounds of general formula 38. Alternatively, intermediates of general formula 35 can be reacted with a suitable coupling agent, such as (hetero)aryl boronic acids and boronic esters, in the presence of a Pd catalyst, followed by reduction, deprotection, and acylation to provide compounds of general formula 37.

[0272] Alternatively, compounds of the present invention can also be synthesized according to the general procedures outlined in Scheme 11. [ka] Scheme 11: All R 3a , R 3b , R 4a , X, X 2 , X 3 , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas. 1 , Hal 2 = Cl, Br, or I, X 4 , X 5 , X 6 =CH or N. FGT = functional group transformation.

[0273] Commercially available starting materials of general formula 39 can be coupled with an azole boronic acid or ester in the presence of a Pd catalyst, followed by coupling with a dihydropyrrole boronic acid or ester in the presence of a Pd catalyst to provide intermediates of general formula 40. Intermediates of general formula 40 can be converted to compounds of general formula 41 by a four-step sequence including displacement of an aryl halide with a nucleophile such as an amine or alcohol in the presence of a Pd catalyst, olefin reduction under conditions such as hydrogen gas with a suitable catalyst (e.g., Pd / C, PtO, etc.), deprotection under acidic conditions (e.g., TFA in DCM or HCl in dioxane), and acylation as described in Scheme 3.

[0274] In yet another approach, compounds of the present invention can be synthesized according to the general procedure of Scheme 12. [ka] Scheme 12: All R 3a , R 3b , R 4a , X, X 2 , X 3 , L 1 and B are as described for the compounds of the invention, and their embodiments and formulas. 1 , Hal 2 = Cl, Br, or I, X 4 , X 5 , X 6 =CH or N. FGT = functional group transformation.

[0275] Intermediates of general formula 40 or 43 can be synthesized from commercially available starting materials of general formula 39 by reaction with boronic acids and boronic esters in the presence of a Pd catalyst. Intermediates of general formula 40 and 43 can be further coupled with appropriate boronic acids and boronic esters in the presence of a Pd catalyst, and then undergo reduction, deprotection, and acylation as described in Scheme 11 to provide compounds of general formula 42.

[0276] The general schemes described above should be considered as non-limiting examples, and it will be understood that compounds of the invention can be obtained by other methods known to those skilled in the art.

[0277] Abbreviations used in this specification, particularly in the schemes and examples, are as follows: AIBN - azobisisobutyronitrile, aq - aqueous solution, ACN - acetonitrile, Ac2O - acetic anhydride, AcOH - acetic acid, BBr3 - boron tribromide, BF3.OEt2 - boron trifluoride diethyl etherate, BINAP - ((2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Boc - tert-butyloxycarbonyl, Boc2O - di-tert-butyldicarbonate, B O3H3 - boric acid, Bu3SnN3 - tributyltin azide, CDCl3 - deuterated chloroform, Conc - concentrated, CBr4 - carbon tetrabromide, CCl4 - carbon tetrachloride, mCPBA - metachloroperbenzoic acid, CuBr2 - copper(II) bromide, CuCN - copper cyanide, CuI - copper iodide, Cu(OAc)2 - copper(II) acetate, CuSO4.5H2O - copper(II) sulfate pentahydrate, Cs2CO3 - cesium carbonate, d - day , DCM - dichloromethane, DCE - 1,2-dichloroethane, DIPEA - diisopropylethylamine, DMF - N,N-dimethylformamide, DMF-DMA - N,N-dimethylformamide dimethyl acetal, DMSO - dimethyl sulfoxide, DMSO-d6-deuterated dimethyl sulfoxide, DPPA - diphenylphosphoryl azide, EDA - ethyl diazoacetate, EDC - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EtOH - ethanol, EtOAc - ethyl acetate, Et2O - diethyl ether, Eq. - equivalent, FA - formic acid, h - hour, HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HCl - hydrogen chloride, HNO3 - nitric acid, H2O2 - hydrogen peroxide, HO(CHO) nH-Paraformaldehyde, HOAt-1-hydroxy-7-azabenzotriazole, HPLC - High Performance Liquid Chromatography, H2SO4 - Sulfuric Acid, IPA - 2-Propanol, K2CO3 - Potassium Carbonate, KCN - Potassium Cyanide, KOH - Potassium Hydroxide, K3PO4 - Potassium Phosphate, LAH - Lithium Aluminum Hydride, LiOH.H2O - Lithium Hydroxide Monohydrate, LG - Leaving Group, MeOH - Methanol, min - Minute, MnO2 - Manganese(IV) Oxide, NaOtBu - Sodium tert-Butoxide, NaBH4 - Sodium Borohydride, NaCNBH3 - Sodium Cyanoborohydride, NaH - Sodium Hydride, NaHCO3 - Sodium Bicarbonate, Na2CO3 - Sodium Carbonate, NaNO2 - Sodium Nitrite, Na2SO4 - Sodium Sulfate, NBS - N-Bromosuccinic Acid Ion amide, NH2NH2.H2O - hydrazine monohydrate, NH2CO2NH4 - ammonium carbamate, NHClOAc - ammonium acetate, (NH4)HCO3 - ammonium bicarbonate, NH4Cl - ammonium chloride, NOBF4 - nitrosyltetrafluoroborate, Pd(amphos)Cl2 - bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), PBr3 - phosphorus tribromide, Pd(PPh3)2Cl2 - bis(triphenylphosphine)palladium(II) dichloride, Pd(PPh3)4 - tetrakis(triphenylphosphine)palladium, Pd2(dba)3 - tris(dibenzylideneacetone)dipalladium, Pd(dppf)Cl2 - (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, Pd(dppf)Cl2.DCM-(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with DCM, Pd(OAc)2-palladium(II) acetate, PPh3-triphenylphosphine, Pet ether-PET ether, PFA-paraformaldehyde, Pic-BH3-2-picoline-borane complex, PhI(OAc)2-(diacetoxyiodo)benzene, Raney Ni - Raney Nickel, RF - Retention Factor, RT - Room Temperature, sat - Saturated, SCX - Strong Cation Exchange, TBAF - Tetra-n-butylammonium fluoride, TBN - tert-butyl nitrite, TiCl4 - Titanium(IV) chloride, TEA - Triethylamine, THF - Tetrahydrofuran, THP - Tetrahydropyranyl, TFA - Trifluoroacetic acid, TFAA - Trifluoroacetic anhydride, Ti(OiPr)4 - Titanium(IV) isopropoxide, TLC - Thin Layer Chromatography, TMS - Trimethylsilyl, TMSN3 - Trimethylsilyl azide, T3P-propanephosphonic anhydride, Xanthphos-4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, XPhos-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, XPhos-Pd-G2-chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), Zn(CN)2-zinc cyanide, ZnEt2-diethylzinc. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

[0278] These examples are provided for the purpose of illustrating the disclosure and should not be construed as limiting the scope of the disclosure.

[0279] Part A: Laboratory Chemistry Procedures All starting materials not explicitly mentioned are either commercially available (details of suppliers such as Acros, Avocado, Aldrich, Fluka, FluoroChem, MatrixScientific, Maybridge, Merck, Sigma can be found, for example, in the SciFinder® database) or their synthesis is well described in the specialist literature (experimental guidelines can be found, for example, in the Reaxys® or SciFinder® databases, respectively) or can be prepared using conventional methods known to those skilled in the art.

[0280] Reactions were carried out under an inert atmosphere (mostly argon and N2) where necessary. The number of equivalents of reagents and the amount of solvent used, as well as the reaction temperature and time, may vary slightly between different reactions carried out by the same method. Workup and purification methods were adapted according to the characteristic properties of each compound and may vary slightly for the same method. The yields of the prepared compounds are not optimized.

[0281] The designation "equivalent" ("eq." or "eq" or "equiv.") means molar equivalent, "room temperature (RT)" or "room temperature (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 written as volume / volume ratios.

[0282] To carry out reactions under microwave radiation, a CEM Microwave (Discover SP) was used (heating rate: 2-6°C / s; temperature: 30-300°C volume-independent infrared (IR) and fiber optic (FO) thermometry from 80-300°C; pressure: 0-435 psi, ActiVent™ technology; power: 0-300 W; magnetron frequency: 2450 MHz; reaction stirring: electromagnetic stirring; air cooling: ≥25 psi (20 L / min flow rate); system control: Synergy™ software).

[0283] Key analytical characterizations were performed for all exemplary compounds and selected intermediates. 1 H-NMR spectroscopy and / or mass spectrometry (MS, [M+H] + and / or [MH] - In certain cases, for example, regioisomers and / or diastereomers may be formed during the reaction, and in some cases, for example, 13 Additional analyses such as C NMR and NOE (nuclear Overhauser effect) NMR experiments were performed.

[0284] For example, NMR analysis was performed using a BRUKER AVANCE 400MHz (Software Topspin) or VARIAN MR 400MHz (VNMRJ Software) machine. LC / MS analysis was performed using, for example, an 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. Analytical HPLC was measured, for example, on an Alliance Waters 2695. Analytical SFC was performed, for example, on a PIC solution (Software: SFC PIC Lab Online), WATERS-X5 (Software MASSLYNX), or WATERS-UPC2 (Empower).

[0285] Preparative HPLC was performed, for example, on a Waters 2545 (Software Empower), Gilson (Software Trilution), or Shimadzu (Software LC Solution). Preparative SFC was performed, for example, on a Waters Thar SFC-80 (Software Chromscope), Waters Thar SFC-150 (Software Chromscope), Waters Thar SFC-200 (Software Chromscope), or PIC SFC-175 (Software SFC PIC Lab Online).

[0286] Structures of exemplary compounds containing stereocenters are drawn and named with absolute stereochemistry, if known. In the case of unknown absolute stereochemistry, the compound can be either a racemate, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia1 and Dia2 mean that diastereoisomers have been isolated but the stereochemistry is unknown. En1 and En2 mean that both enantiomers have been isolated but the absolute configuration is unknown. The suffixes given after the compound code do not imply 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.

[0287] 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).

[0288] Conditions Used for HPLC Analysis in the Experimental Part. The LC / MS analyses mentioned in the experimental part were also performed on an Alliance Waters 2695 HPLC (equipped with a PDA detector) connected to a Waters Quattromicro mass spectrometer (ESCI, multimode ionization). Separation was performed using an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) column, an Acquity BEH C18 (1.7 μm, 2.1 × 100 mm) column, or an X-Bridge C18 (3.5 μm, 4.6 × 75 mm) column thermostatted at 30–35 °C, with the PDA acquisition wavelength set in the range of 210–400 nm (Acquisition Software: MassLynx) (Method L in the table below). Elution was performed as described in the table below. For Methods L1, L6, and L7, Solvent A: 0.1% FA LC-MS grade in milliQ water. Solvent B: 0.1% FA LC-MS grade in ACN LC-MS grade. For methods L2 and L3, Solvent A: 0.05% FA LC-MS grade in milliQ water. Solvent B: 0.05% FA LC-MS grade in ACN LC-MS grade. For methods L4 and L8, Solvent A: 0.05% TFA LC-MS grade in milliQ water. Solvent B: 0.05% TFA LC-MS grade in ACN LC-MS grade. For method L5, Solvent A: 5 mM (NH4)HCO3 in milliQ water. Solvent B: ACN LC-MS grade. [Table 2-1] [Table 2-2]

[0289] Conditions Used for UPLC Analysis in the Experimental Part. The UPLC analysis mentioned in the experimental part was performed on an Acquity UPLC H-Class (equipped with a PDA detector) connected to a mass analyzer, Acquity TQ detector (ESI / ESCI). Separation was performed using an Acquity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column thermostatted at 40 °C, with the PDA acquisition wavelength set in the range of 190–420 nm (Method U in the table below). Elution was performed as described in the table below. For Methods U1 and U2, Solvent A: 10 mM (NH4)OAc in milliQ water containing 5% ACN (UPLC grade, Biosolve). Solvent B: ACN (UPLC grade, Biosolve). For Methods U3, U5, U8, U9, and U10, Solvent A: 0.05% FA LC-MS grade in milliQ water. Solvent B: 0.05% TFA LC-MS grade in ACN. Column temperature = 35 °C. For methods U4, U11, solvent A: 0.05% TFA LC-MS grade in milliQ water. Solvent B: ACN LC-MS grade. Column temperature = 35 °C. For method U6, solvent A: 0.05% TFA LC-MS grade in milliQ water. Solvent B: ACN LC-MS grade. Column temperature = 50 °C. For method U7, solvent A: 0.05% TFA LC-MS grade in milliQ water. Solvent B: ACN LC-MS grade. Column temperature = 35 °C. For method U12, solvent A: 10 mM NH4CO3 in milliQ water. Solvent B: ACN LC-MS grade. Column temperature = ambient temperature. [Table 3-1] [Table 3-2]

[0290] Conditions used for SFC analysis in the experimental part. The SFC analysis mentioned in the experimental part was performed on a WATERS Acquity UPC2 QDa (Empower-3 software) equipped with Acquity PDA and Acquity QDa detectors. Separation was performed using a Chiralpak IF-3 (3 μm, 4.6 × 150 mm) or Chiralpak IG-3 (3 μm, 4.6 × 150 mm) column, CO2 as the mobile phase, and MeOH as the co-solvent. The column was thermostated at 30 °C. Elution was performed using the method described in the table below. [Table 4-1] [Table 4-2]

[0291] The preparative HPLC purifications mentioned in this experimental part have been performed on 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 performed using Luna C18 (5 μm, 21.2 × 250 mm; or 10 μm, 21.2 × 250 mm) columns, X-Bridge C18 (5 μm, 29 × 250 mm; 5 μm, 19 × 150 mm; or 10 μm, 19 × 150 mm) columns, X-Select C18 (5 μm, 19 × 150 mm; 5 μm, 19 × 250 mm; 5 μm, 25 × 150 mm; 10 μm, 25 × 150 mm; or 10 μm, 25 × 250 mm) columns, X-Select CSH Phenyl-Hexyl (5 μm, 19 × 150 mm; or 5 μm, 19 × 250 mm) columns, and Synergi The analysis was carried out using a Polar-RP (5 μm, 21.2 × 250 mm) column, a Kromasil (5 μm, 19 × 150 mm) column, or a YMC-Triart C18 (10 μm, 19 × 250 mm) column. Elution was carried out with the columns and solvents listed in the table below. A gradient system for each individual compound was used using the solvents listed in the table. The detection wavelengths were fixed at 210 nm and 254 nm. [Table 5-1] [Table 5-2]

[0292] The preparative SFC purifications mentioned in this experimental part were carried out using a Thar SCF-200 (Software Chromscope) equipped with a UV / PDA detector and modifier stream injection mode. Separations were performed using Chiralpak IC (5 μm, 30 × 250 mm), Chiralpak IF (5 μm, 30 × 250 mm), or Chiralpak IG (5 μm, 30 × 250 mm) columns, CO2 as the mobile phase, and MeOH as the co-solvent. The columns were thermostated at 30 °C. The detection wavelength was fixed at 214 nm. Elution was performed as described in the table below. [Table 6-1] [Table 6-2]

[0293] Synthesis of 4-(bromomethyl)-1-methylpyridin-2(1H)-one (R1) [ka] Step 1: A solution of methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (2.0 g, 12 mmol) in MeOH (30 mL) was cooled to 0 °C and treated with NaBH (0.684 g, 18 mmol). The mixture was stirred at room temperature for 2 h and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.2, TLC detection: UV. The reaction mixture was diluted with EtOAc (20 mL) and concentrated under reduced pressure to give a pale yellow gum (2.8 g), which was purified by normal-phase flash column chromatography using neutral alumina and a gradient of 0 to 10% MeOH in DCM as the eluent to give 4-(hydroxymethyl)-1-methylpyridin-2(1H)-one as an off-white solid (1.3 g, 75%, LC / MS 96%). (LC / MS; m / z 139.9 [M+H] + ).

[0294] Step 2: A solution of 4-(hydroxymethyl)-1-methylpyridin-2(1H)-one (300 mg, 2.16 mmol) in DCM (20 mL) was cooled to 0 °C and treated with PBr (701 mg, 2.59 mmol). The mixture was stirred at room temperature for 2 h and monitored by TLC. TLC mobile phase: 100% EtOAc, RF: 0.3, TLC detection: UV. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NaHCO (15 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give 4-(bromomethyl)-1-methylpyridin-2(1H)-one (R1) as a brown gum (210 mg, 33%, LC / MS 69%). (LC / MS; m / z 202.0 [M+H] + ). This product was used directly without further purification.

[0295] Synthesis of 2-bromo-5-(bromomethyl)pyridine (R2) [ka] Step 1: A solution of 6-bromonicotinaldehyde (500 mg, 2.68 mmol) in MeOH (5 mL) was cooled to 0 °C and treated with NaBH (199 mg, 5.37 mmol). The mixture was stirred at room temperature for 1 h and monitored by TLC. TLC mobile phase: 20% EtOAc in PET ether, RF: 0.16, TLC detection: UV. The reaction mixture was poured into ice H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (6-bromopyridin-3-yl)methanol as an off-white solid (470 mg, 93%, LC / MS 93%). (LC / MS; m / z 187.2 [M+H] + ).

[0296] Step 2: A solution of (6-bromopyridin-3-yl)methanol (370 mg, 1.96 mmol) and PPh3 (619 mg, 2.36 mmol) in DCM (6 mL) was treated with NBS (420 mg, 2.36 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h and monitored by TLC. TLC mobile phase: 30% EtOAc in PET ether, RF: 0.4, TLC detection: UV. The reaction mixture was poured into ice HO (40 mL) and extracted with DCM (3 × 40 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (800 mg, LC / MS 78%), which was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-10% EtOAc in PET ether as eluent to give 2-bromo-5-(bromomethyl)pyridine (R2) as an off-white solid (250 mg, 44%, LC / MS 87%). (LC / MS; m / z 350.0 [M+H] + ). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.38 (s, 1H), 7.58-7.61 (d, 1H), 7.47-7.49 (d, 1H), 4.42 (s, 2H). The product was used directly without further purification.

[0297] The following reagents were prepared in a similar manner to R2 (using appropriate reagents and purification methods known to those skilled in the art). [Table 7]

[0298] Synthesis of methyl 5-(bromomethyl)nicotinate (R4) [ka] Step 1: A solution of methyl 5-methylnicotinate (1.0 g, 6.6 mmol), NBS (1.40 g, 7.92 mmol), and AIBN (216 mg, 1.32 mmol) in CCl4 (20 mL) was stirred at 80 °C for 4 h and monitored by TLC. TLC mobile phase: 10% EtOAc in PET ether, RF: 0.2, TLC detection: UV. The reaction mixture was cooled to room temperature, filtered through a Celite pad, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give methyl 5-(bromomethyl)nicotinate (R4) as a pale yellow gum (1.2 g, 27%, LC / MS 35%). (LC / MS; m / z 230.0 [M+H] + The product was chemically unstable and was used as is without further purification.

[0299] The following reagents were prepared in a similar manner to R4 (using appropriate reagents and purification methods known to those skilled in the art). [Table 8]

[0300] Synthesis of 1-benzyl-3-(3-bromophenyl)-1H-pyrazole (Int-1) and 3-([1,1'-biphenyl]-3-yl)-1H-pyrazole (Int-2) [ka] Step 1: A mixture of 5-(3-bromophenyl)-1H-pyrazole (600 mg, 2.64 mmol), CsCO (1.74 g, 5.27 mmol), and benzyl bromide (0.345 mL, 2.90 mmol) in DMF (20 mL) was stirred at 65 °C for 2 h. The reaction mixture was poured into ice-HO and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 25 g column (silica) and a gradient of 0–20% EtOAc in PET ether as eluent to give 1-benzyl-3-(3-bromophenyl)-1H-pyrazole (Int-1) (623 mg, 74%). (LC / MS; m / z 313.2 [M+H] + ).

[0301] Step 2: Phenylboronic acid (164 mg, 1.34 mmol), 5-(3-bromophenyl)-1H-pyrazole (200 mg, 0.90 mmol), and KCO (372 mg, 2.68 mmol) were dissolved in 1,4-dioxane (3 mL) and HO (1.2 mL). The mixture was degassed with argon for 5 minutes, and Pd(dppf)Cl (66 mg, 0.09 mmol) was added to the solution. The reaction mixture was stirred at 95 °C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by normal-phase flash column chromatography using a 20 g column (silica) and a gradient of 0–40% EtOAc in PET ether as eluent to give 3-([1,1′-biphenyl]-3-yl)-1H-pyrazole (Int-2) (132 mg, 66%). (LC / MS; m / z 221.1 [M+H] + ).

[0302] The following intermediates were prepared in a similar manner to Int-1 (using appropriate reagents and purification methods known to those skilled in the art). [Table 9]

[0303] The following intermediates were prepared in a similar manner to Int-2 (using appropriate reagents and purification methods known to those skilled in the art). [Table 10]

[0304] Examples 1 and 2: Synthesis of 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)nicotinic acid (Cpd. No. 001) and 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)nicotinamide (Cpd. No. 002) [ka] Step 1: A solution of Int-1 (100 mg, 0.32 mmol), KCO (132 mg, 0.96 mmol), and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (133 mg, 0.48 mmol) in 1,4-dioxane (1.1 mL) and HO (0.4 mL) was degassed with argon for 5 minutes. To the solution was added Pd(dppf)Cl (24 mg, 0.032 mmol), and the mixture was stirred at 95 °C for 2 hours. The reaction mixture was diluted with HO (5 mL) and DCM (10 mL), and the organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 10-80% EtOAc in PET ether as eluent to give ethyl 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)nicotinate (81 mg, 66%). (LC / MS; m / z 384.3 [M+H] + ).

[0305] Step 2: To a mixture of ethyl 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)nicotinate (81 mg, 0.21 mmol) in MeOH (2 mL) was added aqueous LiOH (1.0 M, 0.845 mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was acidified using 1 M aqueous HCl until a precipitate formed. The solid was filtered off, washed with HO, and dried under reduced pressure to give 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)nicotinic acid (Cpd. No. 001) as a white solid (71 mg, 94%). (LC / MS; m / z 356.3 [M+H] + ).

[0306] Step 3: To a solution of NH4Cl (38 mg, 0.70 mmol), DIPEA (0.074 mL, 0.42 mmol), HOAt (19 mg, 0.14 mmol), and Cpd. No. 001 (50 mg, 0.14 mmol) in DMF (1 mL) was added EDC (0.038 mL, 0.21 mmol), and the mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with 10% citric acid solution, HO, 1M aqueous Na2CO3, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)nicotinamide (Cpd. No. 002) as a white solid (37 mg, 74%). (LC / MS; m / z 355.1 [M+H] + ).

[0307] Examples 3-4: Synthesis of 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)pyridin-3-amine (Cpd. No. 003) and N-(5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)pyridin-3-yl)acrylamide (Cpd. No. 004) [ka] Step 1: A solution of Int-1 (100 mg, 0.32 mmol), KCO (132 mg, 0.96 mmol), and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (110 mg, 0.48 mmol) in 1,4-dioxane (1.1 mL) and HO (0.4 mL) was degassed with argon for 5 minutes. To the solution was added Pd(dppf)Cl (24 mg, 0.032 mmol), and the mixture was stirred at 95 °C for 4 hours. The reaction mixture was diluted with HO (5 mL) and DCM (10 mL), and the organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 20-100% EtOAc in PET ether as eluent to give 5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)pyridin-3-amine (Cpd. No. 003) as a white solid (57 mg, 54%). (LC / MS; m / z 327.1 [M+H] + ).

[0308] Step 2: To a solution of Cpd. No. 003 (50 mg, 0.15 mmol) and TEA (0.043 mL, 0.31 mmol) in THF (1.5 mL), acryloyl chloride (0.014 mL, 0.17 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with HO (5 mL) and DCM (10 mL), and the organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 1 to 10% MeOH in DCM as eluent to give N-(5-(3-(1-benzyl-1H-pyrazol-3-yl)phenyl)pyridin-3-yl)acrylamide (Cpd. No. 004) as an off-white solid (23 mg, 38%). (LC / MS; m / z 381.1 [M+H] + ).

[0309] Compound Cpd. No. 005 was prepared in a similar manner to cpd-Cpd No. 003 (using appropriate reagents and purification methods known to those skilled in the art).

[0310] The following compounds were prepared in a similar manner (using appropriate reagents and purification methods known to those skilled in the art) as Cpd. No. 004:c Cpd. No. 006 (using propionic anhydride and TEA in DCM in Step 2), Cpd. No. 007 (using acetyl chloride and TEA in DCM in Step 2), Cpd. No. 008, Cpd. No. 009, Cpd. No. 010, Cpd. No. 011 (prepared from Int-3), Cpd. No. 012 (prepared from Int-4), and Cpd. No. 013 (prepared from Int-5).

[0311] Examples 5 and 6: Synthesis of 3-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (Cpd. No. 014) and 3-((5-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (Cpd. No. 015) [ka] Step 1: A solution of Int-2 (59 mg, 0.27 mmol), CsCO (264 mg, 0.80 mmol), and 3-(bromomethyl)pyridine hydrobromide (75 mg, 0.29 mmol) in DMF (1 mL) was stirred at 55° C. for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by normal-phase flash column chromatography using a 20 g column (silica) and a gradient of 0 to 20% EtOAc in PET ether as eluent to give 3-((3-([1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (Cpd. No. 014) (30 mg, 36%) and 3-((5-([1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (Cpd. No. 015) (1 mg, 1%). (LC / MS; m / z 312.4 [M+H] + ).

[0312] The following compounds were prepared in a similar manner (using appropriate reagents and purification methods known to those skilled in the art): Cpd. No. 014 and Cpd. No. 015: Cpd. No. 016 (prepared from Int-9), Cpd. No. 017 (prepared from Int-9), Cpd. No. 018, Cpd. No. 019, Cpd. No. 020, Cpd. No. 021, Cpd. No. 022, Cpd. No. 023, Cpd. No. 024 (using reagent R1), Cpd. No. 025, Cpd. No. 026 and Cpd. No. 027.

[0313] Examples 7 and 8: Synthesis of 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)picolinamide (Cpd. No. 028) and (5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)methanamine (Cpd. No. 029) [ka] Step 1: A solution of Cpd. No. 027 (125 mg, 0.37 mmol, LC / MS 92%) and NaOH (14 mg, 0.03 mmol) in 1,4-dioxane (1 mL) and HO (1 mL) was stirred at 50 °C for 6 h and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.19, TLC detection: UV. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL) and HO (10 mL). The organic layer was washed with HO (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a pale yellow liquid (130 mg, LC / MS 69%). The crude product was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0–40% EtOAc in PET ether as the eluent to give a pale yellow liquid (70 mg, LC / MS 82%). The product was purified by preparative HPLC method H2. The collected fractions were lyophilized to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)picolinamide (Cpd. No. 028) as a white solid (22 mg, 18%, LC / MS 99%). (LC / MS; m / z 355.2 [M+H] + ).

[0314] Step 2: Cpd. No. 027 (110 mg, 0.32 mmol, LC / MS 92%) in 1,4-dioxane (1 mL) and HO (1 mL) was cooled to 0 °C and treated with NaBH (31 mg, 0.81 mmol). The mixture was stirred at room temperature for 6 h and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.10, TLC detection: UV. The reaction mixture was diluted with EtOAc (10 mL) and HO (10 mL). The organic layer was washed with HO (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a pale yellow solid (120 mg, LC / MS 57%). The crude product was purified by preparative HPLC method H3. The collected fractions were lyophilized to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)methanamine (Cpd. No. 029) as a pale yellow solid (28 mg, 25%, LC / MS 95%). (LC / MS; m / z 341.3 [M+H] + ).

[0315] Examples 9 to 11: Synthesis of 4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)piperidine (Cpd. No. 030), 1-(4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethan-1-one (Cpd. No. 031), and 4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-1-methylpiperidine (Cpd. No. 032) [ka] Step 1: A solution of Int-2 (100 mg, 0.454 mmol) in DMF (5 mL) was cooled to 0 °C and treated with NaH (27 mg, 1.135 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (190 mg, 0.681 mmol). The mixture was stirred at room temperature for 2 h and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.8, TLC detection: UV. The reaction mixture was quenched with ice HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with HO (2 × 30 mL), brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a pale yellow liquid (150 mg). The crude product was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-25% EtOAc in PET ether as eluent to give tert-butyl 4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate as a pale yellow gum (100 mg, 52% LC / MS 98%). (LC / MS; m / z 418.2 [M+H] + ).

[0316] Step 2: A solution of tert-butyl 4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (200 mg, 0.479 mmol) in DCM (5 mL) was cooled to 0°C and treated with HCl (4 M in 1,4-dioxane; 0.6 mL). The mixture was stirred at room temperature for 3 hours and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.2, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give a pale yellow gum (Cpd. No. 030.HCl; 200 mg). Cpd. No. 030.HCl (80 mg) was further purified by preparative HPLC method H3. The collected fractions were lyophilized to give 4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)piperidine (Cpd. No. 030) as a pale yellow gum (30 mg, LC / MS 98%). (LC / MS; m / z 318.3 [M+H] +).

[0317] Step 3: A solution of Cpd. No. 030.HCl (100 mg, 0.283 mmol) in DCM (5 mL) was cooled to 0 °C and treated with a solution of DIPEA (110 mg, 0.849 mmol) and AcO (43 mg, 0.424 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 1 h and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.3, TLC detection: UV. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 × 20 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a pale yellow gum (87 mg), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give 1-(4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethan-1-one (Cpd. No. 031) as a pale yellow gum (45 mg, 44%, LC / MS 99%). (LC / MS; m / z 360.3 [M+H] + ).

[0318] Step 4: Cpd. No. 030.HCl (150 mg, 0.424 mmol) in DCE (5 mL) was treated with PFA (43 mg, 1.413 mmol) and AcOH (0.01 mL) at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with MeOH (5 mL), cooled to 0 °C, and treated with NaBH (45 mg, 1.189 mmol). The mixture was stirred at room temperature for 2 h and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.2, TLC detection: UV. The reaction mixture was poured into ice-HO (5 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with HO (2 × 25 mL), brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (120 mg). The crude product was purified by preparative HPLC method H3. The collected fractions were lyophilized to give 4-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-1-methylpiperidine (Cpd. No. 032) as a pale yellow gum (21 mg, 15%, LC / MS 99%). (LC / MS; m / z 332.3 [M+H] + ).

[0319] Examples 12-13: Synthesis of 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-2-vinylpyridine (Cpd. No. 033) and 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine (Cpd. No. 034) [ka] Step 1: A solution of Int-2 (110 mg, 0.5 mmol) in DMF (4 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil) (40 mg, 1.0 mmol) and 2-bromo-5-(bromomethyl)pyridine (R2) (251 mg, 1.0 mmol). The mixture was stirred at room temperature for 1 h and monitored by TLC. TLC mobile phase: 20% EtOAc in PET ether, RF: 0.1, TLC detection: UV. The reaction mixture was quenched with ice HO (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (285 mg, LC / MS 48%), which was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-20% EtOAc in PET ether as eluent to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-2-bromopyridine as a yellow liquid (152 mg, 57%, LC / MS 73%). (LC / MS; m / z 390.0 [M+H] + ).

[0320] Step 2: A solution of 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-2-bromopyridine (100 mg, 0.25 mmol, LC / MS 73%), potassium vinyltrifluoroborate (103 mg, 0.77 mmol), K2CO3 (71 mg, 0.5 mmol), and PPh3 (13 mg, 0.05 mmol) in DMF (5 mL) was degassed with argon for 15 min. The mixture was treated with Pd(OAc)2 (17 mg, 0.02 mmol), stirred at 100 °C for 6 h, and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.4, TLC detection: UV. The reaction mixture was cooled to room temperature, poured into ice HO (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (90 mg, LC / MS 37%), which was purified by preparative HPLC method H1. The collected fractions were lyophilized to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-2-vinylpyridine (Cpd. No. 033) as a pale yellow gum (9 mg, 14%, LC / MS 99%). (LC / MS; m / z 338.3 [M+H] + ). H1

[0321] Step 3: A solution of 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)-2-bromopyridine (700 mg, 1.79 mmol) and CuI (68 mg, 0.35 mmol) in methanolic NH3 (7 M, 15 mL) was stirred at 150 °C for 6 h (sealed tube) and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.1, TLC detection: UV. The reaction mixture was cooled to room temperature, diluted with HO (40 mL), and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (500 mg, LC / MS 51%), which was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 70-80% EtOAc in PET ether as the eluent to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-amine (Cpd. No. 034) (200 mg, 29%, LC / MS 85%). Cpd. No. 034 (60 mg) was further purified by preparative HPLC method H3. The collected fractions were lyophilized to give Cpd. No. 034 as an off-white solid (19 mg, LC / MS 99%). (LC / MS; m / z 327.2 [M+H] + ).

[0322] Compound Cpd. No. 035 (using reagent R3) was prepared in a similar manner to Cpd. No. 033 (using appropriate reagents and purification methods known to those skilled in the art).

[0323] Compound Cpd. No. 036 (using reagent R3 in step 1 and 33% MeNH2 in EtOH in step 3) was prepared in a similar manner to Cpd. No. 034 (using appropriate reagents and purification methods known to those skilled in the art).

[0324] Examples 14-15: Synthesis of N-(5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)acrylamide (Cpd. No. 037) and 1-(5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)azetidin-2-one (Cpd. No. 038) [ka] Step 1: Cpd. No. 034 (100 mg, 0.31 mmol) and TEA (0.053 mL, 0.38 mmol) in DCM (3 mL) were cooled to -70 °C and treated with acryloyl chloride (0.036 mL, 0.45 mmol). The mixture was stirred at -70 °C for 1 h and monitored by TLC. TLC mobile phase: 70% EtOAc in PET ether, RF: 0.06, TLC detection: UV. The reaction was quenched with ice HO (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (100 mg, LC / MS 68%), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give N-(5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)acrylamide (Cpd. No. 037) as an off-white solid (15 mg, 13% LC / MS 99%). (LC / MS; m / z 381.3 [M+H] + ).

[0325] Step 2: A solution of Cpd. No. 034 (90 mg, 0.27 mmol) in THF (5 mL) was cooled to -20 °C and treated with acryloyl chloride (0.022 mL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours and monitored by TLC. TLC mobile phase: 70% EtOAc in PET ether, RF: 0.06, TLC detection: UV. The reaction mixture was quenched with ice HO (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (85 mg, LC / MS 26%), which was purified by preparative HPLC method H1. The collected fractions were lyophilized to give 1-(5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)azetidin-2-one (Cpd. No. 038) as an off-white solid (15 mg, 14% LC / MS 97%). (LC / MS; m / z 381.3 [M+H] + ).

[0326] Compound Cpd. No. 039 was prepared in a similar manner (using appropriate reagents and purification methods known to those skilled in the art) as Cpd. No. 037 (using propionyl chloride in step 1).

[0327] Examples 16-17: Synthesis of 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)nicotinic acid (Cpd. No. 040) and 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)nicotinamide (Cpd. No. 041) [ka] Step 1: This step was carried out in a similar manner to Step 1 for Cpd. No. 033 (using appropriate reagents and purification methods known to those skilled in the art). Int-2 (200 mg, 0.91 mmol) gave a crude product (350 mg, LC / MS 36%), which was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-10% EtOAc in PET ether as the eluent to give methyl 5-((3-(1,1'-biphenyl)-3-yl)-1H-pyrazol-1-yl)methyl)nicotinate as a pale yellow gum (140 mg, 34%, LC / MS 83%). (LC / MS; m / z 370.2 [M+H] + ).

[0328] Step 2: A solution of methyl 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)nicotinate (100 mg, 0.27 mmol, LC / MS 83%) and LiOH.HO (45 mg, 1.08 mmol) in THF (1.5 mL), MeOH (1.5 mL), and HO (1.5 mL) was stirred at room temperature for 10 h and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.2, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, acidified using 2 M aqueous HCl (pH 5), and extracted with 10% MeOH in DCM (2 x 10 mL). The combined organic layers were washed with brine (8 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (70 mg, LC / MS 84%), which was purified by preparative HPLC method H13. The collected fractions were lyophilized to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)nicotinic acid (Cpd. No. 040) as an off-white solid (21 mg, 26% LC / MS 99%). (LC / MS; m / z 356.2 [M+H] + ).

[0329] Step 3: A solution of methyl 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)nicotinate (135 mg, 0.36 mmol, LC / MS 83%) in aqueous NH3 (25% in HO, 4 mL) was stirred at 60 °C for 20 h (sealed tube) and monitored by TLC. TLC mobile phase: 100% EtOAc, RF: 0.5, TLC detection: UV. The reaction mixture was extracted with EtOAc (10 mL), and the organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (60 mg, LC / MS 80%), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give 5-((3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)nicotinamide (Cpd. No. 041) as an off-white solid (8 mg, 7% LC / MS 99%). (LC / MS; m / z 355.3 [M+H] + ).

[0330] Compound Cpd. No. 042 was prepared in a similar manner (using appropriate reagents and purification methods known to those skilled in the art) as Cpd. No. 040 (using reagent R5).

[0331] Compound Cpd. No. 043 was prepared in a similar manner to Cpd. No. 041 (using reagent R5) (using appropriate reagents and purification methods known to those skilled in the art).

[0332] Example 18: Synthesis of N-phenyl-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)aniline (Cpd. No. 044) [ka] Step 1: A solution of Int-6 (100 mg, 0.31 mmol, LC / MS 88%), aniline (74 mg, 0.79 mmol), and p-terphenyl (16.8 mg, 0.07 mmol) in toluene (5 mL) was treated with NaOtBu (42.8 mg, 0.44 mmol). The mixture was degassed with argon for 15 minutes and treated with BINAP (20 mg, 0.03 mmol) and Pd(OAc) (11 mg, 0.01 mmol). The mixture was stirred at 100 °C for 16 hours and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.4, TLC detection: UV. The reaction mixture was cooled to room temperature, poured into ice HO (30 mL), and filtered through a Celite pad. The filtrate was extracted with EtOAc (2 × 20 mL), and the combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (140 mg, LC / MS 34%), which was purified by normal-phase flash column chromatography using silica gel (100–200 mesh) and a gradient of 0–30% EtOAc in PET ether as the eluent to give N-phenyl-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)aniline (Cpd. No. 044) (90 mg, LC / MS 71%). The product was further purified by preparative HPLC method H16. The collected fractions were concentrated under reduced pressure and lyophilized to give Cpd. No. 044. TFA (23 mg, 19%, LC / MS 99%). The TFA salt was passed through an SCX cartridge to give Cpd. No. 044 as the free base (10 mg, 11%). (LC / MS; m / z 327.3 [M+H] + ).

[0333] The following compounds were prepared in a similar manner (using appropriate reagents and purification methods known to those skilled in the art): Cpd. No. 044: Cpd. No. 045 (prepared from Int-7), and Cpd. No. 046 (prepared from Int-8).

[0334] Example 19: Synthesis of 3-((5-([1,1'-biphenyl]-3-yl)-2H-tetrazol-2-yl)methyl)pyridine (Cpd. No. 047) [ka] Step 1: A mixture of [1,1'-biphenyl]-3-carbonitrile (250 mg, 1.35 mmol), NaN (267 mg, 4.06 mmol), and NH Cl (219 mg, 4.06 mmol) in DMF (10 mL) was stirred at 130 °C for 16 h (sealed tube). The reaction mixture was diluted with HO (10 mL) and acidified with 1 M aqueous HCl until a precipitate formed. The solid was filtered off, washed with HO (10 mL), and dried under reduced pressure to give 5-([1,1'-biphenyl]-3-yl)-2H-tetrazole as a white solid (264 mg, 85%). (LC / MS; m / z 223.1 [M+H] + ).

[0335] Step 2: A mixture of 5-([1,1'-biphenyl]-3-yl)-2H-tetrazole (100 mg, 0.45 mmol), K2CO3 (187 mg, 1.35 mmol), and 3-(bromomethyl)pyridine hydrobromide (228 mg, 0.90 mmol) in DMF (4.5 mL) was stirred at 100 °C for 16 h (sealed tube). The reaction mixture was diluted with HO (5 mL) and DCM (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 10-80% EtOAc in PET ether as eluent to give 3-((5-([1,1'-biphenyl]-3-yl)-2H-tetrazol-2-yl)methyl)pyridine (Cpd. No. 047) as a white solid (43 mg, 30%). (LC / MS; m / z 314.1 [M+H] + ).

[0336] Example 20: Synthesis of N-([1,1'-biphenyl]-3-yl)-2-(pyridin-3-yl)acetamide (Cpd. No. 048) [ka] Step 1: To a solution of [1,1'-biphenyl]-3-amine (200 mg, 1.18 mmol), 2-(pyridin-3-yl)acetic acid (165 mg, 1.18 mmol), HOAt (199 mg, 1.42 mmol), and DIPEA (0.613 mL, 3.55 mmol) in DCM (5 mL) and THF (2.5 mL) was added EDC (0.317 mL, 1.77 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (10 mL), washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 20-80% EtOAc in DCM as eluent to give N-([1,1'-biphenyl]-3-yl)-2-(pyridin-3-yl)acetamide (Cpd. No. 048) as a white solid (205 mg, 60%). (LC / MS; m / z 289.3 [M+H] + ).

[0337] Synthesis of 1-(3-bromo-5-nitrophenyl)ethan-1-one (Int-10) [ka] Step 1: A solution of 3-nitrobenzaldehyde (100 g, 662 mmol) in concentrated H2SO4 (400 mL) was treated with NBS (141 g, 795 mmol) in small portions at room temperature. The reaction mixture was stirred at 65 °C for 2 h and monitored by TLC. TLC mobile phase: 20% EtOAc in PET ether, RF: 0.6, TLC detection: UV. The reaction mixture was poured into ice H2O, and the resulting precipitate was collected by filtration (180 g). The crude product was purified by flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-10% EtOAc in PET ether as the eluent to give 3-bromo-5-nitrobenzaldehyde as an off-white solid (105 g, 69%). 1H NMR (400MHz, CDCl3) δ ppm: 10.06 (s, 1H), 8.62-8.65 (m, 2H), 8.34-8.35 (m, 1H).

[0338] Step 2: To a solution of TiCl4 (42.9 g, 227 mmol) and MeMgBr (131 mL, 262 mmol, 2 M in THF) in THF (700 mL) was added a solution of 3-bromo-5-nitro-benzaldehyde (40 g, 175 mmol) in THF (100 mL) dropwise at -30 °C. The reaction mixture was stirred at -30 °C for 2 h and monitored by TLC. TLC mobile phase: 20% EtOAc in PET ether, RF: 0.3, TLC detection: UV. The reaction mixture was poured into ice HO (300 mL) and extracted with DCM (700 mL). The organic layer was washed with brine (300 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (45 g), which was purified by flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-10% EtOAc in PET ether to give 1-(3-bromo-5-nitrophenyl)ethan-1-ol as an off-white solid (12 g, 28%). 1 H NMR (400MHz, CDCl3) δ ppm: 8.27-8.28(m,1H), 8.17-8.19(m,1H), 7.87-7.88(m,1H), 4.99-5.01(m,1H), 1.53-1.56(m,1H).

[0339] Step 3: A solution of 1-(3-bromo-5-nitrophenyl)ethan-1-ol (12 g, 49.2 mmol) and MnO (21.4 g, 246 mmol) in 1,4-dioxane (200 mL) was stirred at 100 °C for 16 h and monitored by TLC. TLC mobile phase: 20% EtOAc in PET ether, RF: 0.5, TLC detection: UV. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with HO (150 mL) and extracted with EtOAc (300 mL). The organic layer was washed with brine (150 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (14 g), which was purified by flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-10% EtOAc in PET ether to give 1-(3-bromo-5-nitrophenyl)ethan-1-ol (Int-10) as an off-white solid (10 g, 84%). 1 H NMR (400MHz, CDCl3) δ ppm: 8.69-8.70 (m, 1H), 8.56-8.57 (m, 1H), 8.39-8.40 (m, 1H), 2.68 (s, 3H).

[0340] Synthesis of 3-(4-nitro-[1,1'-biphenyl]-3-yl)-1H-pyrazole (Int-11) and 3-(5-bromo-2-nitrophenyl)-1H-pyrazole (Int-12) [ka] Step 1: A mixture of HNO (80 mL) and HSO (12 mL) was treated with 1-(3-bromophenyl)ethan-1-one (20 g, 100 mmol) at −20 °C. The mixture was stirred at −20 °C for 6 h and monitored by TLC. TLC mobile phase: 20% EtOAc in PET ether, RF: 0.51, TLC detection: UV. The reaction mixture was quenched with iced HO (200 mL), and the mixture was stirred for 1 h. The resulting precipitate was collected on a Buchner funnel, washed with HO (200 mL), and dried under reduced pressure to give the crude product (17 g), which was purified by normal-phase flash column chromatography using an 80 g column (silica) and a gradient of 0 to 10% EtOAc in PET ether as eluent to give 1-(5-bromo-2-nitrophenyl)ethan-1-one (11 g, 45%) as an off-white solid. (LC / MS; m / z 245.6 [M+H] + ).

[0341] Step 2: A mixture of 1-(5-bromo-2-nitrophenyl)ethan-1-one (11 g, 45.3 mmol), phenylboronic acid (6.63 g, 54.4 mmol), and 10% Na2CO3 (45 mL) in THF (110 mL) was degassed with argon for 10 minutes. To the solution was added Pd(PPh3)4 (1.05 g, 0.91 mmol) at room temperature, and the reaction mixture was stirred at 80 °C for 18 hours and monitored by TLC. TLC mobile phase: 10% EtOAc in PET ether, RF: 0.39, TLC detection: UV. The reaction mixture was filtered through a Celite pad and washed with EtOAc (110 mL). The filtrate was diluted with HO (110 mL), and the aqueous layer was extracted with EtOAc (110 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (15 g), which was purified by normal-phase flash column chromatography using an 80 g column (silica) and a gradient of 0-10% EtOAc in PET ether as eluent to give 1-(4-nitro-[1,1'-biphenyl]-3-yl)ethan-1-one (10 g, 91%) as a brown solid. (LC / MS; m / z 242.1 [M+H] + )

[0342] Step 3: A solution of 1-(4-nitro-[1,1'-biphenyl]-3-yl)ethan-1-one (10 g, 41.4 mmol) in toluene (110 mL) was treated with DMF-DMA (10 mL) at room temperature. The reaction mixture was stirred at 110°C for 18 hours and monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.31, TLC detection: UV. The reaction mixture was cooled, diluted with HO (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (13 g), which was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-10% EtOAc in PET ether as eluent to give (E)-3-(dimethylamino)-1-(4-nitro-[1,1'-biphenyl]-3-yl)prop-2-en-1-one (9 g, 73%) as a yellow solid. (LC / MS; m / z 297.2 [M+H] + )

[0343] Step 4: A stirred solution of (E)-3-(dimethylamino)-1-(4-nitro-[1,1'-biphenyl]-3-yl)prop-2-en-1-one (9 g, 30.4 mmol) in EtOH (50 mL) was treated with NHNH.HO (50-60% solution in HO) (3.1 g, 60.8 mmol) at room temperature, and the mixture was stirred at 90 °C for 4 h and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.58, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with HO (100 mL) and extracted with EtOAc (2 × 250 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give 3-(4-nitro-[1,1'-biphenyl]-3-yl)-1H-pyrazole (Int-11) as a brown gum (8 g, 99%). (LC / MS; m / z 266.2 [M+H] + )

[0344] Steps 5-6: These steps were carried out in a similar manner to steps 3 and 4 towards Int-11 (using appropriate reagents and purification methods known to those skilled in the art). The starting material (55 g, 226.3 mmol) gave 3-(5-bromo-2-nitrophenyl)-1H-pyrazole (Int-12) as a pale yellow solid (40.8 g, 67%). (LC / MS; m / z 267.9 [M+H] + ).

[0345] Intermediate Int-13 (prepared from Int-10) was prepared in a similar manner to Int-11 (using appropriate reagents and purification methods known to those skilled in the art). [Table 11]

[0346] Synthesis of 3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-amine (Int-14) [ka] Step 1: A solution of 3-(4-nitro-[1,1'-biphenyl]-3-yl)-1H-pyrazole (Int-11) (7 g, 26.4 mmol) in DMF (50 mL) was treated with NaH (60% in mineral oil) (4.44 g, 185 mmol) followed by 3-(chloromethyl)pyridine hydrochloride (5.17 g, 31.7 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h and monitored by TLC. TLC mobile phase: 30% EtOAc in PET ether, RF: 0.41, TLC detection: UV. The reaction mixture was cooled to 0 °C, quenched with ice HO (50 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by normal-phase flash column chromatography using a 48 g column (silica) and a gradient of 0-10% EtOAc in PET ether as eluent to give 3-((3-(4-nitro-[1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridine as a brown solid (5.2 g, 55%). (LC / MS; m / z 357.2 [M+H] + ).

[0347] Step 2: A solution of 3-((3-(4-nitro-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)methyl)pyridine (5.2 g, 14.6 mmol) in EtOH (50 mL) and HO (5 mL) was treated with Fe powder (3.8 g, 73 mmol) and NH Cl (1.58 g, 29.2 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 2 h and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.41, TLC detection: UV. The reaction mixture was cooled and filtered through a Celite pad, washing with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give a brown residue, which was diluted with HO (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure to give the crude product. The crude material was triturated with pentane (50 mL) to give 3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-amine (Int-14) (3.5 g, 76%) as a brown solid. (LC / MS; m / z 327.3 [M+H] + ).

[0348] Intermediate Int-15 (prepared from Int-11), intermediate Int-16 (prepared from Int-13), and Int-17 (prepared from Int-13) were prepared in a similar manner to Int-14 (using appropriate reagents and purification methods known to those skilled in the art). [Table 12]

[0349] Synthesis of 3-((3-(5-bromo-2-nitrophenyl)-1H-pyrazol-1-yl)methyl)pyridine (Int-18) [ka] Step 1: A solution of 3-(5-bromo-2-nitrophenyl)-1H-pyrazole (Int-12) (30 g, 112.4 mmol) in DMF (200 mL) was treated with NaH (60% in mineral oil) (9.4 g, 393 mmol) followed by 3-(chloromethyl)pyridine hydrochloride (21.9 g, 134.8 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h and monitored by TLC. TLC mobile phase: 30% EtOAc in PET ether, RF: 0.28, TLC detection: UV. The reaction mixture was cooled to 0 °C, quenched with ice HO (200 mL), and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-25% EtOAc in PET ether as eluent to give 3-((3-(5-bromo-2-nitrophenyl)-1H-pyrazol-1-yl)methyl)pyridine (Int-18) as a brown solid (15 g, 58%). (LC / MS; m / z 358.8 [M+H] + ).

[0350] The following intermediates were prepared in a similar manner to Int-18 (using appropriate reagents and purification methods known to those skilled in the art). [Table 13]

[0351] Examples 21 to 23: Synthesis of 2-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)ethane-1-sulfonyl fluoride (Cpd. No. 049), N-methyl-2-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)ethane-1-sulfonamide (Cpd. No. 050), and 4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)thiomorpholine 1,1-dioxide (Cpd. No. 051) [ka] Step 1: Ethenesulfonyl fluoride (40 mg, 368 mmol) was added to a stirred solution of 3-(1-pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-amine (Int-14) (100 mg, 0.306 mmol) in AcOH (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.50, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give the crude compound (100 mg), which was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0 to 25% EtOAc in PET ether to give a brown solid (130 mg). The compound was further purified by preparative HPLC method H10. The collected fractions were lyophilized to give 2-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)ethane-1-sulfonyl fluoride (Cpd. No. 049) as an off-white solid (30 mg, 22%). (LC / MS; m / z 437.4 [M+H] + ).

[0352] Step 2: A solution of Cpd. No. 049 (130 mg, 0.297 mmol) in acetone (5 mL) was treated with methylamine in 2M THF (4 mL) at room temperature, and the mixture was stirred at 50° C. for 16 hours (sealed tube) and monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.32, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give the crude product (200 mg), which was purified by preparative HPLC method H9. The collected fractions were lyophilized to give N-methyl-2-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)ethane-1-sulfonamide (Cpd. No. 050) as a brown solid (52 mg, 39%). (LC / MS; m / z 448.4 [M+H] + ).

[0353] Step 3: (Vinylsulfonyl)ethene (362 mg, 3.07 mmol) was added to a stirred solution of 3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-amine (Int-14) (100 mg, 0.306 mmol) and BO3H3 (9.5 mg, 0.153 mmol) in HO (5 mL) and glycerol (10 mg) at room temperature. The mixture was stirred at 100 °C for 18 h (sealed tube) and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.32, TLC detection: UV. The reaction mixture was cooled to room temperature, diluted with HO (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a brown residue (200 mg), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give 4-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)thiomorpholine-1,1-dioxide (Cpd. No. 051) as an off-white solid (10 mg, 7%). (LC / MS; m / z 445.3 [M+H] + ).

[0354] The following compounds were prepared in a similar manner (using appropriate reagents and purification methods known to those skilled in the art) as Cpd. No. 050: Cpd. No. 052 (prepared from Int-16), Cpd. No. 053 and Cpd. No. 054.

[0355] Compound Cpd. No. 055 (prepared from Int-16) was prepared in a similar manner to Cpd. No. 051 (using appropriate reagents and purification methods known to those skilled in the art).

[0356] Examples 24-25: Synthesis of N-methyl-2-((3-(1-methyl-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)ethane-1-sulfonamide (Cpd. No. 056) and 2-((3-(1-(methyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)ethane-1-sulfonic acid (Cpd. No. 057) [ka] Steps 1-2: These steps were carried out in a similar manner to steps 1 and 2 for Cpd. No. 050 (using appropriate reagents and purification methods known to those skilled in the art). From Cpd. No. 050 (370 mg, 1.48 mmol), a crude product (320 mg, LC / MS 28%) was obtained, which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-methyl-2-((3-(1-methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)ethane-1-sulfonamide (Cpd. No. 056) as a white solid (35 mg, 6%, LC / MS 99%) (LC / MS: m / z 369.1 [MH]). - ) and 2-((3-(1-methyl-1H-pyrazol-3-yl)-[1,1-biphenyl]-4-yl)amino)ethane-1-sulfonic acid (Cpd. No. 057) were obtained as a white solid (12 mg, 2%, LC / MS 95%). (LC / MS; m / z 258.2 [M+H]+).

[0357] Compound Cpd. No. 058 was prepared in a similar manner to Cpd. No. 056 (using appropriate reagents and purification methods known to those skilled in the art).

[0358] Examples 26-27: Synthesis of 3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)propanoic acid (Cpd. No. 059) and N-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)propanamide (Cpd. No. 060) [ka] Step 1: A solution of 3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-amine (Int-14) (400 mg, 1.22 mmol) in ACN (10 mL) and HO (2 mL) was treated with methyl acrylate (3.17 g, 36.81 mmol) and TEA (2.5 g, 24.54 mmol) at room temperature. The mixture was stirred at 100 °C for 72 h and monitored by TLC. TLC mobile phase: 5% EtOAc in PET ether, RF: 0.49, TLC detection: UV. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (600 mg), which was purified by normal-phase flash column chromatography using a 24 g column (silica) and a gradient of 0-50% EtOAc in PET ether as eluent to give methyl 3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanoate (300 mg, 59%) as a brown gum. (LC / MS; m / z 413.3 [M+H] + ).

[0359] Step 2: A solution of methyl 3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanoate (100 mg, 0.242 mmol) in THF (3 mL) and HO (1 mL) was treated with LiOH.HO (50 mg, 1.213 mmol). The mixture was stirred at room temperature for 3 h and monitored by TLC. TLC mobile phase: 5% MeOH in DCM, RF: 0.01, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with HO (10 mL) and neutralized using 2 N HCl. The solution was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude compound (55 mg), which was purified by preparative HPLC method H1. The collected fractions were lyophilized to give 3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanoic acid (Cpd. No. 059) as an off-white solid (14 mg, 14%). (LC / MS; m / z 399.3 [M+H] + ).

[0360] Step 3: A solution of methyl 3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanoate (100 mg, 242 mmol) in MeOH was treated with methylamine in MeOH (2 M) (4 mL). The mixture was stirred at 90°C for 12 hours (sealed tube) and monitored by TLC. TLC mobile phase: 5% EtOAc in PET ether, RF: 0.5, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give the crude compound (110 mg), which was purified by preparative HPLC method H1. The collected fractions were lyophilized to give N-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)-propanamide (Cpd. No. 060) as an off-white solid (25 mg, 25%). (LC / MS; m / z 412.3 [M+H] + ).

[0361] Compounds Cpd. No. 061 and Cpd. No. 062 (both prepared from Int-16) were prepared in a similar manner to Cpd. No. 059 and Cpd. No. 060, respectively (using appropriate reagents and purification methods known to those skilled in the art).

[0362] Examples 28-29: Synthesis of 3-((3-(1-methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanoic acid (Cpd. No. 063) and N-methyl-3-((3-(1-methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanamide (Cpd. No. 064) [ka] Steps 1-2: These steps were carried out in a similar manner to Cpd. No. 059 (using appropriate reagents and purification methods known to those skilled in the art). Starting material Int-15 (300 mg, 1.2 mmol) gave a crude product (230 mg), which was purified by preparative HPLC method H5. The collected fractions were lyophilized to give 3-((3-(1-(methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanoic acid (Cpd. No. 063) as an off-white solid (46 mg, 23%). (LC / MS; m / z 322.4 [M+H] + ).

[0363] Step 3: Cpd. No. 063 (130 mg, 0.4 mmol) and HATU (307 mg, 0.8 mmol) in DMF (10 mL) were treated with methylamine (0.8 mL, 1.6 mmol) and DIPEA (130 mg, 1 mmol) in THF (2 M) at 0 °C. The mixture was stirred at room temperature for 16 h and monitored by TLC. TLC mobile phase: 50% EtOAc in PET ether, RF: 0.5, TLC detection: UV. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product (320 mg), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give N-methyl-3-((3-(1-methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)amino)propanamide (Cpd. No. 064) as an off-white solid (110 mg, 95%). (LC / MS; m / z 335.4 [M+H] + ).

[0364] Examples 30 to 31: N-(2-(methylthio)ethyl)-3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-amine (Cpd. No. 065) and imino(methyl)(2-((3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)amino)ethyl)-λ 6 -Synthesis of sulfanone (Cpd. No. 066) [ka] Step 1: To a solution of 3-(1-(pyridin-3-ylmethyl)-1H)-pyrazol-3-yl)-[1,1'-biphenyl]-4-amine (Int-14) (1.0 g, 3.1 mmol) in ACN (10 mL) was added KCO (1.06 g, 7.75 mmol) followed by (2-chloroethyl)(methyl)sulfane (857 mg, 7.75 mmol) at room temperature. The mixture was stirred at 80 °C for 16 h (seale...

Claims

1. A compound of formula I, 【Chemistry 1】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: 【Chemistry 2】 is selected from the group consisting of: 【Chemistry 3】 where the bond marked with "*" is R ２ is bound to X is -CR １０ａ = and -N=; X １ But, CR １ or X is CR １ And X １ But -CR １０ｂ = and -N=; or X is -CR １０ａ = and -N=; X １ But -CR １０ｂ = and -N=; X ２ But -CR １０ｃ = and -N=; X ３ But -CR １０ｄ = and -N=; L １ is -NH- and -(CH ２ ) ｐ - selected from the group consisting of p is 0 or 1; R １ is selected from the group consisting of: (i) hydrogen, (ii) -L ２ -NR ４ａ R ４ｂ , and (iii) an unsubstituted or substituted 4-8 membered heterocycle, wherein one or more of the substituents is selected from the group consisting of: (a) C １ ~C ６ Alkyl, (b)-C(=O)Z ２ (c)-C(=O)OZ ２ 、 (d)-C(=O)NZ ３ Z ４ 、 (e)-S(=O) ２ Z ８ 、 (f)-S(=O) ２ NZ ３ Z ４ 、 (g) cyano, (h) -OZ １ , and (i) a halogen, (iv) unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently -OZ １ , -C(=O)Z ２ , halogen, C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); 【Chemistry 4】 L ２ But -(CH ２ ) ｎ - and C ３ ~C ６ cycloalkylenyl; n is 0 or 1; R ２ is selected from the group consisting of: 【Chemistry 5-1】 【Chemistry 5-2】 R ３ａ is selected from the group consisting of: (i) hydrogen, (ii) a halogen, (iii) cyano, (iv)-OZ １ 、 (v)-C(=O)NZ ３ Z ４ 、 (vi)-NZ ３ Z ４ 、 (vii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) cyano, (b)-C(=O)NZ ３ Z ４ 、 (c)-OZ １ 、 (d)-NZ ３ Z ４ (e) 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) Unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (4) C １ ~C ６ Haloalkyl, (5) C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (6)-C(=O)NZ ３ Z ４ 、 (7)-NZ ３ Z ４ 、 (8) Unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (9) Unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl); (11)-OZ １ 、 (12)-C(=O)OH, (13) hydroxy, (14)-NZ ５ C(=O)Z ２ 、 (15)-N.Z. ５ S (=O) ２ Z ２ , and (16)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (f) unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) C １ ~C ６ Alkyl, and (2) C １ ~C ６ Haloalkyl, (g) unsubstituted or substituted 5-10 membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) Unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (4) C １ ~C ６ Haloalkyl, (5) C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (6)-C(=O)NZ ３ Z ４ 、 (7)-NZ ３ Z ４ 、 (8) Unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ (selected from the group consisting of (9) Unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl); (11)-OZ １ 、 (12)-C(=O)OH, (13) hydroxy, and (14)-NZ ５ C(=O)Z ２ 、 (viii) C １ ~C ６ Haloalkyl, (ix) unsubstituted or substituted C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from halogen and C １ ~C ６ alkyl), (x) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) C １ ~C ６ Alkyl, (b)-C(=O)Z ２ and (c)-S(=O) ２ Z ８ 、 (xi) unsubstituted or substituted 5-10 membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (d) C １ ~C ６ Haloalkyl, (e) Unsubstituted or substituted C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (f)-C(=O)NZ ３ Z ４ 、 (')-NZ ３ Z ４ 、 (h) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (i) Unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (j) unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl); (k)-OZ １ 、 (l)-C(=O)OH, (m) hydroxy, and (n)-NZ ５ C(=O)Z ２ 、 R ３ｂ , R ３ｃ , and R ３ｄ is independently selected from the group consisting of: (i) hydrogen, (ii) a halogen, (iii) cyano, (iv)-C(=O)NZ ３ Z ４ 、 (v) unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (vi) C １ ~C ６ Haloalkyl, (vii) C ３ ~C ６ Cycloalkyl, and ()) １ 、 q is 0, 1, or 2; R ４ａ 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) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ 、 (h)-C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、&& (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (iii) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ (h) C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、 (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (x) C １ ~C ６ Alkyl, (y) C １ ~C ６ Haloalkyl, and (z) C ３ ~C ６ Cycloalkyl, (iv) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently -C(=O)OZ ２ , halogen, and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (v)-C (=O)Z ２ (vi)-C(=O)OZ ２ 、 (vii)-C(=O)NZ ３ Z ４ 、 ()) ()) ２ : ８ 、 (ix)-S(=O) ２ NZ ３ Z ４ 、 (8)-S(=O)(=NZ ６ )Z ２ 、 (xi)-S(=Z ６ )(=NZ ７ )Z ２ and ( ) ( ) ( ) ( ) ６ )!: ３ : ４ 、 R ４ｂ is selected from the group consisting of: (i) hydrogen, and (ii) C １ ~C ６ Alkyl, Each Z １ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (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 is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (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 ３ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, (vii) C １ ~C ６ Haloalkyl, (viii) cyano, and () ２ 、 Each Z ４ , Z ５ , Z ６ and Z ７ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii) C ３ ~C ６ Cycloalkyl, Each Z ８ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (iv) a halogen; (v) hydroxy, R ３ｂ and R ３ｃ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl (iii) C １ ~C ６ Haloalkyl, and (iv) C ３ ~C ６ Cycloalkyl, 【Chemistry 6】 is selected from the group consisting of: (i) C ３ ~C ６ Cycloalkyl, (ii) a 4- to 10-membered heterocycle, (iii) C ６ ~C １０ Aryl, and (iv) 5-10 membered heteroaryl, Each R ５ is independently selected from the group consisting of: (i) a halogen, (ii) hydroxy, (iii) cyano, (iv)-OZ １ 、 (v)-SZ １ 、 (vi)-NZ ３ Z ４ 、 (vii)-C(=O)Z ２ (viii)-C(=O)OH, (ix)-C(=O)OZ ２ 、 (x)-C(=O)NZ ３ Z ４ 、 (xi)-NZ ５ C(=O)Z ２ 、 ())!: ５ (#) ２ 、 ())!? ５ [(#)]] ３ : ４ 、 (xiv)-S(=O) ２ Z ８ 、 (xv)-S(=O) ２ NZ ３ Z ４ 、 (xvi)-S(=O)(=NZ ６ )Z ２ 、 (xvii)-S(=Z ６ )(=NZ ７ )Z ２ 、 (xviii)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (xix)-NZ ５ S(=O) ２ Z ２ 、 (xx)-NZ ５ S(=O) ２ NZ ３ Z ４ 、 (xxi)-NZ ５ S(=O)(=NZ ６ )Z ２ 、 (xxii)-NZ ５ S(=NZ ６ )(=NZ ７ )Z ２ 、 (xxiii)-NZ ５ S(=O)(=NZ ６ )NZ ３ Z ４ 、 (xxiv) unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (xxv) C １ ~C ６ Haloalkyl, (xxvi) C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (xxvii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (xxviii) unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (xxix) unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl and C １ ~C ６ haloalkyl); R ６ａ is selected from the group consisting of: (i) hydrogen, and (ii) C １ ~C ６ Alkyl, R ６ｂ is selected from the group consisting of: (i) hydrogen, and (ii) C １ ~C ６ Alkyl m is 0, 1, 2, 3 or 4; R １０ａ , R １０ｂ , R １０ｃ , and R １０ｄ But independently, (i) hydrogen, (ii) cyano, (iii) hydroxy, (iv)-OZ １ 、 (v)-SZ １ 、 (vi)-NZ ３ Z ４ 、 (vii) C １ ~C ６ Alkyl, and (viii) C １ ~C ６ The compound of formula I, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: haloalkyl.

2. A compound of formula II, 【Chemistry 7】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: 【Chemistry 8】 is selected from the group consisting of: 【Chemistry 9】 where the bond marked with "*" is R ２ is bound to X is -CR １０ａ = and -N=; X １ But, CR １ or X is CR １ And X １ But -CR １０ｂ = and -N=; or X is -CR １０ａ = and -N=; X １ But -CR １０ｂ = and -N=; X ２ But -CR １０ｃ = and -N=; X ３ But -CR １０ｄ = and -N=; L １ is -NH- and -(CH ２ ) ｐ - selected from the group consisting of p is 0 or 1; R １ is selected from the group consisting of: (i) hydrogen, (ii) -L ２ N.R. ４ａ R ４ｂ , and (iii) an unsubstituted or substituted 4-8 membered heterocycle, wherein one or more of the substituents is selected from the group consisting of: (a) C １ ~C ６ Alkyl, (b)-C(=O)Z ２ (c)-C(=O)OZ ２ 、 (d)-C(=O)NZ ３ Z ４ 、 (e) -S(=O) ２ Z ８ , and (f)-S(=O) ２ NZ ３ Z ４ 、 L ２ But -(CH ２ ) ｎ - and C ３ ~C ６ cycloalkylenyl; n is 0 or 1; R ２ is selected from the group consisting of: 【Chemistry 10】 R ３ａ 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) hydroxy, (b)-OZ １ 、 (c) 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) Unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (4) C １ ~C ６ Haloalkyl, (5) C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (6)-C(=O)NZ ３ Z ４ 、 (7)-NZ ３ Z ４ 、 (8) Unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (9) Unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl); (11)-OZ １ 、 (12)-C(=O)OH, (13) hydroxy, (14)-NZ ５ C(=O)Z ２ 、 (15)-N.Z. ５ S (=O) ２ Z ２ , and (16)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (d) unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) C １ ~C ６ Alkyl, and (2) C １ ~C ６ Haloalkyl, (e) unsubstituted or substituted 5-10 membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) Unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (4) C １ ~C ６ Haloalkyl, (5) C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (6)-C(=O)NZ ３ Z ４ 、 (7)-NZ ３ Z ４ 、 (8) Unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ (selected from the group consisting of (9) Unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (10) Unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl); (11)-OZ １ 、 (12)-C(=O)OH, (13) hydroxy, and (14)-NZ ５ C(=O)Z ２ 、 (iii) C １ ~C ６ Haloalkyl, (iv) unsubstituted or substituted C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from halogen and C １ ~C ６ alkyl), (v) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) C １ ~C ６ Alkyl, (b)-C(=O)Z ２ and (c)-S(=O) ２ Z ８ 、 (vi) unsubstituted or substituted 5-10 membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (d) C １ ~C ６ Haloalkyl, (e) Unsubstituted or substituted C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (f)-C(=O)NZ ３ Z ４ 、 (')-NZ ３ Z ４ 、 (h) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (i) Unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (j) unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl and C １ ~C ６ haloalkyl); (k)-OZ １ 、 (l)-C(=O)OH, (m) hydroxy, and (n)-NZ ５ C(=O)Z ２ 、 R ３ｂ , R ３ｃ , and R ３ｄ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) C １ ~C ６ Haloalkyl, and (iv) C ３ ~C ６ Cycloalkyl, q is 0, 1, or 2; R ４ａ 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) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ (h) C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、&& (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (iii) an unsubstituted or substituted 4-10 membered heterocycle, wherein one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ (h) C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、 (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (x) C １ ~C ６ Alkyl, (y) C １ ~C ６ Haloalkyl, and (z) C ３ ~C ６ Cycloalkyl, (vv)-C(=O)Z ２ (v)-C(=O)OZ ２ 、 (vi)-C(=O)NZ ３ Z ４ 、 (vii)-S(=O) ２ Z ８ 、 ()) ()) ２ !: ３ : ４ 、 (ix)-S(=O)(=NZ ６ )Z ２ 、 (xi)-S(=Z ６ )(=NZ ７ )Z ２ and (8)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 R ４ｂ is selected from the group consisting of: (i) hydrogen, and (ii) C １ ~C ６ Alkyl, Each Z １ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (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 is independently selected from the group consisting of: (i) C １ ~C ６ Alkyl, (ii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents is selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (iii) C ２ ~C ６ Alkynyl, (iv) C ３ ~C ６ Cycloalkyl, (v) C ３ ~C ６ Cycloalkenyl, and (vi) C １ ~C ６ Haloalkyl, Each Z ３ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (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 ４ , Z ５ , Z ６ and Z ７ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii) C ３ ~C ６ Cycloalkyl, Each Z ８ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (iv) a halogen, and (v) hydroxy, R ３ｂ and R ３ｃ is independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (ii) C １ ~C ６ Haloalkyl, and (iii) C ３ ~C ６ Cycloalkyl, 【Chemistry 11】 is selected from the group consisting of: (i) C ３ ~C ６ Cycloalkyl, (ii) a 4- to 10-membered heterocycle, (iii) C ６ ~C １０ Aryl, and (iv) 5-10 membered heteroaryl, Each R ５ is independently selected from the group consisting of: (i) a halogen, (ii) hydroxy, (iii) cyano, (iv)-OZ １ 、 (v)-SZ １ (vi)-NZ ３ Z ４ 、 (vii)-C(=O)Z ２ (viii) C(=O)OH, (ix)-C(=O)OZ ２ 、 (x)-C(=O)NZ ３ Z ４ 、 (xi)-NZ ５ C(=O)Z ２ 、 ())!: ５ (#) ２ 、 ())!? ５ [(#)]] ３ : ４ 、 (xiv)-S(=O) ２ Z ８ 、 (xv)-S(=O) ２ NZ ３ Z ４ 、 (xvi)-S(=O)(=NZ ６ )Z ２ 、 (xvii)-S(=Z ６ )(=NZ ７ )Z ２ 、 (xviii)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (xix)-NZ ５ S(=O) ２ Z ２ 、 (xx)-NZ ５ S(=O) ２ NZ ３ Z ４ 、 (xxi)-NZ ５ S(=O)(=NZ ６ )Z ２ 、 (xxii)-NZ ５ S(=NZ ６ )(=NZ ７ )Z ２ 、 (xxiii)-NZ ５ S(=O)(=NZ ６ )NZ ３ Z ４ 、 (xxiv) unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents are independently hydroxy, -OZ １ , and -N.Z. ３ Z ４ (selected from the group consisting of (xxv) C １ ~C ６ Haloalkyl, (xxvi) C ３ ~C ６ Cycloalkyl (wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl, hydroxy, and -NZ ３ Z ４ (selected from the group consisting of (xxvii) unsubstituted or substituted C ２ ~C ６ alkenyl (wherein one or more of the substituents are independently selected from halogen and unsubstituted or substituted C １ ~C ６ alkyl, and one or more of the substituents are independently selected from the group consisting of -NZ ３ Z ４ and 4- to 8-membered heterocycles, (xxviii) unsubstituted or substituted C ６ ~C １０ Aryl (wherein one or more of the substituents are independently halo, -OZ １ , C １ ~C ６ Alkyl, cyano, hydroxy, and C １ ~C ６ haloalkyl); (xxix) unsubstituted or substituted 4-10 membered heterocycles, wherein one or more of the substituents are independently selected from the group consisting of C １ ~C ６ Alkyl and C １ ~C ６ haloalkyl); R ６ａ is selected from the group consisting of: (i) hydrogen, and (ii) C １ ~C ６ Alkyl, R ６ｂ is selected from the group consisting of: (i) hydrogen, and (ii) C １ ~C ６ Alkyl, m is 0, 1, 2, or 3; R １０ａ , R １０ｂ , R １０ｃ , and R １０ｄ But independently, (i) hydrogen, (ii) cyano, (iii) hydroxy, (iv)-OZ １ 、 (v)-SZ １ 、 (vi)-NZ ３ Z ４ 、 (vii) C １ ~C ６ Alkyl, and (viii) C １ ~C ６ haloalkyl, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

3. A compound according to claim 1 or 2 of formula III, 【Chemistry 12】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

4. A compound according to claim 1 or 2 of formula IV, 【Chemistry 13】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

5. X, X ２ , and X ３ 5. The compound of claim 1, 2, or 4, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

6. X is -N=, and X ２ and X ３ 5. The compound of claim 1, 2, or 4, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

7. X and X ３ is -CH=, and X ２ 5. The compound of claim 1, 2, or 4, wherein N=, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

8. X and X ２ is -CH=, and X ３ 5. The compound of claim 1, 2, or 4, wherein N=, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

9. A compound according to claim 1 or 2 of formula V, 【Chemistry 14】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

10. X １ , X ２ , and X ３ 10. The compound of claim 1, 2, or 9, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

11. X １ is -N=, and X ２ and X ３ 10. The compound of claim 1, 2, or 9, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

12. X １ and X ３ is -CH=, and X ２ 10. The compound of claim 1, 2, or 9, wherein N=, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

13. X １ and X ２ is -CH=, and X ３ 10. The compound of claim 1, 2, or 9, wherein N=, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

14. R １ But, -L ２ -NR ４ａ R ４ｂ 14. The compound of any one of claims 1 to 13, wherein:

15. L ２ But -(CH ２ ) ｎ 15. The compound of claim 14, wherein: -, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

16. 16. The compound of claim 15, wherein n is 0, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

17. 17. The compound of claim 16, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein n is 1.

18. R ４ａ But -C(=O)Z ２ , -C(=O)OZ ２ , -C(=O)NZ ３ Z ４ , -S(=O) ２ Z ８ , and -S(=O) ２ New Zealand ３ Z ４ 18. The compound of any one of claims 1 to 17, selected from the group consisting of:

19. Z ２ But, C １ ~C ６ Alkyl and C2-C ６ alkenyl, Z ３ But, C １ ~C ６ Alkyl and C2-C ６ alkenyl, Z ４ 20. The compound of claim 18, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: is hydrogen.

20. R １ is an unsubstituted or substituted 4-8 membered heterocycle, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

21. R １ 21. The compound of claim 20, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: 【Chemistry 15】

22. A compound according to claim 1 or 2 of formula VI, 【Chemistry 16】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: X is -CR １０ａ = and -N=; X １ But -CR １０ｂ The compound, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: -N= and -N=.

23. X, X １ , X ２ , and X ３ 23. The compound of claim 1, 2, or 22, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

24. Compounds according to claim 1 or 2 of formula VII, 【Chemistry 17】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

25. A compound according to claim 1 or 2 of formula VIII, 【Chemistry 18】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

26. R ６ａ is hydrogen and C １ ~C ４ 30. The compound of claim 1, 2, or 25, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein the compound is selected from the group consisting of: alkyl.

27. A compound according to claim 1 or 2 of formula IX, 【Chemistry 19】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

28. R ６ｂ is hydrogen and C １ ~C ４ 30. The compound of claim 1, 2, or 27, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein the compound is selected from the group consisting of: alkyl.

29. R ２ But, R ２ 29. The compound of any one of claims 1 to 28, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R is -1. 【Request 30】 【Chemical 20】 But, C ６ ~C １０ 30. The compound of any one of claims 1 to 29, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, which is aryl.

31. 【Chemical 21】 is phenyl, R ５ The compound of any one of claims 1 to 30, wherein is halo and m is 1 or 2.

32. 3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: 1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one, (S)-1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one, and (R)-1-(3-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(4-fluorophenyl)pyridin-3-yl)pyrrolidin-1-yl)prop-2-en-1-one.

33. 33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

34. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use as a medicament.

35. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal, or human.

36. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder selected from the group consisting of cancer, fibrosis, and a YAP / TAZ-TEAD activation-mediated congenital disorder.

37. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder 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, mesothelial tumors, and / or sarcoma.

38. 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, spinal cord tumor, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic 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, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular carcinoma, hormone refractory prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelioma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and and non-Hodgkin's), malignancies 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 natto carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma 34. A compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder selected from: rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung cancer, 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.

39. A method for preventing or treating 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 claims 1 to 32.

40. The method for treating or preventing a YAP / TAZ-TEAD activation-mediated disorder described in claim 39 for a patient in need of such treatment or prevention in combination with one or more other drugs selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor.

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