Tetrahydronaphthyridines and related analogs for inhibition of YAP / TAZ-TEAD

Abstract

The present disclosure relates to a novel compound, the compound for use as a medicament, more particularly for use in the prevention or treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription, and more particularly for use in the prevention or treatment of cancer or fibrosis. The present disclosure also relates to a method for preventing or treating said disease comprising the use of a novel compound.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 502,605, filed May 16, 2023, the entire contents of which are hereby incorporated by reference. Technical Field

[0002] This disclosure relates to novel compounds. It also relates to compounds used as medicines, and more specifically, for the prevention or treatment of diseases mediated by the transcriptional activity of YAP / TAZ-TEAD, such as those 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] This disclosure also relates to pharmaceutical compositions or formulations of novel compounds, and compositions or formulations used as medicines, for example for the prevention or treatment of diseases mediated by the transcriptional activity of YAP / TAZ-TEAD, such as the prevention or treatment of cancer or fibrosis. Methods for preparing the compounds are also disclosed herein. Background Technology

[0004] Hippo signaling is crucial for limiting organ size by inactivating the YAP / TAZ-TEAD transcriptional complex. In several aggressive solid cancers, Hippo signaling is inactivated by loss-of-function mutations or deletions in genes encoding upstream regulators (e.g., NF2, MST1 / 2, or LATS1 / 2), thereby releasing constitutive YAP / TAZ-TEAD transcriptional activity and leading to uncontrolled tumor growth and metastasis. Knockout, knockdown, or pharmacological inactivation of YAP / TAZ-TEAD is sufficient to impair YAP / TAZ-TEAD-dependent tumorigenesis. Pharmacological inactivation of the YAP / TAZ-TEAD complex can be achieved by targeting and disrupting the YAP / TAZ-TEAD protein-protein interaction interface or through the allosteric self-palmitoylation pocket in TEAD.

[0005] The primary physiological function of the Hippo pathway is to limit 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 co-activators, and DNA-binding partner cells. In mammals, Ste20-like kinases MST1 / 2 (… Fruit flies (Drosophila) Hippo homologs phosphorylate and activate large tumor suppressor 1 / 2 (LATS1 / 2). NF2 is the scaffold of core Hippo kinases, which promotes LATS1 / 2 activation by linking MST1 / 2 to LATS1 / 2 (Lallemand et al., 2003, Genes Dev., 17, 1090-1100; Zhang wait people, 2010, Dev. Cell, 19(1), 27-38). LATS kinase then phosphorylates and inactivates two highly homologous transcriptional coactivators via ubiquitin-mediated degradation induced by 14-3-3 cytoplasmic segregation and β-TRCPE3 ligase: Yes-associated protein (YAP) and transcriptional coactivator (TAZ) with a PDZ-binding motif. When the Hippo pathway is inactivated, YAP and TAZ translocate in the nucleus to bind to the TEAD transcription factor family to induce the expression of specific markers, thereby promoting matrix remodeling, cell proliferation, survival, and migration. TEAD1-4 can also bind to VGLL4 in the nucleus and act as transcriptional repressors. VGLL4 is structurally independent of YAP / TAZ, but competes with YAP / TAZ based on partially overlapping binding sites on TEAD (Johnson). et al. , 2014, Nat. Rev. Drug Discov., 13, 63-79).

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

[0007] In Drosophila, due to dysregulation of cell proliferation and resistance to apoptosis, loss of function of Hippo or Warts kinases (MST1 / 2 or LATS1 / 2 in mammals), or Yorkie (YAP and TAZ) fruit flies Overexpression of YAP (a homolog of TEAD) leads to a dramatic overgrowth of the stratum corneum, resulting in increased organ size. In mice, YAP overexpression, loss of MST1 / 2 or LATS1 / 2 kinase activity, or loss of NF2 leads to upregulation of TEAD target genes and progenitor cell proliferation, resulting in liver and heart overgrowth and ultimately cancer formation in the liver, small intestine, and skin. Conversely, the serine-to-alanine mutation at position 94 of YAP (which prevents binding to TEAD) is not oncogenic. et al.(Zhang et al., 2008, Genes Dev., 22, 1962-1971). Similarly, dominant-negative TEAD mutants that cannot bind DNA overcome YAP-driven liver tumorigenesis. Furthermore, loss of heterozygosity of Yap significantly inhibits NF2-mutant hepatocellular carcinoma (Zhang et al., 2010, Dev. Cell, 19, 27-38). Finally, in these models, verteporfin (a small molecule that inhibits YAP-TEAD association) significantly inhibited the oncogenic activity of YAP (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, has been reported in many solid malignancies, including liver cancer, lung cancer, breast cancer, skin cancer, colon cancer, and ovarian cancer. YAP / TAZ promotes the acquisition of several important cancer cell phenotypes, such as proliferation, apoptosis resistance, invasion, and immunosuppression (e.g., by attracting bone marrow-derived suppressor cells (Wang et al., 2016, Cancer Discov., 6, 80-95)). Furthermore, gene fusions with YAP1 have been identified in several cancer types, including ependymoma, angiomyolipoma, cervical cancer, and poriocarcinoma, leading to constitutive activation of YAP-TEAD, which is oncogenic in mice (Szulzewsky). et al. (2020, GenesDev., 34: 1-14). Furthermore, several germline or somatic mutations in Hippo pathway components associated with various cancer types have been identified in targeted and whole-genome sequencing studies. A prime example is the NF2 locus, which is frequently mutated in neurofibromatosis. Loss of NF2 and LATS2 is also commonly observed in schwannomas. Another tumor type typically (accounting for approximately 70% of all cases) associated with constitutive YAP-TEAD activation via genetic inactivation of NF2, LATS1 / 2, MST1 / 2, or SAV1 is malignant mesothelioma (Bueno et al., 2016, Nat Genet 48, 407-416). Recent studies have demonstrated that several mesothelioma cell lines with loss-of-function mutations in NF2 exhibit reduced YAP phosphorylation and increased YAP-TEAD reporter gene activity. YAP-TEAD transcription and activity in NF2 mutant mesothelioma cell lines (not WT mesothelioma) are influenced by YAP siRNA (the effect of which can be rescued by overexpression of siRNA to resist YAP) and sensitivity to treatment with verteporfen (a YAP antagonist). (Zhang) et al.,2017, J. Cell Mol. Med., 21: 2663-2676).

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

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

[0011] YAP / TAZ-TEAD activation has also been demonstrated to play a significant role in other diseases besides cancer, such as fibrosis and certain congenital disorders. A hallmark of fibrosis is the excessive deposition of the extracellular matrix (ECM), including cross-linked collagen fibers, which leads to tissue hardening and ultimately dysfunction of the affected organs. ECM hardening promotes nuclear activity of YAP / TAZ in cancer-associated fibroblasts and fibroblasts in the liver, kidneys, lungs, and skin. 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 increased myofibroblast differentiation and matrix remodeling. Several genes encoding key secretory factors involved in fibrosis are direct targets of YAP / TAZ-TEAD. These genes include well-characterized pro-fibrotic factors such as connective tissue growth factor (CTGF), plasminogen activator inhibitor 1 (PAI-1), and the lysine oxidase (LOX) family of collagen crosslinking enzymes. Several pieces of evidence support that YAP / TAZ is a contributing factor to fibrotic diseases in vivo. This evidence includes reports of elevated YAP / TAZ levels and transcriptional activity in fibroblasts, alveoli, and respiratory epithelium from 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 (a chronic fibrotic condition of liver injury). Expression of YAP or TAZ in hepatic ductal cells drives fibrosis progression, paralleling fibrosis in nonalcoholic fatty liver disease (MACARD). et al. (J. Hepatol., 2015, 63, 962-970). In summary, these studies suggest that targeting aberrant YAP / TAZ activity in fibrotic diseases may be a promising therapeutic approach.

[0012] Neurofibromatosis type 2 is characterized by tumors of the nervous system, including schwannomas, meningiomas, and ependymomas. Neurofibromatosis type 2 is a heritable disorder caused by NF2 inactivation (Striedinger et al., 2008, Neoplasia 10, 1204-1210). Loss of NF2 leads to constitutive activation of YAP / TAZ-TEAD. Sturge-Weber syndrome is a congenital neurocutaneous disorder characterized by port-wine stains affecting the distribution of the ophthalmic branch of the trigeminal nerve in the skin, capillary venous vascular abnormalities in the brain and choroidal pia mater, glaucoma, seizures, stroke, and intellectual disability. Sturge-Weber syndrome and port-wine stains are caused by somatic activation mutations in GNAQ, which leads to transcriptional activation of YAP / TAZ-TEAD (Shirley et al., 2013, NEJM, 368, 1971-1979). Therefore, YAP / TAZ-TEAD inhibitors can be used to treat several congenital conditions characterized by constitutive YAP / TAZ-TEAD activation.

[0013] Several publications describe inhibitors of YAP-TEAD transcriptional activation. Inventiva highlighted YAP-TEAD protein-protein interaction inhibitors in WO 2020 / 070181, WO2018 / 185266, and WO 2017 / 064277. General Hospital Corporation, Boston described a self-palmitoylation inhibitor in WO 2017 / 053706. Vivace Therapeutics, Inc. disclosed non-fused tricyclic compounds (WO 2018 / 204532), benzosulfonyl compounds (WO2019 / 040380), benzocarbonyl compounds (WO 2019 / 113236), oxadiazole compounds (WO 2019 / 222431), and bicyclic compounds (WO 2020 / 097389) that regulate 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 WO 2013 / 188138 and WO 2017 / 058716, respectively. Kyowa Hakko Kirin Co., Ltd. disclosed α,β-unsaturated amide compounds exhibiting anticancer activity in WO 2018 / 235926 and US2019 / 0010136. Genentech, Inc. disclosed carboxamide and sulfonamide derivatives that can be used as inhibitors of YAP-TEAD protein-protein interactions in WO 2019 / 232216 and WO 2020 / 051099. Dana-Farber Cancer Institute, Inc. highlighted inhibitors of TEAD transcription factors in WO 2020 / 081572. Trustees of Indiana University describe small molecules bound within the hydrophobic palmitate binding pocket of TEAD in WO2020 / 087063. Wenchao Lu et al. disclose vinylsulfonamide as a covalent TEAD self-palmitoylation inhibitor (2019, European Journal of Medicinal Chemistry, 184, p. 111767).The Korean Research Institute of Chemical Technology disclosed a benzo[cd]indole-2(1H)-one derivative that inhibits the binding of YAP-TEAD in WO 2020 / 096416.

[0014] However, there remains a need for novel, alternative, and / or superior therapeutic agents for the prevention or treatment of YAP / TAZ-TEAD-mediated diseases, such as cancer and fibrosis, and other potential indications. Therapeutic agents with enhanced potency, fewer side effects, higher activity, lower toxicity, or better pharmacokinetic or pharmacodynamic properties, or combinations thereof, would be highly desirable.

[0015] This 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] This disclosure is based on the finding that at least one of the problems mentioned above can be solved by compounds of the class described below.

[0017] This disclosure provides novel compounds that have been shown to have inhibitory activity against YAP / TAZ-TEAD transcription. This disclosure further demonstrates that these compounds effectively inhibit the activity of YAP / TAZ-TEAD transcription. Therefore, these compounds constitute a useful new class of potent compounds that can be used to treat and / or prevent Hippo-mediated diseases in animals, mammals, and humans, and more specifically for the treatment and / or prevention of (i) cancers, more specifically such as 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 cancer, and prostate cancer, mesothelioma and / or sarcoma, (ii) fibrosis, and (iii) congenital diseases associated with YAP / TAZ-TEAD activation, etc.

[0018] In some respects, the compounds described herein can be used to treat and / or prevent Hippo-mediated diseases in animals, mammals, and humans, and more specifically for the treatment and / or prevention of diseases such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocyte, medulloblastic, adenocarcinoma, angiosarcoma, astrocytoma, granulocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative dysplasia (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, and Ewing's tumor. Malignant tumors of the following types: fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus. And hyperproliferative disorders, T-cell or B-cell-derived lymphomas, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary carcinoma, pineal tumor, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0019] This disclosure further relates to the use of such compounds as medicines and their use in the manufacture of medicines, more specifically for the treatment and / or prevention of YAP / TAZ-TEAD activation-mediated diseases, particularly (i) cancers, more specifically such as 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 cancer and prostate cancer, mesothelioma and / or sarcoma, and (ii) fibrosis in animals or mammals, more specifically in humans.

[0020] This disclosure also relates to methods for preparing the compounds described herein and pharmaceutical compositions comprising, for example, an effective amount of the compounds.

[0021] In some embodiments, this disclosure relates to the use of the compounds of the invention as medicines, the use of such compounds as medicines, and their use in the manufacture of medicines, more specifically for the treatment and / or prevention of YAP / TAZ-TEAD activation-mediated diseases, and more specifically for the treatment and / or prevention of, for example, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocyte, medulloblastic, adenocarcinoma, angiosarcoma, astrocytoma, granulocytic monocyte and promyelocytic leukemia), acute T cell leukemia, ... Basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative dysplasia (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing Hodgkin's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell tumors. The sources include malignant lymphomas, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline NUT carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and nephroblastoma.

[0022] This disclosure also relates to a method of treating or preventing TEAD-mediated conditions in humans by administering one or more such compounds (optionally in combination with one or more other drugs) to a patient in need.

[0023] This disclosure also relates to methods for preparing the compounds described herein, including, for example, steps for synthesizing the compounds described herein. Detailed Implementation

[0024] definition The term "YAP / TAZ-TEAD activation-mediated disease" refers to diseases in which hippo signaling is inactivated and YAP / TAZ-TEAD activation contributes to, drives, persists, realizes, or has similar effects. This can occur through 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), releasing constitutive YAP-TEAD transcriptional activity, leading to uncontrolled tumor growth and metastasis in some cancers. This can also occur, particularly through YAP1 or WWTR1 (TAZ) gene amplification, gene fusion, or activating mutations, or YAP / TAZ overexpression or high activity. Therefore, YAP / TAZ-TEAD activation-mediated diseases refer to cancer, but also include fibrosis and certain congenital conditions. Cancers included in YAP / TAZ-TEAD-mediated diseases are (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 bile duct cancer), skin cancer, pancreatic cancer, gastric cancer, brain cancer, and prostate cancer, mesothelioma and / or sarcoma. Also included are (i) squamous cell carcinomas of the lung, cervix, ovary, head and neck, esophagus and / or skin, or (ii) cancers originating from neuroectodermal-derived tissues, such as ependymoma, 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 are (but not limited to) liver fibrosis, pulmonary fibrosis and cardiac fibrosis. Congenital conditions included in YAP / TAZ-TEAD-mediated diseases are (but not limited to) Sturge-Weber syndrome and neurofibromatosis type 2.

[0025] YAP / TAZ-TEAD-mediated diseases also include cancers that have developed resistance to previous treatments, such as EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors, and other inhibitors.

[0026] 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 achieving a therapeutic or preventive benefit by inhibiting YAP / TAZ-TEAD transcription. Treatment includes reversing, improving, alleviating, inhibiting the progression of a disease, condition, or disorder or one or more symptoms of such a disease, condition, or disorder mediated by YAP / TAZ-TEAD transcription, reducing its severity, or preventing said disease, condition, or disorder or one or more symptoms of such a disease, condition, or disorder. "Therapeutic benefit" means eradicating, improving, reversing, alleviating, inhibiting the progression of the treated underlying condition, or reducing its severity. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, resulting in an observed improvement in a patient, even though in some embodiments the patient has the underlying condition. For preventive benefits, in some embodiments, the composition is administered to a patient at risk of developing a specific disease or a patient reporting one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0027] As used in this article, the term "subject" refers to an animal, such as a mammal, such as a human or a patient, that is the target of treatment, observation, or experimentation or that requires such treatment.

[0028] As used herein, the term "therapeutic effective amount" means the amount of an active compound or agent that elicits a biological or medical response in a tissue system, animal, or human that is sought by an investigator, veterinarian, physician, or other clinician, including relief or partial relief of symptoms of the disease or condition being treated.

[0029] As used herein, the term "composition" is intended to cover products containing a therapeutically effective amount of a specified ingredient, and any product derived directly or indirectly from a specified amount of a specified ingredient.

[0030] As used in this article, the terms "antagonist" or "inhibitor" refer to compounds that can produce a functional antagonistic effect on YAP / TAZ-TEAD activation depending on the environment.

[0031] It should be noted that the term "comprising" as used in the claims should not be construed as limited to the components listed below; it does not exclude other elements or steps.

[0032] Throughout this specification, references to “an embodiment” or “implementation” mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of this disclosure. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner, as will be apparent to those skilled in the art based on this disclosure. Unless otherwise specifically stated, when using indefinite or definite articles, references to singular nouns (e.g., “a” or “an”, “the”) include the plural form of said noun.

[0033] Similarly, it should be understood that in the description of exemplary embodiments of this disclosure, for the purpose of simplifying this disclosure and aiding in the understanding of one or more aspects of the invention, various features of this disclosure are sometimes grouped together in a single embodiment, figure, or description thereof.

[0034] In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms that are typically best present in the substituent or linker; it should be understood that, where otherwise indicated in this application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.

[0035] As used herein, the term "leaving group" or "LG" refers to a chemical group that is readily replaced by a nucleophile or cleaved or hydrolyzed under basic or acidic conditions. In specific embodiments, the leaving group is selected from halogen atoms (e.g., Cl, Br, I) or sulfonate groups (e.g., methanesulfonate, toluenesulfonate, trifluoromethanesulfonate).

[0036] The term "protecting group" refers to a part of a compound that masks or alters the properties of its functional groups or the properties of the compound as a whole. The chemical substructure of protecting groups varies widely. One function of protecting groups is to act as intermediates in the synthesis of parent drug substances. Chemical protecting groups and strategies used 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 used to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions (e.g., the orderly and planned creation and breaking of chemical bonds). In addition to the reactivity of the protected functional groups, protecting the functional groups of a compound also alters other physical properties, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by common analytical tools. Chemically protected intermediates may be biologically active or biologically inactive.

[0037] Protected compounds may also exhibit altered, and in some cases optimized, in vitro and in vivo properties, such as resistance to cell membranes and to enzyme degradation or isolation. In this role, the protected compound with the intended therapeutic effect can be called a prodrug. Another function of the protecting group is to convert the parent drug into a prodrug, thereby releasing the parent drug during prodrug conversion in vivo. Because the active prodrug can be absorbed more efficiently than the parent drug, it can have greater in vivo potency. The protecting group is removed in vitro (in the case of chemical intermediates) or in vivo (in the case of prodrugs). Regarding chemical intermediates, the physiological acceptability of the resulting product (e.g., an alcohol) after deprotection is not particularly important, although pharmacologically harmless products are generally preferred.

[0038] As used in this article, the terms "alkyl" or "C" 1-18 "Alkyl" refers to a C1-C group that does not have an unsaturated site. 18 Linear, branched, or straight-chain hydrocarbons, whether n-, secondary, or tertiary. Examples include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl. just Gengji, just Sinki, just Renji just guiji, just Undecyl, just dodecyl, just Tridecyl, just Tetradecyl, just Pentadecyl, just hexadecyl, just Heptadecanyl just Octadecyl, just nonadecanyl and just Eicosyl. In specific embodiments, the term alkyl refers to C16. 1-12 Alkyl (C) 1-12 Hydrocarbons), and more specifically C 1-9 Alkyl (C) 1-9 Hydrocarbons), and more specifically, C as further defined above. 1-6 Alkyl (C) 1-6 hydrocarbon).

[0039] The term "haloalkyl" as a group or part of a group refers to an alkyl group having the meaning as defined above, wherein one, two, or three hydrogen atoms are each replaced by a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, etc.

[0040] The term "alkoxy" or "alkyloxy" as a group or part of a group refers to a group having the formula -OR b The group, wherein R b C as defined above 1-6 Alkyl group. Suitable C 1-6 Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and hexyloxy.

[0041] The term "haloalkoxy" as a group or part of a group refers to the formula -OR c The group, wherein R c It is a haloalkyl group as defined herein. Non-limiting examples of suitable haloalkoxy groups 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.

[0042] As used herein and unless otherwise stated, the term "cycloalkyl" or "C3-" is used in conjunction with other terms. 18 "Cycloalkyl" means alkyl formed by C244-C ... 3-10 Monocyclic saturated hydrocarbons or C 7-18 The saturated hydrocarbon is composed of or comprises a monovalent group of 3 to 18 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylidene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, flavyl, trimethyltricycloheptyl, decahydronaphthyl, adamantyl, etc. In a specific embodiment, the term cycloalkyl refers to C... 3-12 cycloalkyl (saturated cyclic C 3-12 Hydrocarbons), and more specifically C 3-9 cycloalkyl (saturated cyclic C 3-9 Hydrocarbons), or more specifically, C as further defined above. 3-6 cycloalkyl (saturated cyclic C 3-6(Hydrocarbons). To avoid ambiguity, fused systems of cycloalkyl rings and heterocycles are considered heterocycles, and not related to the ring bonded to the core structure. Fused systems of cycloalkyl rings and aryl rings are considered aryl, and not related to the ring bonded to the core structure. Fused systems of cycloalkyl rings and heteroaryl rings are considered heteroaryl, and not related to the ring bonded to the core structure.

[0043] As used in this article, the terms "alkenyl" or "C" 2-18 "Alkenyl" is a C2-C group having at least one (usually 1 to 3, preferably 1) unsaturated site (i.e., carbon-carbon sp2 double bond). 18 Linear, branched, or straight-chain hydrocarbons, whether normal, secondary, or tertiary. Examples include, but are not limited to, vinyl (ethylene or vinyl, -CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). The double bond may be in cis or trans configuration. In a specific embodiment, the term alkenyl refers to C... 2-12 alkenyl (C 2-12 Hydrocarbons), and more specifically C 2-9 alkenyl (C 2-9 Hydrocarbons, more specifically, refer to carbon-carbon hydrocarbons having at least one (usually one to three, preferably one) unsaturated site (i.e., a carbon-carbon sp2 double bond) as further defined above. 2-6 alkenyl (C 2-6 hydrocarbon).

[0044] The term "alkenyloxy group" as a group or part of a group refers to a group having the formula -OR d The group, wherein R d It is an alkenyl group as defined above.

[0045] As used herein, the term "cycloalkenyl" refers to a group having 5 to 18 carbon atoms and at least one (usually 1 to 3, preferably 1) unsaturated site (i.e., carbon-carbon sp2 double bond) and consisting of C5- 10 Monocyclic hydrocarbons or C 7-18 A non-aromatic hydrocarbon group comprising or containing a polycyclic hydrocarbon. Examples include, but are not limited to, cyclopentenyl (-C5H7), cyclopentenylpropylene, methylcyclohexeneyl, and cyclohexenyl (-C6H9). The double bond may be in cis or trans configuration. In a specific embodiment, the term cycloalkenyl refers to C... 5-12 Cycloalkenyl (cyclic C) 5-12 Hydrocarbons), and more specifically C 5-9 Cycloalkenyl (cyclic C) 5-9 Hydrocarbons, more specifically, refer to carbon atoms having at least one unsaturated site (i.e., a carbon-carbon sp2 double bond) as further defined above. 5-6 Cycloalkenyl (cyclic C) 5-6(Hydrocarbons). To avoid ambiguity, fused systems of cycloalkenyl rings with heterocycles are considered heterocycles, and not related to the ring bonded to the core structure. Fused systems of cycloalkenyl rings with aryl rings are considered aryl rings, and not related to the ring bonded to the core structure. Fused systems of cycloalkenyl rings with heteroaryl rings are considered heteroaryl rings, and not related to the ring bonded to the core structure.

[0046] As used in this article, the terms "alkynyl" or "C" are used to refer to the alkynyl group. 2-18 "Alkyne" refers to a C2-C group having at least one (usually 1 to 3, preferably 1) unsaturated site (i.e., a carbon-carbon sp triple bond). 18 Linear branched or straight-chain hydrocarbons, including but not limited to: ethynyl (-C≡CH), 3-ethyl-cycloheptane-1-ynyneyl and 1-propynyl (propynyl, -CH2C≡CH). In specific embodiments, the term ynyneyl refers to C... 2-12 alkynyl (C 2-12 Hydrocarbons), and more specifically C 2-9 alkynyl (C 2-9 Hydrocarbons, and more specifically, hydrocarbons having at least one (usually one to three, preferably one) unsaturated site (i.e., carbon-carbon sp triple bond) as further defined above. 2-6 alkynyl (C 2-6 hydrocarbon).

[0047] The term "alkynyloxy group" as a group or part of a group refers to a group having the formula -OR e The group, wherein R e It is an alkynyl group as defined above.

[0048] As used herein, the term "cycloalkynyl" refers to a group having 5 to 18 carbon atoms and at least one (usually 1 to 3, preferably 1) unsaturated site (i.e., a carbon-carbon sp triple bond) and consisting of C 5-10 Monocyclic hydrocarbons or C 7-18 A non-aromatic hydrocarbon group that constitutes or includes the hydrocarbon is a polycyclic hydrocarbon. Examples include, but are not limited to, cyclohepta-1-yne, 3-ethyl-cyclohepta-1-ynyne, 4-cyclohepta-1-yne-methylene, and ethyl-cyclohepta-1-yne. In a specific embodiment, the term cycloynyne refers to C144-C ... 5-10 Cycloalkynyl (cyclic C) 5-10 Hydrocarbons), and more specifically C 5-9 Cycloalkynyl (cyclic C) 5-9 Hydrocarbons, more specifically, refer to carbon-carbon hydrocarbons having at least one (usually one to three, preferably one) unsaturated site (i.e., carbon-carbon sp triple bond) as further defined above. 5-6 Cycloalkynyl (cyclic C) 5-6(Hydrocarbons). To avoid ambiguity, fused systems of cycloalkynyl rings with heterocycles are considered heterocycles, and not related to the ring bonded to the core structure. Fused systems of cycloalkynyl rings with aryl rings are considered aryl rings, and not related to the ring bonded to the core structure. Fused systems of cycloalkynyl rings with heteroaryl rings are considered heteroaryl rings, and not related to the ring bonded to the core structure.

[0049] As used herein, the term "alkylene" refers to 1–18 carbon atoms (more specifically, C16-C18). 1-12 C 1-9 Or C 1-6 A saturated branched or straight-chain hydrocarbon group (containing a carbon atom) and having two monovalent group centers derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. Typical alkylene groups include, but are not limited to: methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), etc.

[0050] As used herein, the term "alkenyl" refers to 2-18 carbon atoms (more specifically C) having at least one (usually 1 to 3, preferably 1) unsaturated site (i.e., carbon-carbon sp2 double bond). 2-12 C 2-9 Or C 2-6 A branched or straight-chain hydrocarbon (carbon atom) having two monovalent centers derived from the same carbon atom or two different carbon atoms of a parent olefin by removing two hydrogen atoms.

[0051] As used herein, the term "ethynyl group" refers to 2-18 carbon atoms (more specifically C) having at least one (usually 1 to 3, preferably 1) unsaturated site (i.e., carbon-carbon sp triple bond). 2-12 C 2-9 Or C 2-6 A branched or straight-chain hydrocarbon (containing carbon atoms) and having two monovalent centers derived from the same carbon atom or two different carbon atoms of a parent alkyne by removing two hydrogen atoms.

[0052] As used herein, the term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by one or more atoms selected from the group consisting of oxygen, nitrogen, or sulfur atoms. Therefore, the term heteroalkyl includes -OR b -NR o -R b -R a -OR b and -SR b , where R a It is an alkylene group, R b It is an alkyl group, and R oIt is hydrogen or an alkyl group as defined herein. In specific embodiments, the term refers to C 1-12 Heteroalkyl, C 1-9 Heteroalkyl or C 1-6 Heteroalkyl. In some embodiments, the heteroalkyl is selected from the group consisting of: alkyloxy, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di)alkyl-amino-alkyl, alkylthio and alkyl-thio-alkyl.

[0053] As used herein, the term "heteroalkenyl" refers to an acyclic alkenyl group in which one or more carbon atoms are replaced by one or more atoms selected from oxygen, nitrogen, or sulfur atoms. Therefore, the term heteroalkenyl includes -OR d -NH-(R d ), -N(R d ))2、-N(R b (R) d ) and -SR d , where R b It is an alkyl group and R d Alkenyl groups are defined herein. In specific embodiments, the term refers to C0. 2-12 Heterene, C 2-9 Heterene or C 2-6 Heteroalkenyl. In some embodiments, the heteroalkenyl is selected from the group consisting of: alkenyloxy, alkenyl-oxy-alkenyl, (mono or di)alkenylamino, (mono or di)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl.

[0054] As used herein, the term "heterynyl" refers to an acyclic ynyl group in which one or more carbon atoms are replaced by oxygen, nitrogen, or sulfur atoms. Therefore, the term heterynyl 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 It is an alkyl group, R e It is an alkynyl group, and R d Alkenyl groups are defined herein. In specific embodiments, the term refers to C0. 2-12 Neyne group, C 2-9 pyrynyl or C 2-6 Xyrynyl. In some embodiments, the term xyrynyl is selected from the group consisting of: alkynyloxy, alkynyl-oxy-alkynyl, (mono or di)alkynylamino, (mono or di)alkynyl-amino-alkynyl, alkynylthio and alkynyl-thio-alkynyl.

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

[0056] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms are replaced by one or more oxygen, nitrogen, or sulfur atoms.

[0057] As used in this article, the term "heteroyne" refers to an ynyne group in which one or more carbon atoms are replaced by one or more oxygen, nitrogen, or sulfur atoms.

[0058] As used herein, the term "aryl" refers to an aromatic hydrocarbon of 6-20 carbon atoms derived by removing hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, one ring or two or three rings fused together derived from benzene, naphthalene, anthracene, biphenyl, etc. In specific embodiments, the term aryl refers to an aromatic ring of 6-14 carbon atoms, and more specifically, an aromatic ring of 6-10 carbon atoms. A fused system of an aryl ring with a cycloalkyl ring, a cycloalkenyl ring, or a cycloalkynyl ring is considered aryl, regardless of the ring bonded to the core structure. A fused system of an aryl ring with a heterocyclic ring is considered heterocyclic, regardless of the ring bonded to the core structure. Therefore, indoline, dihydrobenzofuran, dihydrobenzothiophene, etc., are considered heterocyclic according to this disclosure. A fused system of an aryl ring with a heteroaryl ring is considered heteroaryl, regardless of the ring bonded to the core structure.

[0059] The term "aryloxy group" as a group or part of a group refers to a group having the formula -OR g The group, wherein R g It is an aryl group as defined above.

[0060] As used herein, the term "arylalkyl" or "arylalkyl-" refers to an alkyl group in which one hydrogen atom bonded to a carbon atom (usually a terminal or sp3 carbon atom) is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylvinyl-1-yl, naphthylmethyl, 2-naphthylethyl, etc. Arylalkyl groups contain 6 to 20 carbon atoms; for example, an alkyl group may have 1 to 6 carbon atoms and an aryl group may have 6 to 14 carbon atoms.

[0061] The term "arylalkyloxy" as a group or part of a group refers to a group having the formula -OR a -R g The group, wherein R g It is aryl, and R a It is an alkylene group as defined above.

[0062] As used herein, the term "aryl-alkenyl" or "aryl-alkenyl-" refers to an alkenyl group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Aryl-alkenyl groups contain 6 to 20 carbon atoms; for example, the alkenyl portion of an aryl-alkenyl group has 1 to 6 carbon atoms and the aryl portion has 6 to 14 carbon atoms.

[0063] As used herein, the term "arylynyl" or "arylynyl-" refers to an ynyl group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Arylynyl groups contain 6 to 20 carbon atoms; for example, the ynyl portion of an arylynyl group has 1 to 6 carbon atoms and the aryl portion has 6 to 14 carbon atoms.

[0064] As used herein, the term "arylhexaalkyl" or "arylhexaalkyl-" refers to a heteroalkyl group in which one hydrogen atom bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by an aryl group. Arylhexaalkyl groups contain 6 to 20 carbon atoms; for example, the heteroalkyl portion of an arylhexaalkyl group has 1 to 6 carbon atoms and the aryl portion has 6 to 14 carbon atoms. In some embodiments, the arylhexaalkyl group is selected from the group consisting of aryl-O-alkyl, arylalkyl-O-alkyl, aryl-NH-alkyl, aryl-N(alkyl)2, arylalkyl-NH-alkyl, arylalkyl-N-(alkyl)2, aryl-S-alkyl, and arylalkyl-S-alkyl.

[0065] As used herein, the term "arylhexeneyl" or "arylhexeneyl-" refers to a heteroalkenyl group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Arylhexeneyl groups contain 6 to 20 carbon atoms; for example, the heteroalkenyl portion of an arylhexeneyl group has 1 to 6 carbon atoms and the aryl portion has 6 to 14 carbon atoms. In some embodiments, the arylhexeneyl group is selected from the group consisting of: aryl-O-alkenyl, aryl-alkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl)2, aryl-alkenyl-NH-alkenyl, aryl-alkenyl-N-(alkenyl)2, aryl-S-alkenyl, and aryl-alkenyl-S-alkenyl.

[0066] As used herein, the term "aryl-pyrynyl" or "aryl-pyrenyl-" refers to a pyrynyl group in which one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Aryl-pyrynyl groups contain 6 to 20 carbon atoms; for example, the pyrynyl portion of an aryl-pyrynyl group has 1 to 6 carbon atoms and the aryl portion has 6 to 14 carbon atoms. In some embodiments, the aryl-pyrynyl group is selected from the group consisting of: aryl-O-ynyl, aryl-ynyl-O-ynyl, aryl-NH-ynyl, aryl-N(ynyl)2, aryl-ynyl-NH-ynyl, aryl-ynyl-N-(ynyl)2, aryl-S-ynyl, and aryl-ynyl-S-ynyl.

[0067] As used herein, the term "heterocycle" or "heterocyclic group" refers to a non-aromatic, fully saturated, or partially unsaturated ring system (e.g., a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) comprising 3 to 18 atoms of at least one N, O, S, or P. Each ring of the heterocycle or heterocyclic group may have one, two, three, or four heteroatoms selected from N, O, and / or S, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatomium may optionally be quaternized; and wherein at least one carbon atom of the heterocyclic group may be oxidized to form at least one C=O. Where valence permits, the heterocycle may be linked at any heteroatom or carbon atom of the ring or ring system. The rings of a polycyclic heterocyclic group or heterocycle may be fused, bridged, and / or linked by one or more spiro atoms. A system of fused heterocycles or heterocyclic groups with aryl rings is considered a heterocycle or heterocyclic group, regardless of the ring bonded to the core structure. A heterocyclic or fused system of heterocyclic groups and heteroaryl rings is considered a heteroaryl group, independent of the rings bound to the core structure.

[0068] Non-limiting exemplary heterocyclic or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolylyl, aziridinyl, oxiranyl, thiiranyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, 2-imidazolinyl, pyrazolylyl, imidazolinyl, isoxazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolyl, succinimide, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrroleyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinazinyl, 2-oxopiperazinyl, 2-pyrazolylyl, 3-pyrrolinyl, 2-pyrrolylylyl, 3-pyrrolinylyl, 2-oxopiperazinyl, 2-pyrazolyl ... Azolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanecycloyl, 1,4-dioxane, 2,5-dioxoimidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolylyl, indololinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetra Hydroisoquinoline-3-yl, tetrahydroisoquinoline-4-yl, thiomorpholine-4-yl, thiomorpholine-4-yl sulfoxide, thiomorpholine-4-yl sulfone, 1,3-dioxolanecycloyl, 1,4-oxothiacyclohexyl, 1,4-dithiaalkyl, 1,3,5-trioxalyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiopheneyl, N-formylpiperazinyl, and morpholine-4-yl. The term "aziridinyl" as used herein includes aziridin-1-yl and aziridin-2-yl. The term "epoxyethyl" as used herein includes epoxyethyl-2-yl. The term "thiocyclopropyl" as used herein includes thiocyclopropyl-2-yl. The term "azircyclobutyl" as used herein includes azircyclobutyl-1-yl, azircyclobutyl-2-yl, and azircyclobutyl-3-yl. As used herein, the term "oxetane-butyl" includes oxetane-2-yl and oxetane-3-yl. As used herein, the term "thioheterobutyl" includes thioheterobutyl-2-yl and thioheterobutyl-3-yl. As used herein, the term "pyrrolyl" includes pyrrolidine-1-yl, pyrrolidine-2-yl, and pyrrolidine-3-yl. As used herein, the term "tetrahydrofuranyl" includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. As used herein, the term "tetrahydrothiophenyl" includes tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl. As used herein, the term "succinimide" includes succinimide-1-yl and succinimide-3-yl. As used herein, the term "dihydropyrrole" includes 2,3-dihydropyrrole-1-yl, 2,3-dihydro-1H-pyrrole-2-yl, 2,3-dihydro-1H-pyrrole-3-yl, 2,5-dihydropyrrole-1-yl, 2,5-dihydro-1H-pyrrole-3-yl, and 2,5-dihydropyrrole-5-yl.As used herein, the term "2H-pyrrole" includes 2H-pyrrole-2-yl, 2H-pyrrole-3-yl, 2H-pyrrole-4-yl, and 2H-pyrrole-5-yl. As used herein, the term "3H-pyrrole" includes 3H-pyrrole-2-yl, 3H-pyrrole-3-yl, 3H-pyrrole-4-yl, and 3H-pyrrole-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 "dihydrothiophene" includes 2,3-dihydrothiophene-2-yl, 2,3-dihydrothiophene-3-yl, 2,3-dihydrothiophene-4-yl, 2,3-dihydrothiophene-5-yl, 2,5-dihydrothiophene-2-yl, 2,5-dihydrothiophene-3-yl, 2,5-dihydrothiophene-4-yl, and 2,5-dihydrothiophene-5-yl. As used herein, the term "imidazolidinyl" includes imidazolin-1-yl, imidazolin-2-yl, and imidazolin-4-yl. As used herein, the term "pyrazolylyl" includes pyrazollin-1-yl, pyrazollin-3-yl, and pyrazollin-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 "dioxolaneyl" (also known as "1,3-dioxolaneyl") includes dioxolane-2-yl, dioxolane-4-yl, and dioxolane-5-yl. As used herein, the term "dioxacyclopentenyl" (also known as "1,3-dioxacyclopentenyl") includes dioxacyclopenten-2-yl, dioxacyclopenten-4-yl, and dioxacyclopenten-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 "isooxazolidinyl" 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 "thiazolinyl" includes thiazolinyl-2-yl, thiazolinyl-3-yl, thiazolinyl-4-yl, and thiazolinyl-5-yl. As used herein, the term "isothiazolinyl" includes isothiazolyl-2-yl, isothiazolyl-3-yl, isothiazolyl-4-yl, and isothiazolyl-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 piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl. As used herein, the term "dihydropyridyl" 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 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 "tetrahydropyridyl" includes 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6- Tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, and 2,3,4,5-tetrahydropyridin-6-yl. The term "tetrahydropyranyl" (also known as "oxalyl" or "tetrahydro-2H-pyranyl") as used herein 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-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl, and 3,6-dihydro-2H-pyran-6-yl. 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. Similarly, 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 "dioxane" includes 1,2-dioxane-3-yl, 1,2-dioxane-4-yl, 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, 1,3-dioxane-5-yl, and 1,4-dioxane-2-yl. As used herein, the term "dithiaalkyl" includes 1,2-dithiaalkyl-3-yl, 1,2-dithiaalkyl-4-yl, 1,3-dithiaalkyl-2-yl, 1,3-dithiaalkyl-4-yl, 1,3-dithiaalkyl-5-yl, and 1,4-dithiaalkyl-2-yl. As used herein, the term "oxothiacyclohexyl" includes oxothiacyclohexyl-2-yl and oxothiacyclohexyl-3-yl. As used herein, the term "trioxyl" includes 1,2,3-trioxane-4-yl, 1,2,3-trioxane-5-yl, 1,2,4-trioxane-3-yl, 1,2,4-trioxane-5-yl, 1,2,4-trioxane-6-yl, and 1,3,4-trioxane-2-yl. As used herein, the term "azhecyclic heptyl" includes azhecyclic hept-1-yl, azhecyclic hept-2-yl, azhecyclic hept-3-yl, and azhecyclic hept-4-yl. As used herein, the term "homoperazinyl" includes hooperazin-1-yl, hooperazin-2-yl, hooperazin-3-yl, and hooperazin-4-yl. As used herein, the term "indolineyl" includes indoline-1-yl, indoline-2-yl, indoline-3-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, and indoline-7-yl. As used herein, the term "quinazinyl" includes quinazin-1-yl, quinazin-2-yl, quinazin-3-yl, and quinazin-4-yl. As used herein, the term "isoindoline" includes isoindoline-1-yl, isoindoline-2-yl, isoindoline-3-yl, isoindoline-4-yl, isoindoline-5-yl, isoindoline-6-yl, and isoindoline-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 "quinazinyl" includes quinazin-1-yl, quinazin-2-yl, quinazin-3-yl, and quinazin-4-yl. As used herein, the term "quinazinyl" includes quinazin-1-yl, quinazin-2-yl, quinazin-3-yl, and quinazin-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 "tetrahydroisoquinoline" includes tetrahydroisoquinoline-1-yl, tetrahydroisoquinoline-2-yl, tetrahydroisoquinoline-3-yl, tetrahydroisoquinoline-4-yl, tetrahydroisoquinoline-5-yl, tetrahydroisoquinoline-6-yl, tetrahydroisoquinoline-7-yl, and tetrahydroisoquinoline-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-pyrrolizine" includes 1H-pyrrolizine-1-yl, 1H-pyrrolizine-2-yl, 1H-pyrrolizine-3-yl, 1H-pyrrolizine-5-yl, 1H-pyrrolizine-6-yl, and 1H-pyrrolizine-7-yl. As used herein, the term "3H-pyrrolizine" includes 3H-pyrrolizine-1-yl, 3H-pyrrolizine-2-yl, 3H-pyrrolizine-3-yl, 3H-pyrrolizine-5-yl, 3H-pyrrolizine-6-yl, and 3H-pyrrolizine-7-yl.

[0069] The term "heteroaryl" refers to an aromatic ring system containing 5 to 18 atoms of at least one N, O, S, or P, comprising one or two rings, wherein the one or two rings may be fused together or covalently linked, and each ring typically contains 5 to 6 atoms; at least one of the rings is aromatic, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatomium may optionally be quaternized, and wherein at least one carbon atom of the heteroaryl group may be oxidized to form at least one C=O. A system of heteroaryl rings fused with cycloalkyl, cycloalkenyl, or cycloalkynyl rings is considered a heteroaryl, regardless of the ring bonded to the core structure. A system of heteroaryl rings fused with heterocycles is considered a heteroaryl, regardless of the ring bonded to the core structure. A system of heteroaryl rings fused with aryl rings is considered a heteroaryl, regardless of the ring bonded to the core structure. Non-limiting examples of such heteroaryl groups include: triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrroleyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxtriazolyl, thiatriazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxazinyl, thiazolyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3, [2-b]thiophene, thiopheno[2,3-d][1,3]thiazolyl, thiopheno[2,3-d]imidazolyl, tetrazo[1,5-a]pyridyl, indole, indazinyl, isoindole, benzofuranyl, isobenzofuranyl, benzothiophene, isobenzothiophene, indazole, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzoisoxazolyl, 2,1-benzoisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-Benzoxadiazolyl, 2,1,3-Benzoxadiazolyl, 1,2,3-Benzothiadiazolyl, 2,1,3-Benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridyl, purinyl, imidazo[1,2-a]pyridyl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridazin-1(2H)-yl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridazin-1(2H)-yl, 1,3-benzyl The heteroaryl group is selected from the group consisting of pyridyl, pyrazinyl, isoquinolinyl, cenolinyl, quinazolinyl, and quinoxalinyl; in some embodiments, the heteroaryl group is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, isoxazolyl, thiopheneyl, imidazoleyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furanyl, thiopheneyl, triazolyl, and thiazolyl; in some embodiments, the heteroaryl group is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, indolyl, and benzimidazolyl.

[0070] As used herein, the term "pyrroleyl" (also known as azole) includes pyrrole-1-yl, pyrrole-2-yl, and pyrrole-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 imidazo-1-yl, imidazo-2-yl, imidazo-4-yl, and imidazo-5-yl. As used herein, the term "oxazolyl" (also known as 1,3-oxazolyl) includes oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl. As used herein, the term "isoxazolyl" (also known as 1,2-oxazolyl) includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. As used herein, the term "thiazolyl" (also known as 1,3-thiazolyl) includes thiazolyl-2-yl, thiazolyl-4-yl, and thiazolyl-5-yl (also known as 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). As used herein, the term "isothiazolyl" (also known as 1,2-thiazolyl) includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. As used herein, the term "triazolyl" includes triazol-2-yl, 1H-triazolyl, and 4H-1,2,4-triazolyl; "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; and "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 "oxadiazole-4-yl" includes 1,2,3-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl, 1,2,5-oxadiazole-3-yl, and 1,3,4-oxadiazole-2-yl. As used herein, the term "thiadiazole-4-yl" includes 1,2,3-thiadiazole-4-yl, 1,2,3-thiadiazole-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,5-thiadiazole-3-yl (also known as furazan-3-yl), and 1,3,4-thiadiazole-2-yl.As used herein, the term "tetrazolyl" includes 1H-tetrazolyl-1-yl, 1H-tetrazolyl-5-yl, 2H-tetrazolyl-2-yl, and 2H-tetrazolyl-5-yl. As used herein, the term "oxarizolyl" includes 1,2,3,4-oxarizolyl-5-yl and 1,2,3,5-oxarizolyl-4-yl. As used herein, the term "thiatrizolyl" includes 1,2,3,4-thiatrizolyl-5-yl and 1,2,3,5-thiatrizolyl-4-yl. As used herein, the term "pyridinyl" (also known as "pyridyl") includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also known as 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl). As used herein, the term "pyrimidinyl" includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-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 known as "1,4-oxazinyl") includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl. As used herein, the term "dioxacyclohexenyl" (also known as "1,4-dioxacyclohexenyl") includes 1,4-dioxacyclohexen-2-yl and 1,4-dioxacyclohexen-3-yl. As used herein, the term "thiazinyl" (also known 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]thiazolyl-2-yl, imidazo[2,1-b][1,3]thiazolyl-3-yl, imidazo[2,1-b][1,3]thiazolyl-5-yl, and imidazo[2,1-b][1,3]thiazolyl-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]thienoyl" includes thieno[3,2-b]thieno-2-yl, thieno[3,2-b]thieno-3-yl, thieno[3,2-b]thieno-5-yl, and thieno[3,2-b]thieno-6-yl.As used herein, the term "thieno[2,3-d][1,3]thiazolyl" includes thieno[2,3-d][1,3]thiazolyl-2-yl, thieno[2,3-d][1,3]thiazolyl-5-yl, and thieno[2,3-d][1,3]thiazolyl-6-yl. As used herein, the term "thieno[2,3-d]imidazolyl" includes thieno[2,3-d]imidazolyl-2-yl, thieno[2,3-d]imidazolyl-4-yl, and thieno[2,3-d]imidazolyl-5-yl. As used herein, the term "tetrazo[1,5-a]pyridyl" includes tetrazo[1,5-a]pyridyl-5-yl, tetrazo[1,5-a]pyridyl-6-yl, tetrazo[1,5-a]pyridyl-7-yl, and tetrazo[1,5-a]pyridyl-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 "inazinyl" includes inazin-1-yl, inazin-2-yl, inazin-3-yl, inazin-5-yl, inazin-6-yl, inazin-7-yl, and inazin-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 known as 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 known as 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 "benzothiophene" (also known as benzo[b]thiophene) includes 2-benzo[b]thiophene, 3-benzo[b]thiophene, 4-benzo[b]thiophene, 5-benzo[b]thiophene, 6-benzo[b]thiophene, and -7-benzo[b]thiophene (also known as benzothiophene-2-yl, benzothiophene-3-yl, benzothiophene-4-yl, benzothiophene-5-yl, benzothiophene-6-yl, and benzothiophene-7-yl). As used herein, the term "isobenzothiophene" (also known as benzo[c]thiophene) includes isobenzothiophene-1-yl, isobenzothiophene-3-yl, isobenzothiophene-4-yl, isobenzothiophene-5-yl, isobenzothiophene-6-yl, and isobenzothiophene-7-yl.As used herein, the term "indazole" (also known as 1H-indazole or 2-azaindole) includes 1H-indazole-1-yl, 1H-indazole-3-yl, 1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, 1H-indazole-7-yl, 2H-indazole-2-yl, 2H-indazole-3-yl, 2H-indazole-4-yl, 2H-indazole-5-yl, 2H-indazole-6-yl, and 2H-indazole-7-yl. As used herein, the term "benzimidazole" includes benzimidazole-1-yl, benzimidazole-2-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, and benzimidazole-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. Similarly, as used herein, the term "1,2-benzoisoxazolyl" includes 1,2-benzoisoxazol-3-yl, 1,2-benzoisoxazol-4-yl, 1,2-benzoisoxazol-5-yl, 1,2-benzoisoxazol-6-yl, and 1,2-benzoisoxazol-7-yl. 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. Similarly, 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. As used herein, the term "2,1-benzisothiazolyl" includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl, and 2,1-benzisothiazol-7-yl. As used herein, the term "benzotriazoleyl" includes benzotriazole-1-yl, benzotriazole-4-yl, benzotriazole-5-yl, benzotriazole-6-yl, and benzotriazole-7-yl. As used herein, the term "1,2,3-benzoxadiazole" includes 1,2,3-benzoxadiazole-4-yl, 1,2,3-benzoxadiazole-5-yl, 1,2,3-benzoxadiazole-6-yl, and 1,2,3-benzoxadiazole-7-yl.As used herein, the term "2,1,3-benzoxadiazole" includes 2,1,3-benzoxadiazole-4-yl, 2,1,3-benzoxadiazole-5-yl, 2,1,3-benzoxadiazole-6-yl, and 2,1,3-benzoxadiazole-7-yl. Similarly, as used herein, the term "1,2,3-benzothiadiazole" includes 1,2,3-benzothiadiazole-4-yl, 1,2,3-benzothiadiazole-5-yl, 1,2,3-benzothiadiazole-6-yl, and 1,2,3-benzothiadiazole-7-yl. As used herein, the term "2,1,3-benzothiadiazole" includes 2,1,3-benzothiadiazole-4-yl, 2,1,3-benzothiadiazole-5-yl, 2,1,3-benzothiadiazole-6-yl, and 2,1,3-benzothiadiazole-7-yl. As used herein, the term "thienopyridyl" includes thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, and thieno[3,2-b]pyridyl. 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]pyridyl" 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-benzodioxacyclopentenyl" includes 1,3-benzodioxacyclopenten-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, and 1,3-benzodioxacyclopenten-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. The term "isoquinolinyl" as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl. The term "ciolinyl" as used herein includes ciolin-3-yl, ciolin-4-yl, ciolin-5-yl, ciolin-6-yl, ciolin-7-yl, and ciolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl. As used herein, the term "quinoxalinyl" includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0071] As used herein, heteroaryl and heterocyclic or heterocyclic groups include (for example, but not limited to) the groups described below: Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (WABenjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley and Sons, New York, 1950 to present), specifically 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.

[0072] The term "heterocyclic oxy group" or "heterocyclic oxy group" as a group or part of a group refers to a group having the formula -OR i The group, wherein R i It is a heterocyclic group as defined above.

[0073] The terms "heterocyclic alkyloxy" or "heterocyclic alkoxy" as a group or part of a group refer to a group having the formula -OR a -R i The group, wherein R i It is a heterocyclic group as defined above, and R a It is an alkyl group as defined above.

[0074] The term "heteroaryloxy" as a group or part of a group refers to a group having the formula -OR k The group, wherein R k It is a heteroaryl group as defined above.

[0075] The term "heteroarylalkyloxy" as a group or part of a group refers to a group having the formula -OR a -R i The group, wherein R i It is a heteroaryl group as defined above, and R a It is an alkyl group as defined above.

[0076] The term "heterocyclic-alkyl" or "heterocyclic-alkyl" as a group or part of a group refers to an alkyl group in which a hydrogen atom bonded to a carbon atom (usually a terminal or sp3 carbon atom) is replaced by a heterocyclic group. A non-limiting example of a heterocyclic-alkyl or heterocyclic-alkyl group is 2-piperidinyl-methylene. A heterocyclic-alkyl or heterocyclic-alkyl group may contain 6 to 20 atoms, for example, the alkyl moiety may be 1 to 6 carbon atoms and the heterocyclic moiety may be 3 to 14 atoms.

[0077] The term "heterocyclic-alkenyl" or "heterocyclic-alkenyl" as a group or part of a group refers to an alkenyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heterocyclic group. Heterocyclic-alkenyl or heterocyclic-alkenyl groups can contain 6 to 20 atoms, for example, the alkenyl portion has 2 to 6 carbon atoms and the heterocyclic portion has 3 to 14 atoms.

[0078] The term "heterocyclic-ynyl" or "heterocyclic-ynyl" as a group or part of a group refers to an ynyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heterocyclic group. Heterocyclic-ynyl or heterocyclic-ynyl can contain 6 to 20 atoms; for example, the ynyl moiety can contain 2 to 6 carbon atoms and the heterocyclic moiety can contain 3 to 14 atoms.

[0079] The term "heterocyclic-heteroalkyl" or "heterocyclic-heteroalkyl" as a group or part of a group refers to a heteroalkyl group in which a hydrogen atom bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by a heterocyclic group. A heterocyclic-heteroalkyl or heterocyclic-heteroalkyl group may contain 6 to 20 atoms; for example, the heteroalkyl moiety may contain 1 to 6 carbon atoms and the heterocyclic moiety may contain 3 to 14 atoms. In some embodiments, the heterocyclic-heteroalkyl or heterocyclic-heteroalkyl group is selected from the group consisting of: heterocyclic-O-alkyl, heterocyclic-alkyl-O-alkyl, heterocyclic-NH-alkyl, heterocyclic-N(alkyl)2, heterocyclic-alkyl-NH-alkyl, heterocyclic-alkyl-N-(alkyl)2, heterocyclic-S-alkyl, and heterocyclic-alkyl-S-alkyl.

[0080] The term "heterocyclic-heterenyl" or "heterocyclic-heterenyl" as a group or part of a group refers to a heteroalkene group in which one hydrogen atom bonded to a carbon atom is replaced by a heterocyclic group. A heterocyclic-heterenyl or heterocyclic-heterenyl group may contain 6 to 20 atoms; for example, the heteroalkene moiety may contain 2 to 6 carbon atoms and the heterocyclic moiety may contain 3 to 14 atoms. In some embodiments, the heterocyclic-heterenyl or heterocyclic-heterenyl group is selected from the group consisting of: heterocyclic-O-alkenyl, heterocyclic alkyl-O-alkenyl, heterocyclic-NH-alkenyl, heterocyclic-N(alkenyl)2, heterocyclic alkyl-NH-alkenyl, heterocyclic alkyl-N-(alkenyl)2, heterocyclic-S-alkenyl, and heterocyclic alkenyl-S-alkenyl.

[0081] The term "heterocyclic-heteroyne" or "heterocyclic-heteroyne" as a group or part of a group refers to a heteroynyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heterocyclic group. A heterocyclic-heteroyne or heterocyclic-heteroyne may contain 6 to 20 atoms; for example, the heteroyne moiety may contain 2 to 6 carbon atoms and the heterocyclic moiety may contain 3 to 14 atoms. In some embodiments, the heterocyclic-heteroyne is selected from the group consisting of: heterocyclic-O-ynyl, heterocyclic-ynyl-O-ynyl, heterocyclic-NH-ynyl, heterocyclic-N(ynyl)2, heterocyclic-ynyl-NH-ynyl, heterocyclic-ynyl-N-(ynyl)2, heterocyclic-S-ynyl, and heterocyclic-ynyl-S-ynyl.

[0082] The term "heteroaryl-alkyl" as a group or part of a group refers to an alkyl group in which a hydrogen atom bonded to a carbon atom (usually a terminal or sp3 carbon atom) is replaced by a heteroaryl group. An example of a heteroaryl-alkyl group is 2-pyridyl-methylene. Heteroaryl-alkyl groups can contain 6 to 20 atoms; for example, the alkyl portion of a heteroaryl-alkyl group can contain 1 to 6 carbon atoms and the heteroaryl portion can contain 5 to 14 atoms.

[0083] The term "heteroaryl-alkenyl" as a group or part of a group refers to an alkenyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. Heteroaryl-alkenyl groups can contain 6 to 20 atoms; for example, the alkenyl portion of a heteroaryl-alkenyl group can contain 2 to 6 carbon atoms and the heteroaryl portion can contain 5 to 14 atoms.

[0084] As used herein, the term "heteroaryl-ynyl" as a group or part of a group refers to an ynyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. A heteroaryl-ynyl group contains 6 to 20 atoms; for example, the ynyl portion of a heteroaryl-ynyl group has 2 to 6 carbon atoms and the heteroaryl portion has 5 to 14 atoms.

[0085] As used herein, the term "heteroaryl-heteroalkyl" as a group or part of a group refers to a heteroalkyl group in which a hydrogen atom bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by a heteroaryl group. A heteroaryl-heteroalkyl group comprises 7 to 20 atoms, for example, the heteroalkyl portion of a heteroaryl-heteroalkyl group has 2 to 6 carbon atoms and the heteroaryl portion has 5 to 14 atoms. In some embodiments, the heteroaryl-heteroalkyl group is selected from the group consisting of: heteroaryl-O-alkyl, heteroarylalkyl-O-alkyl, heteroaryl-NH-alkyl, heteroaryl-N(alkyl)2, heteroarylalkyl-NH-alkyl, heteroarylalkyl-N-(alkyl)2, heteroaryl-S-alkyl, and heteroarylalkyl-S-alkyl.

[0086] As used herein, the term "heteroaryl-heterenyl" as a group or part of a group refers to a heteroalkenyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. A heteroaryl-heterenyl group comprises 8 to 20 atoms, for example, the heteroalkenyl portion of a heteroaryl-heterenyl group has 3 to 6 carbon atoms and the heteroaryl portion has 5 to 14 atoms. In some embodiments, the heteroaryl-heterenyl group is selected from the group consisting of: heteroaryl-O-alkenyl, heteroaryl-O-alkenyl, heteroaryl-NH-alkenyl, heteroaryl-N(alkenyl)2, heteroaryl-NH-alkenyl, heteroaryl-N-(alkenyl)2, heteroaryl-S-alkenyl, and heteroaryl-S-alkenyl.

[0087] As used herein, the term "heteroaryl-heterynyl" as a group or part of a group refers to a heteroynyl group in which one hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. A heteroaryl-heterynyl group comprises 8 to 20 atoms, for example, the heteroynyl portion of a heteroaryl-heterynyl group has 2 to 6 carbon atoms and the heteroaryl portion has 5 to 14 atoms. In some embodiments, the heteroaryl-heterynyl group is selected from the group consisting of: heteroaryl-O-ynyl, heteroarylynyl-O-ynyl, heteroaryl-NH-ynyl, heteroaryl-N(ynyl)2, heteroarylynyl-NH-ynyl, heteroarylynyl-N-(ynyl)2, heteroaryl-S-ynyl, and heteroarylynyl-S-ynyl.

[0088] For example, carbon-bonded heterocyclic rings (or heterocycles) can be bonded at positions 2, 3, 4, 5, or 6 of pyridine, positions 3, 4, 5, or 6 of pyridazine, positions 2, 4, 5, or 6 of pyrimidine, positions 2, 3, 5, or 6 of pyrazine, positions 2, 3, 5, or 6 of furan, tetrahydrofuran, thiophene, pyrrole, or tetrahydropyrrole, positions 2, 3, 4, or 5 of oxazole, imidazole, or thiazole, positions 3, 4, or 5 of isoxazole, pyrazole, or isothiazole, positions 2 or 3 of aziridine, positions 2, 3, or 4 of aziridine, positions 2, 3, or 4 of aziridine, positions 2, 3, 4, 5, 6, 7, or 8 of quinoline, or positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline. More generally, the heteroaryl and heterocyclic groups of the carbon-bonded group 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. For example, the heterocyclic bond of the nitrogen-bonded group is located at position 1 in aziridinium, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrroleline, imidazole, imidazoline, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, and 1H-indazole; position 2 in isoindole or isoindoline; position 4 in morpholine; and position 9 in carbazole or β-carbline. More generally, the heteroaryl or heterocyclic group of the nitrogen-bonded group includes 1-aziridinyl, 1-aziridine, 1-azetedyl, 1-pyrrole, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0089] As used herein and unless otherwise stated, the terms “alkoxy,” “cycloalkoxy,” “aryloxy,” “arylalkyloxy,” “heteroaryloxy,” “heterocyclicoxy,” “alkylthio,” “cycloalkylthio,” “arylthio,” “arylalkylthio,” “heteroarylthio,” and “heterocyclicthio” refer to, respectively, a substituent in which an alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or heterocyclic group (each of which, as defined herein, is attached by a single bond to an oxygen or sulfur atom, such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl, etc. The same definitions will apply to alkenyl and ynyl groups instead of alkyl.

[0090] The term "alkylthio" as a group or part of a group refers to a group having the formula -SR b The group, wherein R bAlkyl groups are defined as above. Non-limiting examples of alkyl thio groups include methyl thio (-SCH3), ethyl thio (-SCH2CH3), n-propyl thio, isopropyl thio, n-butyl thio, isobutyl thio, sec-butyl thio, tert-butyl thio, etc.

[0091] The term "alkene thio" as a group or part of a group refers to a group having the formula -SR d The group, wherein R d It is an alkenyl group as defined above.

[0092] The term "alkynylthio" as a group or part of a group refers to a group having the formula -SR e The group, wherein R e It is an alkynyl group as defined above.

[0093] The term "arylthio" as a group or part of a group refers to a group having the formula -SR g The group, wherein R g It is an aryl group as defined above.

[0094] The term "arylalkylthio" as a group or part of a group refers to a group having the formula -SR a -R g The group, wherein R a It is an alkylene group as defined above and R g It is an aryl group as defined above.

[0095] The term "heterocyclic thio" as a group or part of a group refers to a group having the formula -SR i The group, wherein R i It is a heterocyclic group as defined above.

[0096] The term "heteroarylthio" as a group or part of a group refers to a group having the formula -SR k The group, wherein R k It is a heteroaryl group as defined above.

[0097] The term "heterocyclic alkyl thio" as a group or part of a group refers to a group having the formula -SR a -R i The group, wherein R a It is an alkylene group as defined above and R i It is a heterocyclic group as defined above.

[0098] The term "heteroarylalkylthio" as a group or part of a group refers to a group having the formula -SR a -R k The group, wherein R a It is an alkylene group as defined above and R kIt is a heteroaryl group as defined above.

[0099] The term "monoalkylamino or dialkylamino" as a group or part of a group refers to the formula -N(R o (R) b ) groups, wherein R o R is hydrogen or alkyl. b The alkyl group is alkyl. Therefore, alkylamino groups include 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 monoalkylamino or dialkylamino groups include... just Propylamino, isopropylamino just Butylamino, different Butylamino, Zhong Butylamino, Uncle Butylamino, Pentylamino, just Hexylamino, di just Propylamino, di different propylamino, ethylmethylamino, methyl- just propylamino, methyl- different propylamino, just Butylmethylamino, different Butylmethylamino, Uncle Butylmethylamino, ethyl- just propylamino, ethyl- different propylamino, just Butylethylamino, isobutylethylamino, Uncle Butylethylamino, di just Butylamino, di different Butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, etc.

[0100] The term "monoarylamino or diarylamino" as a group or part of a group refers to the formula -N(R q (R) r ) groups, wherein R q and R r Each is independently selected from hydrogen, aryl, or alkyl, wherein R q Or R r At least one of them is aryl.

[0101] The term "monoarylene or diarylene" as a group or part of a group refers to the formula -N(R u (R) v ) groups, wherein R u and R v Each is independently selected from hydrogen, heteroaryl, or alkyl, wherein Ru Or R v At least one of them is a heteroaryl group as defined herein.

[0102] The term "mono-heterocyclic amino or di-heterocyclic amino" as a group or part of a group refers to the formula -N(R w (R) x ) groups, wherein R w and R x Each is independently selected from hydrogen, heterocyclic or alkyl, wherein R w Or R x At least one of them is a heterocyclic group as defined in this paper.

[0103] As used herein and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0104] As used herein, the term "chemical group that optionally comprises one or more heteroatoms selected from atoms composed of O, S, and N" refers to a group in which one or more carbon atoms are replaced by oxygen, nitrogen, or sulfur atoms, and therefore, depending on the group mentioned, includes in particular heteroalkyl, heteroalkenyl, heteroynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, arylheteroynyl, heteroarylynyl, heteroarylheteroynyl. Thus, depending on the group mentioned, this term particularly includes alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-heteroalkyl, heterocyclic-heteroalkyl, heteroaryl-alkoxy, and heterocyclic-alkoxy as examples. Therefore, as an example, the term "alkyl group optionally comprising one or more heteroatoms selected from atoms composed of O, S, and N" refers to a heteroalkyl group, meaning an alkyl group containing one or more heteroatoms in a hydrocarbon chain, where the heteroatoms can be located at the beginning, middle, or end of the hydrocarbon chain. Examples of heteroalkyl groups 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-, and many other examples. Therefore, as an example, the term "arylalkylene group optionally comprising one or more heteroatoms in an alkylene chain, where the heteroatoms are selected from atoms composed of O, S, and N" refers to an arylhexanealkylene group, meaning an arylalkylene group containing one or more heteroatoms in a hydrocarbon chain, where the heteroatoms can be located at the beginning, middle, or end of the hydrocarbon chain. Therefore, "arylhexenealkylene" includes aryloxy, arylalkoxy, aryl-alkyl-NH-, etc., and examples include phenyloxy, benzyloxy, aryl-CH2-S-CH2-, aryl-CH2-O-CH2-, aryl-NH-CH2-, and many other examples. The same applies to the terms "hexaenealkylene," "hexaynylenealkylene," and other terms used herein when referring to "optionally containing one or more heteroatoms selected from atoms composed of O, S, and N."

[0105] As used herein, the term "wherein two or more hydrogen atoms on the carbon atom or heteroatom of the group optionally form =O or =S" refers to a group in which two or more hydrogen atoms on the carbon atom or heteroatom of the group optionally form =O or =S. As an example, the term refers to "alkyl group, wherein two or more hydrogen atoms on the carbon atom or heteroatom of the alkyl group optionally form =O or =S", including other examples such as CH3-C(O)-CH2-, CH3-C(O)-, CH3-C(S)-CH2-, CH3-S(O)2-CH2-, and (CH3)2-CH2-C(O)-CH2-CH2-.

[0106] The combination of a group that "optionally contains one or more heteroatoms selected from atoms composed of O, S, and N" and "wherein two or more hydrogen atoms on the carbon atom or heteroatom of the group can together form =O or =S" can combine the two aspects described above, and if the group mentioned is an alkyl group, it includes other examples such as 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-.

[0107] The term “single bond” used herein for linking groups (i.e., in this text, some linking groups are selected from single bonds, etc.) refers to a molecule in which no linking group exists, and therefore refers to a compound in which there is a direct link between two parts connected by a linking group via a single bond.

[0108] As used herein with respect to substituents, and unless otherwise stated, the term "substituted" in the likenesses of "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted aryl", "substituted heteroaryl", "substituted heterocyclic", "substituted arylalkyl", "substituted heteroaryl-alkyl", "substituted heterocyclic-alkyl", etc., means a chemical structure as defined herein, and wherein the alkyl, alkenyl, alkynyl and / or the aryl, heteroaryl or heterocyclic group may optionally be substituted by one or more (preferably 1, 2, 3, 4, 5 or 6) substituents, which means that one or more hydrogen atoms are each independently substituted by at least one substituent. Typical substituents include, but are not limited to, and in specific embodiments, the substituents are independently selected from the group consisting of: halogen, amino, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclic, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl-alkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl-alkyl, heterocyclic-alkyl, heteroaryl-alkenyl, heterocyclic-alkenyl and heteroaryl-alkynyl, heterocyclic-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, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, aryl, heteroaryl, heterocyclic, cycloalkyl, protecting group or prodrug moiety, and the two Zs bonded to the nitrogen atom may together with the nitrogen atom to which they are bonded to form a heteroaryl or heterocyclic group. ()alkylene, ()alkenyl and ()ynylene may also be similarly substituted.

[0109] The name of any substituent found at one or more sites in the compounds disclosed herein should be chosen independently.

[0110] Substituents may be named with or without a bond. Regardless of the bond indication, if the substituent is multivalent (based on its position in the mentioned structure), any and all possible orientations of the substituent are expected.

[0111] As used herein and unless otherwise stated, the term "solvent" includes any combination that can be formed from derivatives of this disclosure with suitable inorganic solvents (e.g., hydrates) or organic solvents (such as, but not limited to, alcohols, ketones, esters, ethers, nitriles, etc.).

[0112] As used herein, the term "heteroatom" refers to an atom selected from the following: nitrogen that can be quaternized; oxygen; and sulfur (including sulfoxide and sulfone).

[0113] As used in this article, the term "hydroxyl" refers to -OH.

[0114] As used in this article, the term "carbonyl" refers to a carbon atom bonded to oxygen via a double bond, i.e., C=O.

[0115] As used in this article, the term "amino" refers to the -NH2 group.

[0116] This disclosure provides novel compounds that have been shown to possess YAP / TAZ-TEAD transcriptional repressive activity. This disclosure further demonstrates that these compounds effectively inhibit TEAD activation and thereby inhibit YAP / TAZ-TEAD transcriptional activation. Therefore, these compounds constitute a useful new class of potent compounds that can be used to treat and / or prevent YAP / TAZ-TEAD activation-mediated diseases in subjects, and more specifically for the treatment and / or prevention of other diseases such as cancer and fibrosis.

[0117] This disclosure further relates to compounds used as pharmaceuticals and their use in the manufacture of pharmaceuticals for the treatment and / or prevention of cancer or fibrosis. This disclosure relates to compounds used as pharmaceuticals for the treatment and / or prevention of YAP / TAZ-TEAD activation-mediated diseases (such as cancer or fibrosis) in animals, mammals, and more specifically humans. This disclosure also relates to methods for preparing all such compounds and pharmaceutical compositions comprising an effective amount of said compounds. This disclosure also relates to methods for treating or preventing cancer or fibrosis in humans by administering one or more of these compounds (optionally in combination with one or more other pharmaceuticals) to a patient in need. This disclosure also relates to compounds for veterinary use and their use as pharmaceuticals for the prevention or treatment of diseases in non-human mammals (such as cancer and fibrosis in non-human mammals).

[0118] In one embodiment, this disclosure provides a compound of formula I: I, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Z is chosen freely = N-, = N + The group consisting of - and =C-; Q 1 =N- or =CX 1 -; Q 2 =N- or =CX 2 -; Q 3 =N- or =CX 3 -; X 1 X 2 and X 3 Choose independently from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from Z. 1 The group formed (v) C1-C6 haloalkyl, (vi) -OZ 1 ,as well as (vii) -NZ 3 Z 4 ; When Z is equal to C-, R 1 Choose from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) C1-C6 alkyl groups, (v) C1-C6 haloalkyl, (vi) -OZ 1 ,as well as (vii) -NZ 3 Z 4 ; When Z is =N- or =N + - At that time, R 1 -O - Or it may not exist; R 2 Choose from the following groups: (i) Hydrogen, (ii) C1-C6 alkyl groups, (iii) -(CH2) n -R 3a , (iv) -O-(CH2) n -R 3a , (v) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from the group consisting of: i. Hydrogen, ii. Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: 1. Halogen, 2. Hydroxyl group, 3. Cyano group, 4. -OZ 1 , 5. -SZ 1 , 6. -NZ 3 Z 4 , 7. -C(=O)Z 2 8. -C(=O)OH, 9. -C(=O)OZ 2 , 10. -C(=O)NZ 3 Z 4 , 11. -NZ 5 C(=O)Z 2 , 12. -NZ 5 C(=O)OZ 2 , 13. -NZ 5C(=O)NZ 3 Z 4 , 14. -S(=O)2Z 8 , 15. -S(=O)2NZ 3 Z 4 , 16. -S(=O)(=NZ 6 )Z 2 , 17. -S(=Z 6 )(=NZ 7 )Z 2 , 18. -S(=O)(=NZ 6 )NZ 3 Z 4 , 19. -NZ 5 S(=O)2Z 2 , 20. -NZ 5 S(=O)2NZ 3 Z 4 , 21. -NZ 5 S(=O)(=NZ 6 )Z 2 , 22. -NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and 23. -NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , iii. -C(=O)Z 2 iv. -C(=O)OZ 2 , v. -C(=O)NZ 3 Z 4 , vi. -S(=O)2Z 8 , vii. -S(=O)2NZ 3 Z 4 , viii. -S(=O)(=NZ 6 )Z 2 , ix. -S(=Z6 (=NZ) 7 )Z 2 , x. -S(=O)(=NZ 6 NZ 3 Z 4 ,as well as (vi) -(CH2)-NR 3a R 3b ; n is 0 or 1; R 3a Choose from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) -OZ 1 , (d) -SZ 1 , (e) -NZ 3 Z 4 , (f) -C(=O)Z 2 (g)-C(=O)OH, (h) -C(=O)OZ 2 , (i) -C(=O)NZ 3 Z 4 , (j) -NZ 5 C(=O)Z 2 , (k) -NZ 5 C(=O)OZ 2 , (l) -NZ 5 C(=O)NZ 3 Z 4 , (m) -S(=O)2Z 8 , (n) -S(=O)2NZ 3 Z 4 , (o) -S(=O)(=NZ 6 )Z 2 , (p) -S(=Z 6 (=NZ) 7 )Z2 , (q) -S(=O)(=NZ 6 NZ 3 Z 4 , (r) -NZ 5 S(=O)2Z 2 , (s) -NZ 5 S(=O)2NZ 3 Z 4 , (t) -NZ 5 S(=O)(=NZ 6 )Z 2 , (u) -NZ 5 S(=NZ 6 (=NZ) 7 )Z 2 ,as well as (v) -NZ 5 S(=O)(=NZ 6 NZ 3 Z 4 , (iii) -C(=O)Z 2 , (iv) -C(=O)OZ 2 , (v) -C(=O)NZ 3 Z 4 , (vi) -S(=O)2Z 8 , (vii) -S(=O)2NZ 3 Z 4 , (viii) -S(=O)(=NZ 6 )Z 2 , (ix) -S(=Z 6 (=NZ) 7 )Z 2 , (x) -S(=O)(=NZ 6 NZ 3 Z 4 ,as well as (xi) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, C2-C8 alkenyl and C1-C6 alkyl, and zero or more heterocyclic carbons may be oxidized to form C=O; R 3bSelect from the group consisting of hydrogen and C1-C6 alkyl groups; R 4 Choose from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C6-C 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano group (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6) -OZ 1 , (7) C2-C6 alkenyl groups, and (8) C2-C6 ynyl group, (b) Unsubstituted or substituted C3-C6 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano group (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl groups, and (6) -OZ 1 , (c) C2-C6 alkynyl group, and (d) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein zero or more heterocyclic carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, C2-C8 alkenyl groups, and C1-C6 alkyl groups. (ii) Unsubstituted or substituted C6-C 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 The group formed (iii) Unsubstituted or substituted 5- to 9-membered heteroaryl groups, wherein zero or more heteroaryl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 The group formed (iv) Unsubstituted or substituted C3-C6 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, and (f) -OZ 1 , (v) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein zero or more heterocyclic carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, and (f) -OZ 1 , (vi) -S(=O)2Z 2 ,as well as (vii) -C(=O)Z 2 ; Each Z 1 Choose independently from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: a. Cyano group, b. -S(=O)2Z 8 , c. C3-C8 cycloalkyl groups, d. -C(=O)OH, e. -S(=O)2Z 8 , f. -NZ 3 Z 4 , g. Halogens, h. An unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heterocyclic carbons can be oxidized to form C=O. i. Unsubstituted or substituted 3- to 9-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and j. Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and cyano groups. (iii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from the group consisting of: a. Cyano group, b. -S(=O)2Z 8 , c. Halogens, and d. Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: i. Cyano group ii. -S(=O)2Z 8 , iii. C3-C8 cycloalkyl, iv. -C(=O)OH, v. -S(=O)2Z 8 , vi. -NZ 3 Z 4 , vii. Halogen, viii. An unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O. ix. Unsubstituted or substituted 3- to 9-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and x. Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 haloalkyl groups, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consisting of unsubstituted or substituted 3- to 8-membered heterocycles, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O. (iv) C2-C6 ynyl group (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl (vii) Unsubstituted or substituted C3-C8 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from halogens, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (viii) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of halogens, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (ix) Unsubstituted or substituted 3- to 8-membered heteroaryl groups, wherein zero or more heteroaryl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups. (x) Unsubstituted or substituted 3- to 8-membered heterocycles, wherein zero or more heterocyclic carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups and C2-C6 alkenyl groups; Each Z 2 Choose independently from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from C2-C6 alkenyl, cyano, -C(=O)OH, -S(=O)2Z 8 Halogen, -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 The group consisting of halogens and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iv) C2-C6 ynyl group (v) C3-C6 cycloalkyl groups, and (vi) C3-C6 cycloalkenyl; Each Z 3 Choose independently from the following groups: (i) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from C2-C6 alkenyl, cyano, -C(=O)OH, -S(=O)2Z 8 Halogen, -N (unsubstituted or substituted C1-C6 alkyl) Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (ii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 The group consisting of halogens and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 -N (unsubstituted or substituted C1-C6 alkyl)Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iii) An unsubstituted or substituted C2-C6 alkynyl group, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 The group consisting of halogens and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from cyano, OZ 1 -S(=O)2Z 8 -N (unsubstituted or substituted C1-C6 alkyl)Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iv) Unsubstituted or substituted C3-C6 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from halogens, cyano groups, and -S(=O)2Z. 8 -N (unsubstituted or substituted C1-C6 alkyl)Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4-N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consisting of 4 to 8-membered heterocycles, wherein zero or more heterocyclic carbons can be oxidized to form C=O, and (v) An unsubstituted or substituted C3-C6 cycloalkenyl group, wherein zero or more cycloalkenyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from halogens, cyano groups, and -S(=O)2Z. 8 -N (unsubstituted or substituted C1-C6 alkyl)Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consisting of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O; Each Z 4 Z 5 Z 6 and Z 7 Choose independently from the following groups: (i) Hydrogen, (ii) C1-C6 alkyl groups, and (iii) C3-C6 cycloalkyl; Each Z 8 Choose independently from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of halogens, cyano groups, and C1-C6 alkyl groups. (iii) An unsubstituted or substituted C2-C6 alkenyl group, wherein one or more substituents are independently selected from the group consisting of a halogen and an unsubstituted or substituted C1-C6 alkyl group, wherein one or more substituents are independently selected from -N(unsubstituted or substituted C1-C6 alkyl)Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iv) Halogens, and (v) Hydroxyl group.

[0119] In another embodiment, this disclosure provides a compound of formula II: II, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Q 1 Q 2 Q 3 X 1 X 2 X 3 R 2 R 3a R 3b R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 and Z 8 As defined in conjunction with Equation I.

[0120] In another embodiment, this disclosure provides a compound of formula II or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0121] In another embodiment, this disclosure provides a compound of formula II or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0122] In another embodiment, this disclosure provides a compound of formula II or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0123] In another embodiment, this disclosure provides a compound of formula III: III Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Q 1 Q 2 Q 3 X 1 X 2 X 3 R 2 R 3a R 3b R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 and Z 8 As defined in conjunction with Equation I.

[0124] In another embodiment, this disclosure provides a compound of formula III or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0125] In another embodiment, this disclosure provides a compound of formula III or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0126] In another embodiment, this disclosure provides a compound of formula III or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0127] In another embodiment, this disclosure provides a compound of formula IV: IV, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: X 1 X 2 X 3 R 2 R 3a R 3b R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 and Z 8 As defined in conjunction with Equation I.

[0128] In another embodiment, this disclosure provides a compound of formula IV or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 X 2 and X 3 Independently selected from the group consisting of -H, -OH, substituted or unsubstituted C1-C6 alkyl groups (e.g., methyl), and -O-methyl. In another embodiment, this disclosure provides a compound of formula IV or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 X2 and X 3 It is independently selected from the group consisting of -H, -OH and -O-methyl.

[0129] In another embodiment, this disclosure provides a compound of formula IV or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0130] In another embodiment, this disclosure provides a compound of formula IV or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0131] In another embodiment, this disclosure provides a compound of formula V: V, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: X 1 X 2 X 3 R 2 R 3a R 3b R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 and Z 8 As defined in conjunction with Equation I.

[0132] In another embodiment, this disclosure provides a compound of formula V or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein X 1 X 2 and X 3 It is independently selected from the group consisting of -H, -OH and -O-methyl.

[0133] In another embodiment, this disclosure provides a compound of formula V or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0134] In another embodiment, this disclosure provides a compound of formula V or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0135] In another embodiment, this disclosure provides a compound of formula VI: VI, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: R 2 R 3a R 3b R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6Z 7 and Z 8 As defined in conjunction with Equation I.

[0136] In another embodiment, this disclosure provides a compound of formula VI or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0137] In another embodiment, this disclosure provides a compound of formula VI or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0138] In another embodiment, this disclosure provides compounds of formula VII: VII, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: R 2 R 3a R 3b R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 and Z 8 As defined in conjunction with Equation I.

[0139] In another embodiment, this disclosure provides a compound of formula VII or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0140] In another embodiment, this disclosure provides a compound of formula VII or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0141] In another embodiment, this disclosure provides a compound of formula VIII: VIII, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Q 1 Q 2 Q 3 X 1 X 2 X 3 R 3a R 4 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 Z 8 As defined in conjunction with Equation I.

[0142] In another embodiment, this disclosure provides a compound of formula VIII or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0143] In another embodiment, this disclosure provides a compound of formula VIII or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0144] In another embodiment, this disclosure provides a compound of formula VIII or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0145] In another embodiment, this disclosure provides a compound of formula IX: IX, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein Q 1 Q 2 Q 3 X 1 X 2 X 3 R 3a R 4 Z 1 Z2 Z 3 Z 4 Z 5 Z 6 Z 7 Z 8 As defined in conjunction with Equation I.

[0146] In another embodiment, this disclosure provides a compound of formula IX or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0147] In another embodiment, this disclosure provides a compound of formula IX or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0148] In another embodiment, this disclosure provides a compound of formula IX or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0149] In another embodiment, this disclosure provides a compound of formula X: X, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Z is chosen freely = N-, = N + The group consisting of - and =C-; X 1 It is selected from the group consisting of -H, -O (C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl (e.g., methyl) and -OH; When Z is =N- or =N + - At that time, R 1 -O - Or it may not exist; When Z is =C-, R 1 For -OR 6 When the C2-C6 alkyl group is either unsubstituted or substituted, one or more of the substituents are independently selected from R. 6 The group formed; R 2 Choose from the following groups: (i) -OR 3 , (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from R 3 The group formed, and (iii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from R 4 The group formed; R 3 Choose from the following groups: (i) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from R 4 The group formed (ii) -C(=O)R 4 ,as well as (iii) -NHR 4 ; R 4 Choose from the following groups: (i) -C(=O)R 5 , (ii) -S(=O)2R 5 , (iii) -OH, and (iv) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O; R 5 Choose from the following groups: (i)-C1-C6 alkyl, (ii) -C2-C6 alkenyl, (iii) -O(C1-C6 alkyl), (iv) -NH-C1-C6 alkyl, (v)-OH, and (vi) Unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more cycloalkyl carbons may be oxidized to form C=O; R 6 The group consisting of unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from R. 7 The group consists of, among which R 7 Choose from the following groups: (i) Unsubstituted or substituted 3- to 6-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and (ii) An unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O.

[0150] In another embodiment, this disclosure provides a compound of formula X or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein X 1 The group selected is free from -H, -OH, substituted or unsubstituted C1-C6 alkyl groups (e.g., methyl), and -O-methyl. In another embodiment, this disclosure provides a compound of formula X or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 Choose from the group consisting of -H, -OH, and -O-methyl.

[0151] In another embodiment, this disclosure provides a compound of formula X or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein Z is =N-.

[0152] In another embodiment, this disclosure provides a compound of formula X or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein Z is =C-.

[0153] In another embodiment, this disclosure provides a compound of formula X or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein R 2 For being an R 3 Substituent-substituted C1 alkyl group, and the one R 3 The substituent is -NHR 4 .

[0154] In another embodiment, this disclosure provides a compound or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof selected from the group consisting of: N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)- or (S)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetic acid; N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)- or (S)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)- or (S)-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthidine 1-oxide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)cyclopropaneformamide; N-(methylaminosulfonyl)-1-[1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,5-naphthid-3-yl]methylamine; (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acrylic acid; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)oxy)acetic acid; and N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)oxetane-3-amine.

[0155] In another embodiment, this disclosure provides a compound or its tautomer, a pharmaceutically acceptable salt or solvate selected from the group consisting of: N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (S)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (S)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; Methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; (R)-methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; (S)-Methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; and (S)-N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0156] In another embodiment, this disclosure provides a compound or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof selected from the group consisting of: N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; N-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthid-3-yl)methyl)acetamide; (2S)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)pyrrolidine-2-carboxamide; (2R)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)pyrrolidine-2-carboxamide; 1-Methyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)-1H-imidazol-5-carboxamide; 1-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)pyrrolidine-2-one; N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)acetamide; N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide-2,2,2-d3; 2-Phenylacetyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidyl-3-yl)methyl)acetamide; N-Acryloyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)glycine; N-acetyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)glycine; 3,3,3-Trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)- or (S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isobutyramide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)benzamide; 1-(4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)prop-2-en-1-one; N-((6-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 1-Methyl-3-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)urea; N-((7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)acetamide; N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((7-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((7-chloro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((1-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; N-((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthid-3-yl)methyl)acetamide; N-((6-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)acetamide; N-((6-cyclopropyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-cyano-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthidine-2-carboxamide; N-((6-(difluoromethoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-(difluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; and N-((6-ethynyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0157] In another embodiment, this disclosure provides a compound or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof selected from the group consisting of: N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; (S)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; 3,3,3-Trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; and (S)-N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0158] In another embodiment, this disclosure provides a compound or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof selected from the group consisting of: N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; and (S)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0159] Preferred or specific statements (features) and embodiments of the compounds disclosed herein are listed below. Unless expressly indicated to the contrary, each statement, aspect, and embodiment of this disclosure as so defined may be combined with any other statement, aspect, and / or embodiment. In particular, any feature indicated as preferred, specific, or advantageous may be combined with any other feature or statement indicated as preferred, specific, or advantageous. Thus, this disclosure is specifically captured by any combination of one or more of the statements and embodiments numbered below with any other statement, aspect, and / or embodiment (unnumbered).

[0160] Implementation Scheme 1: A compound of Formula I: I, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Z is chosen freely = N-, = N + The group consisting of - and =C-; Q 1 =N- or =CX 1 -; Q 2 =N- or =CX 2 -; Q 3 =N- or =CX 3 -; X 1 X 2 and X 3 Choose independently from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) C1-C6 alkyl groups, (v) C1-C6 haloalkyl, (vi) -OZ 1 ,as well as (vii) -NZ 3 Z 4 ; When Z is equal to C-, R 1 Choose from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from Z. 1 The group formed (v) C1-C6 haloalkyl, (vi) -OZ 1 ,as well as (vii) -NZ 3 Z 4 ; When Z is =N- or =N + - At that time, R 1 -O - Or it may not exist; R 2 Choose from the following groups: (i) Hydrogen, (ii) C1-C6 alkyl groups, (iii) -(CH2) n -R 3a , (iv) -O-(CH2) n -R 3a , (v) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from the group consisting of: i. Hydrogen, ii. Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: 1. Halogen, 2. Hydroxyl group, 3. cyanide, 4. -OZ 1 , 5. -NW 1 , 6. -NZ 3 With 4 , 7. -C(=O)Z 2 8. -C(=O)OH, 9. -C(=O)OZ 2 , 10. -C(=O)NZ 3 With 4 , 11. -NZ 5 C(=O)Z 2 , 12. -NZ 5 C(=O)OZ 2 , 13. -NZ 5 C(=O)NZ 3 With 4 , 14. -S(=O)2Z 8 , 15. -S(=O)2NZ 3 With 4 , 16. -S(=O)(=NZ) 6 )Z 2 , 17. -S(=Z 6 )(=NZ 7 )Z 2 , 18. -S(=O)(=NZ) 6 )NZ 3 With 4 , 19. -NZ 5 S(=O)2Z 2 , 20. -NZ 5 S(=O)2NZ 3 With 4 , 21. -NZ 5 S(=O)(=NZ) 6 )Z 2 , 22. -NZ 5 S(=NZ 6 )(=NZ 7 )Z2 ,as well as 23. -NZ 5 S(=O)(=NZ 6 NZ 3 Z 4 , iii. -C(=O)Z 2 iv. -C(=O)OZ 2 , v. -C(=O)NZ 3 Z 4 , vi. -S(=O)2Z 8 , vii. -S(=O)2NZ 3 Z 4 , viii. -S(=O)(=NZ 6 )Z 2 , ix. -S(=Z 6 (=NZ) 7 )Z 2 , x. -S(=O)(=NZ 6 NZ 3 Z 4 ,as well as (vi) -(CH2)-NR 3a R 3b ; n is 0 or 1; R 3a Choose from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) -OZ 1 , (d) -SZ 1 , (e) -NZ 3 Z 4 , (f) -C(=O)Z 2 (g)-C(=O)OH, (h) -C(=O)OZ 2 , (i) -C(=O)NZ3 With 4 , (j) -NZ 5 C(=O)Z 2 , (k) -NZ 5 C(=O)OZ 2 , (l) -NZ 5 C(=O)NZ 3 With 4 , (m) -S(=O)2Z 8 , (n) -S(=O)2NZ 3 With 4 , (o) -S(=O)(=NZ 6 )Z 2 , (p) -S(=Z 6 )(=NZ 7 )Z 2 , (q) -S(=O)(=NZ 6 )NZ 3 With 4 , (r) -NZ 5 S(=O)2Z 2 , (s) -NZ 5 S(=O)2NZ 3 With 4 , (t) -NZ 5 S(=O)(=NZ) 6 )Z 2 , (u) -NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , as well as (in) -NZ 5 S(=O)(=NZ) 6 )NZ 3 With 4 , (iii) -C(=O)Z 2 , (iv) -C(=O)OZ 2 , (v) -C(=O)NZ 3 With 4 , (vi) -S(=O)2Z 8 , (vii) -S(=O)2NZ 3 Z 4 , (viii) -S(=O)(=NZ 6 )Z 2 , (ix) -S(=Z 6 (=NZ) 7 )Z 2 , (x) -S(=O)(=NZ 6 NZ 3 Z 4 ,as well as (xi) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, C2-C8 alkenyl and C1-C6 alkyl, and zero or more heterocyclic carbons may be oxidized to form C=O; R 3b Select from the group consisting of hydrogen and C1-C6 alkyl groups; R 4 Choose from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C6-C 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano group (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6) -OZ 1 , (7) C2-C6 alkenyl groups, and (8) C2-C6 ynyl group, (b) Unsubstituted or substituted C3-C6 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (7) Halogen, (8) Cyano group (9) C1-C6 alkyl, (10) C3-C6 cycloalkyl, (11) C1-C6 haloalkyl groups, and (12) -OZ 1 , (c) C2-C6 alkynyl group, and (d) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein zero or more heterocyclic carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, C2-C8 alkenyl groups, and C1-C6 alkyl groups. (viii) Unsubstituted or substituted C6-C 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 The group formed (ix) Unsubstituted or substituted 5- to 9-membered heteroaryl groups, wherein zero or more heteroaryl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 The group formed (x) Unsubstituted or substituted C3-C6 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, and (f) -OZ 1 , (xi) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein zero or more heterocyclic carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, and (f) -OZ 1 , (xii) -S(=O)2Z 2 ,as well as (xiii) -C(=O)Z 2 ; Each Z 1 Choose independently from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: a. Cyano group, b. -S(=O)2Z 8 , c. C3-C8 cycloalkyl groups, d. -C(=O)OH, e. -S(=O)2Z 8 , f. -NZ 3 Z 4 , g. Halogens, h. An unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heterocyclic carbons can be oxidized to form C=O. i. Unsubstituted or substituted 3- to 9-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and j. Unsubstituted or substituted C6-C10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and cyano groups. (iii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from the group consisting of: a. Cyano group, b. -S(=O)2Z 8 , c. Halogens, and d. Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of: i. Cyano group ii. -S(=O)2Z 8 , iii. C3-C8 cycloalkyl, iv. -C(=O)OH, v. -S(=O)2Z 8 , vi. -NZ 3 Z 4 , vii. Halogen, viii. An unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O. ix. Unsubstituted or substituted 3- to 9-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and x. Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 haloalkyl groups, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consisting of unsubstituted or substituted 3- to 8-membered heterocycles, wherein one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O. (iv) C2-C6 ynyl group (v) C3-C6 cycloalkenyl, (vi) Unsubstituted or substituted C3-C8 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from halogens, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (vii) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of halogens, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (viii) Unsubstituted or substituted 3- to 8-membered heteroaryl groups, wherein zero or more heteroaryl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups, and C2-C6 alkenyl groups. (ix) Unsubstituted or substituted 3- to 8-membered heterocycles, wherein zero or more heterocyclic carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, C1-C6 alkyl groups and C2-C6 alkenyl groups; Each Z 2 Choose independently from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from C2-C6 alkenyl, cyano, -C(=O)OH, -S(=O)2Z 8 Halogen, -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 The group consisting of halogens and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 -NZ 3 Z 4The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iv) C2-C6 ynyl group (v) C3-C6 cycloalkyl groups, and (vi) C3-C6 cycloalkenyl; Each Z 3 Choose independently from the following groups: (i) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from C2-C6 alkenyl, cyano, -C(=O)OH, -S(=O)2Z 8 Halogen, -N (unsubstituted or substituted C1-C6 alkyl) Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (ii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 The group consisting of halogens and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iii) An unsubstituted or substituted C2-C6 alkynyl group, wherein one or more substituents are independently selected from cyano, -S(=O)2Z 8 The group consisting of halogens and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from cyano, OZ 1 -S(=O)2Z 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iv) Unsubstituted or substituted C3-C6 cycloalkyl groups, wherein zero or more cycloalkyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from halogens, cyano groups, and -S(=O)2Z.8 -NZ 3 Z 4 The group consisting of 4 to 8-membered heterocycles, wherein zero or more heterocyclic carbons can be oxidized to form C=O, and (v) An unsubstituted or substituted C3-C6 cycloalkenyl group, wherein zero or more cycloalkenyl carbons may be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from halogens, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consisting of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O; Each Z 4 Z 5 Z 6 and Z 7 Choose independently from the following groups: (i) Hydrogen, (ii) C1-C6 alkyl groups, and (iii) C3-C6 cycloalkyl; Each Z 8 Choose independently from the following groups: (i) Hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of halogens, cyano groups, and C1-C6 alkyl groups. (iii) An unsubstituted or substituted C2-C6 alkenyl group, wherein one or more substituents are independently selected from the group consisting of a halogen and an unsubstituted or substituted C1-C6 alkyl group, wherein one or more substituents are independently selected from -N(unsubstituted or substituted C1-C6 alkyl)Z 4 -N (unsubstituted or substituted C2-C6 alkenyl)Z 4 -N (unsubstituted or substituted C2-C6 ynyl group)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkyl)Z 4 -N (unsubstituted or substituted C3-C6 cycloalkenyl)Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (iv) Halogens, and (v) Hydroxyl group.

[0161] Implementation Scheme 2: The compound as described in Implementation Scheme 1, having Formula II: II, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0162] Implementation Scheme 3: The compound as described in Implementation Scheme 2, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0163] Implementation Scheme 4: The compound as described in Implementation Scheme 2, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0164] Implementation Scheme 5: The compound as described in Implementation Scheme 2, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0165] Implementation Scheme 6: The compound as described in Implementation Scheme 1, having Formula III: III Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0166] Implementation Scheme 7: The compound as described in Implementation Scheme 6, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates, wherein Q 1 Q2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0167] Implementation Scheme 8: The compound as described in Implementation Scheme 6, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0168] Implementation Scheme 9: The compound as described in Implementation Scheme 6, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0169] Implementation Scheme 10: A compound as described in Implementation Scheme 1, having Formula IV: IV, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0170] Implementation Scheme 11: The compound as described in Implementation Scheme 10, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates, wherein X 1 X 2 and X 3 Independently selected from the group consisting of -H, -OH, substituted or unsubstituted C1-C6 alkyl (e.g., methyl) and -O-methyl.

[0171] Implementation Scheme 12: The compound as described in Implementation Scheme 10, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0172] Implementation Scheme 13: The compound as described in Implementation Scheme 10, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0173] Implementation Scheme 14: The compound as described in Implementation Scheme 1, having formula V: V, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0174] Implementation Scheme 15: The compound as described in Implementation Scheme 14, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein X 1 X 2 and X 3 It is independently selected from the group consisting of -H, -OH and -O-methyl.

[0175] Implementation Scheme 16: The compound as described in Implementation Scheme 14, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0176] Implementation Scheme 17: The compound as described in Implementation Scheme 14, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0177] Implementation Scheme 18: The compound as described in Implementation Scheme 1, having formula VI: VI, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0178] Implementation Scheme 19: The compound as described in Implementation Scheme 18, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0179] Implementation Scheme 20: The compound as described in Implementation Scheme 18, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0180] Implementation Scheme 21: The compound as described in Implementation Scheme 1, having formula VII: VII, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0181] Implementation Scheme 22: The compound as described in Implementation Scheme 21, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0182] Implementation Scheme 23: The compound as described in Implementation Scheme 21, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0183] Implementation Scheme 24: A compound as described in Implementation Scheme 1, having formula VIII: VIII, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0184] Implementation Scheme 25: The compound as described in Implementation Scheme 24, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX 2 - and =CX 3 -

[0185] Implementation Scheme 26: The compound as described in Implementation Scheme 24, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0186] Implementation Scheme 27: The compound as described in Implementation Scheme 24, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0187] Implementation Scheme 28: The compound as described in Implementation Scheme 1, having formula IX: IX, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0188] Implementation Scheme 29: The compound as described in Implementation Scheme 28, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein Q 1 Q 2 and Q 3 =CX 1 -、=CX2 - and =CX 3 -

[0189] Implementation Scheme 30: The compound as described in Implementation Scheme 28, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 4 C6-C, whether unsubstituted or substituted 10 Aryl, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0190] Implementation Scheme 31: The compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates as described in Implementation Scheme 28, wherein R 4 It is a substituted C6 aryl group, wherein zero or more aryl carbons may be oxidized to form C=O, and one or more substituents are C1 haloalkyl groups.

[0191] Implementation Scheme 32: A compound of formula X: X, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Z is chosen freely = N-, = N + The group consisting of - and =C-; X 1 It is selected from the group consisting of -H, -O (C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl (e.g., methyl) and -OH; When Z is =N- or =N + - At that time, R 1 -O - Or it may not exist; When Z is =C-, R 1 For -OR 6 When the C2-C6 alkyl group is either unsubstituted or substituted, one or more of the substituents are independently selected from R.6 The group formed; R 2 Choose from the following groups: (i) -OR 3 , (ii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from R 3 The group formed, and (iii) Unsubstituted or substituted C2-C6 alkenyl groups, wherein one or more substituents are independently selected from R 4 The group formed; R 3 Choose from the following groups: (i) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from R 4 The group formed (ii) -C(=O)R 4 ,as well as (iii) -NHR 4 ; R 4 Choose from the following groups: (i) -C(=O)R 5 , (ii) -S(=O)2R 5 , (iii) -OH, and (iv) Unsubstituted or substituted 3- to 6-membered heterocycles, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O; R 5 Choose from the following groups: (i)-C1-C6 alkyl, (ii) -C2-C6 alkenyl, (iii) -O(C1-C6 alkyl), (iv) -NH-C1-C6 alkyl, (v)-OH, and (vi) Unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more cycloalkyl carbons may be oxidized to form C=O; R 6 Choose from the following groups: (i) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from R 6 (ii) and R6 (iii) The group that makes up the group. (ii) Unsubstituted or substituted 3- to 6-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and (iii) An unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O.

[0192] Implementation Scheme 33: The compound as described in Implementation Scheme 32, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein X 1 It is selected from the group consisting of -H, -OH, substituted or unsubstituted C1-C6 alkyl (e.g., methyl) and -O-methyl.

[0193] Implementation Scheme 34: The compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates as described in Implementation Scheme 32, wherein Z is =N-.

[0194] Implementation Scheme 35: The compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates as described in Implementation Scheme 32, wherein Z is =C-.

[0195] Implementation Scheme 36: The compound as described in Implementation Scheme 32, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein R 2 For being an R 3 Substituent-substituted C1 alkyl group, and the one R 3 The substituent is -NHR 4 .

[0196] Implementation Scheme 37: A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; R)- or (S)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetic acid; N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)- or (S)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)- or (S)-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthidine 1-oxide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)cyclopropaneformamide; N-(methylaminosulfonyl)-1-[1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,5-naphthid-3-yl]methylamine; (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acrylic acid; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)oxy)acetic acid; and N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)oxetane-3-amine.

[0197] Implementation Scheme 38: A compound, or a tautomer thereof, a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (S)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (S)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; Methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; (R)-methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; (S)-Methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)carbamate; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; and (S)-N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0198] Implementation Scheme 39. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; N-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthid-3-yl)methyl)acetamide; (2S)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)pyrrolidine-2-carboxamide; (2R)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)pyrrolidine-2-carboxamide; 1-Methyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)-1H-imidazol-5-carboxamide; 1-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)pyrrolidine-2-one; N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)acetamide; N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide-2,2,2-d3; 2-Phenylacetyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidyl-3-yl)methyl)acetamide; N-Acryloyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)glycine; N-acetyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)glycine; 3,3,3-Trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)- or (S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isobutyramide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)benzamide; 1-(4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)prop-2-en-1-one; N-((6-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 1-Methyl-3-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)urea; N-((7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methyl)acetamide; N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)- or (S)-N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((7-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((7-chloro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((1-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; N-((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthid-3-yl)methyl)acetamide; N-((6-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)acetamide; N-((6-cyclopropyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-cyano-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthidine-2-carboxamide; N-((6-(difluoromethoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-(difluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; and N-((6-ethynyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0199] Implementation Scheme 40. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; (S)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide-2,2,2-d3; 3,3,3-Trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (R)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; (S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide; N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; and (S)-N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0200] Implementation Scheme 41. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide; (R)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidin-3-yl)methyl)acetamide; and (S)-N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acetamide.

[0201] Implementation Scheme 42: A pharmaceutical composition comprising the compound of any one of Implementation Schemes 1-41, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0202] Implementation Scheme 43: The compound of any one of Implementation Schemes 1-41, or the pharmaceutical composition of Implementation Scheme 42, used as a drug.

[0203] Implementation Scheme 44: The compound of any one of Implementation Schemes 1-41 or the pharmaceutical composition of Implementation Scheme 42, for the prevention or treatment of YAP / TAZ-TEAD activation-mediated diseases in animals, mammals or humans.

[0204] Implementation Scheme 45: The compound as described in Implementation Scheme 44, or the pharmaceutical composition as described in Implementation Scheme 44, wherein the YAP / TAZ-TEAD activation-mediated condition is selected from the group consisting of cancer, fibrosis, and YAP / TAZ-TEAD activation-mediated congenital conditions.

[0205] Implementation Scheme 46: The compound as described in Implementation Scheme 44, or the pharmaceutical composition according to Implementation Scheme 44, wherein the YAP / TAZ-TEAD activation-mediated disease is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to bile duct cancer), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma and / or sarcoma.

[0206] Implementation Scheme 47: The compound as described in Implementation Scheme 44, or the pharmaceutical composition according to Implementation Scheme 44, wherein the YAP / TAZ-TEAD activation-mediated disease is selected from acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocyte, medulloblastic, adenocarcinoma, angiosarcoma, astrocytoma, granulomatous monocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, spinal cord injury, etc. Choroid tumor, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative abnormalities (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell carcinoma Testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, and malignant lymphomas of T-cell or B-cell origin. Medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline NUT carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and nephroblastoma.

[0207] Implementation Scheme 48: A method for preventing or treating YAP / TAZ-TEAD activation-mediated diseases in animals, mammals or humans, the method comprising administering an effective dose of any one of Implementation Schemes 1-41 to the animal, mammal or human in need of such prevention or treatment.

[0208] Implementation Scheme 49: The method of Implementation Scheme 48, further comprising administering one or more additional drugs selected from the group consisting of EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors and RAS inhibitors.

[0209] More generally, this disclosure relates to compounds of the formulas described herein, and embodiments, statements, and aspects thereof, which may be used as biologically active agents or as diagnostic agents. Any use mentioned in this disclosure may be limited to non-medical, non-therapeutic, non-diagnostic, or specific in vitro uses, or uses relating to cells remote from animals.

[0210] The disclosed compounds are small molecule YAP / TAZ-TEAD inhibitors. Small molecule YAP / TAZ-TEAD inhibitors can be used to treat, for example, 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 bile duct cancer), skin cancer, pancreatic cancer, gastric cancer, brain cancer, and prostate cancer, mesothelioma, and / or sarcoma. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors can be used to treat squamous cell carcinomas characterized by lung, cervical, ovarian, head and neck, esophageal, and / or skin cancers. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors can be used to treat cancers derived from neuroectodermal-derived tissues, such as ependymoma, meningioma, schwannoma, peripheral nerve sheath tumors, and / or neuroblastoma. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors can be used to treat vascular cancers (such as epithelioid hemangioendothelioma) or to treat supratentorial ependymoma or sweat pore cancer. In some embodiments, the solid tumor has gain-of-function gene amplification, gene fusion, or activation mutations in the YAP1 or WWTR1 (TAZ) genes. In some embodiments, the solid tumor has loss-of-function mutations or deletions in the NF2, LATS1 / 2, BAP1, FAT1, SAV1, and / or MST1 / 2 genes. In some embodiments, the solid tumor has gain-of-function mutations in the GNAQ and / or GNA11 genes (e.g., in uveal melanoma). In some embodiments, the solid cancer is characterized by the presence of constitutive nuclei of YAP and / or TAZ. In some embodiments, the solid cancer is characterized by overexpression of YAP / TAZ-TEAD marker genes (including, but not limited to, CTGF, CYR61, AMOTL2, and / or ANKRD1).

[0211] Small molecule YAP / TAZ-TEAD inhibitors can also be used to treat cancers that have developed resistance to prior treatment. This may include, for example, treating cancers that have developed resistance to chemotherapy or targeted therapy. In some implementations, this may include treating cancers that have developed resistance to: receptor tyrosine kinase inhibitors, such as EGFR inhibitors (afatinib, erlotinib hydrochloride). Hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or AXL inhibitors (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, durbmatinib); inhibitors of RAS-MAPK signaling cascade components, including RAS inhibitors themselves (such as AMG510, MRTX849, BI1701963, ARS1620), B-RAF inhibitors (sorafinib tosylate). Tosylate, dabrafenib, vemurafenib, regorafenib), or MEK1 / 2 inhibitors (trametinib, selumetinib, cobimetinib, mirdametinib).

[0212] Small molecule YAP / TAZ-TEAD inhibitors may also be used in combination with other agents used to treat cancer, whether administered concurrently or subsequently. This can include, for example, co-treatment with inhibitors or monoclonal antibodies targeting receptor tyrosine kinases, such as inhibitors or monoclonal antibodies targeting EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canenatinib, cetuximab) or inhibitors or monoclonal antibodies targeting AXL (crizotinib, cabozantinib, gipretinib, cetravatinib, besentinib, dubotinib); inhibitors of RAS-MAPK signaling cascade components, including inhibitors of RAS itself (e.g., AMG510, MRTX849, BI1701963, ARS1620), B-RAF inhibitors (sorafenib tosylate, dabrafenib, vemurafenib, regorafenib), or MEK1 / 2 inhibitors (trametinib, selmetinib, cmetinib, mirametinib).

[0213] Small molecule YAP / TAZ-TEAD inhibitors can also be used to treat metastatic cancers. In some cases, metastatic cancers are 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.

[0214] In some implementation schemes, the cancer being treated may be malignant pleural mesothelioma or lung cancer.

[0215] In some embodiments, the compounds disclosed herein can be used to treat acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, medulloblastic, adenocarcinoma, angiosarcoma, astrocytoma, granulocytic leukemia, and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, and chronic... Myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative dysplasia (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, glial carcinoma Tumors, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell-derived lymphomas, medullary carcinoma, medulloblastoma, melanoma, meningitis Tumors, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline NUT carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and nephroblastoma.

[0216] Malignant pleural mesothelioma Small molecule YAP / TAZ-TEAD inhibitors can also be used as a single agent or in combination with inhibitors such as pemetrexed disodium, raltitrexed, carboplatin, oxaliplatin, gemcitabine, doxorubicin, or monoclonal antibodies such as bevacizumab for the treatment of malignant pleural mesothelioma. They can also be combined with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. Furthermore, they can be combined with cell therapies such as chimeric antigen receptor (CAR) T-therapy or CAR NK therapy, which may, for example, use mesothelin (MSLN) as an antigen. Combined with monoclonal antibodies that recognize mesothelin as an antigen, such as BMS-986148, BAY94-9343, amatuximab, and / or LMB-100.

[0217] lung cancer Small molecule YAP / TAZ-TEAD inhibitors can also be used as monotherapy or in combination with inhibitors such as afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, and / or onartuzumab for the treatment of lung cancer. They can also be used in combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivorumab. Combined with cisplatin, carboplatin, paclitaxel, paclitaxel-binding protein, 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, tevantinib, onatusumab, pembrolizumab, atezolizumab, and / or nivorumab.

[0218] In some embodiments, small molecule YAP / TAZ-TEAD inhibitors can be used, for example, to treat congenital conditions. In some embodiments, the congenital disease is mediated by activation of a transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif. In some embodiments, the congenital disease is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the congenital disease is characterized by a loss-of-function mutation or deletion in the NF2 gene. Exemplary congenital diseases include, but are not limited to, Sturge-Weber syndrome, port-wine stain, and neurofibromatosis. In some embodiments, the congenital disease is neurofibromatosis, including, but not limited to, neurofibromatosis type 2.

[0219] In some implementations, small molecule YAP / TAZ-TEAD inhibitors can be used, for example, to treat fibrotic conditions such as fibrosis of the liver, lungs, kidneys, heart, or skin. In some implementations, fibrosis can be treated in the context of non-alcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, chronic kidney disease, and / or myocardial infarction injury.

[0220] The disclosed compound inhibits YAP / TAZ-TEAD transcriptional activation. The compound has been shown to inhibit YAP / TAZ-TEAD transcriptional activity in cell and animal models. It has also been shown to inhibit the growth of cancer cell lines and cancers dependent on YAP / TAZ-TEAD transcriptional activity in xenograft cancer models.

[0221] The disclosed compounds can optionally be covalently bound to an insoluble matrix and used for affinity chromatography (separation, depending on the nature of the compound's functional groups; for example, compounds with side aryl groups can be used for hydrophobic affinity separation).

[0222] When using one or more derivatives of the formula as defined herein: - The active ingredient of the compound may be administered to the animal or mammal (including humans) to be treated by any method known in the art (i.e., oral, intranasal, subcutaneous, intramuscular, intradermal, intravenous, intra-arterial, non-intestinal, or via catheter insertion).

[0223] - In particular, the therapeutically effective amount of a compound formulation for treating diseases mediated by YAP / TAZ-TEAD transcriptional activity in humans and other mammals (such as cancer, fibrosis, and certain congenital disorders) is preferably the amount of YAP / TAZ-TEAD transcriptional inhibition of the compound as defined herein, and corresponds to an amount that ensures inhibition of YAP / TAZ-TEAD activation and is at a plasma level between 1 μg / ml and 100 mg / ml.

[0224] Appropriate doses of the disclosed compounds or compositions are used to treat or prevent a target disease in a subject. Depending on the pathological condition to be treated and the patient's condition, the effective dose may be divided into several subunits per day or may be administered at intervals of more than one day.

[0225] According to specific embodiments of this disclosure, the disclosed compounds can be used in combination with other therapeutic agents to treat or prevent diseases mediated by YAP / TAZ-TEAD transcriptional activity in humans and other mammals (such as cancer, fibrosis, and certain congenital conditions). Therefore, this disclosure relates to the use of compositions comprising: (a) One or more compounds of the formulas and aspects, statements and embodiments thereof, and (b) One or more other therapeutic or preventive agents for the prevention or treatment of cancer or fibrosis, which are used as bioactive agents in combination formulations for simultaneous, single or sequential use.

[0226] The compound or composition may be administered concurrently with, before or after one or more other therapeutic agents, which are different from the compound described herein and may be used as, for example, a combination therapy.

[0227] Examples of other such therapeutic agents used in combination include agents that are inhibitors of the following: • EGFR inhibitors (such as afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, carnetinib, cetuximab), • AXL (such as crizotinib, cabozantinib, gipritinib, cetravatinib, besentinib, dubotinib), • Components of the RAS-MAPK signaling cascade include inhibitors of RAS itself (such as AMG510, MRTX849, BI1701963, and ARS1620). • B-RAF (such as sorafenib tosylate, dabrafenib, vemurafenib, regorafenib), or • MEK1 / 2 (trametinib, selmetinib, clotrimazole, milaminetinib).

[0228] The pharmaceutical compositions or formulations disclosed herein may contain compounds of the present disclosure in a wide range of amounts, depending on the intended use and intended effect of the formulation. Typically, the content of derivatives of the present disclosure in the formulation is in the range of 0.1% to 99.9% by weight, preferably 1% to 99% by weight, and more preferably 5% to 95% by weight.

[0229] Those skilled in the art will also recognize that the compounds disclosed herein can exist in many different protonated states, depending in particular on the pH of their environment. Although the structural formulas provided herein depict compounds in only one of several possible protonated states, it should be understood that these structures are illustrative only, and this disclosure is not limited to any particular protonated state; any and all protonated forms of the compounds are intended to fall within the scope of this disclosure.

[0230] As used herein, the term "pharmaceutically acceptable salt" means a therapeutically active, non-toxic salt form that compounds of the present formulation can form. Therefore, the compounds disclosed herein optionally comprise salts of the compounds herein, particularly containing, for example, Na. + Li + K + Ca 2+ and Mg 2+Pharmaceutically acceptable non-toxic salts. Such salts may include those derived by combining suitable cations (such as alkali and alkaline earth metal ions or ammonium and quaternary ammonium ions) with an acidic anionic moiety (typically a carboxylic acid). The compounds disclosed herein may carry multiple positive or negative charges. The net charge of the compounds disclosed herein may be positive or negative. Any associated counterion is typically determined by the synthetic and / or isolation method used to obtain the compound. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halide ions, acetate, trifluoroacetate, and mixtures thereof. It should be understood that the identity of any associated counterion is not a key feature of this disclosure, and this disclosure covers compounds associated with any type of counterion. Furthermore, since compounds can exist in many different forms, this disclosure is intended to cover not only forms associated with counterions (e.g., dry salts) but also forms not associated with counterions (e.g., aqueous solutions or organic solutions). Metal salts are typically prepared by reacting a metal hydroxide with the compounds disclosed herein. Examples of metal salts prepared in this manner are those containing Li + Na + and K + Salts. Less soluble metal salts can precipitate from solutions of more soluble salts by adding a suitable metal compound. Furthermore, salts can be formed by the addition of certain organic and inorganic acids to a basic center (usually an amine) or an acidic group. Examples of such suitable acids include, for example, inorganic acids such as hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic 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, etc. In addition, this term also includes compounds of this formula and solvates to which their salts can form, such as hydrates, alcohols, etc. Finally, it should be understood that the compositions herein comprise the disclosed compounds in their non-ionized and zwitterionic forms and in combination with stoichiometric amounts of water, as in hydrates.

[0231] Salts of the parent compound and one or more amino acids, particularly naturally occurring amino acids found as protein components, are also included within the scope of this disclosure. Amino acids are typically amino acids with side chains having basic or acidic groups (e.g., lysine, arginine, or glutamic acid) or neutral groups (such as glycine, serine, threonine, alanine, isoleucine, or leucine).

[0232] The disclosed compounds also include their physiologically acceptable salts. Examples of physiologically acceptable salts of the disclosed compounds include those derived from suitable bases (such as alkali metals (e.g., sodium)), alkaline earth metals (e.g., magnesium), ammonium, and NX4. + Salts of compounds containing a hydrogen atom or an amino group (where X is a C1-C4 alkyl group). Physiologically acceptable salts include the following: organic carboxylic acids, such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, ethanesulfonic 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 aminosulfonic acid. Physiologically acceptable salts of compounds containing a hydroxyl group include the anion of the compound with a suitable cation (such as Na+). + and NX4 + (where X is typically selected independently from H or C1-C4 alkyl groups). However, salts of acids or bases that are not physiologically acceptable may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of this disclosure.

[0233] As used herein and unless otherwise stated, the term “enantiomer” means each individual optically active form of the compounds disclosed herein having an optical purity of at least 80% (e.g., at least 90% of one enantiomer and at most 10% of another enantiomer), preferably at least 90%, and more preferably at least 98%, or an enantiomeric excess (as determined by standard methods in the art).

[0234] As used herein, the term "isomer" refers to all possible isomers that a compound of this formula may have, including tautomers and stereochemical forms, but excluding positional isomers. Generally, the structures shown herein illustrate only one tautomer or resonance form of the compound, but corresponding substitution configurations are also considered. Unless otherwise stated, the chemical name of a compound represents a mixture of all possible stereochemical isomers, containing all diastereomers and enantiomers of the basic molecular structure (since compounds of this formula may have at least one chiral center), as well as stereochemically pure or enriched compounds. More specifically, the stereoisomer source center may have an R configuration or an S configuration, and multiple bonds may have... Cis configuration or trans Configuration.

[0235] The pure isomer of the compound is defined as an isomer that substantially does not contain other enantiomers or diastereomers with the same basic molecular structure. Specifically, the terms "stereoisomerically pure" or "chirally pure" refer to a compound with a stereoisomeric excess of at least about 80% (e.g., at least 90% of one isomer and at most 10% of another 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 and diastereomeric excesses of the mixture under discussion, respectively.

[0236] The separation of stereoisomers is accomplished by standard methods known to those skilled in the art. An enantiomer of the disclosed compound can be separated substantially without its relative enantiomer by methods such as forming diastereomers using optically active resolving agents (EL Eliel, McGraw Hill, "Stereochemistry of Carbon Compounds," (1962); Lochmuller, CH, (1975) J. Chromatogr., 113:(3) 283-302). The separation of isomers in a mixture can be accomplished by any suitable method comprising: (1) forming an ionic diastereoisomeric salt with a chiral compound and separating it by stepwise crystallization or other methods; (2) forming a diastereoisomeric compound with a chiral derivatizing agent, separating the diastereomer, and converting it to a pure enantiomer; or (3) separating the enantiomers directly under chiral conditions. In method (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base (such as dimethoxystrychnine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), etc.) with an asymmetric compound (such as a carboxylic acid and a sulfonic acid) having an acidic function. The diastereomeric salts can be induced to be separated by stepwise crystallization or ion chromatography. To separate the optical isomers of amino compounds, the addition of a chiral carboxylic acid or sulfonic acid (such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid) can lead to the formation of diastereomeric salts. Alternatively, by method (2), the substrate to be separated can be reacted with an 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). Diastereomers can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent (such as a menthol derivative), followed by separation of the diastereomer and hydrolysis to produce a free enantiomer-enriched compound. Methods for determining optical purity involve preparing a racemic mixture of chiral esters (such as menthol ester or Mosher ester (α-methoxy-α-(trifluoromethyl)phenylacetate) (Jacob III. (1982) J. Org.Chem. 47:4165)) and analyzing NMR spectra for the presence of two trans-restricted diastereomers. Stable diastereomers can be separated using normal-phase and reversed-phase chromatography, following the method used for separating the trans-restricted isomer naphthyl-isoquinoline (Hoye, T., WO 96 / 15111).In 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. A commercially available polysaccharide-based chiral stationary phase is ChiralCeI. TM CA, OA, OB5, OC5, OD, OF, OG, OJ, and OK, along with Chiralpak TM AD, AS, OP(+), and OT(+). A suitable elution mobile phase used in combination with the chiral stationary phase of the polysaccharide is hexane modified with an alcohol (such as ethanol, isopropanol, etc.). (“Chiral Liquid Chromatography” (1989) WJ Lough, ed., Chapman and Hall, New York; Okamoto, (1990) “Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase”, J. of Chromatogr. 513:375-378).

[0237] the term Cis and trans The positions of substituents on the ring moiety are used and included in this document in accordance with chemical abstract nomenclature. The absolute stereochemical configuration of compounds of the formulas described herein can be readily determined by those skilled in the art using well-known methods (e.g., X-ray diffraction).

[0238] This disclosure also includes isotopically labeled compounds that are identical to those listed herein, but in fact have one or more atoms replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, such as... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36CI. The compounds disclosed herein and pharmaceutically acceptable salts of said compounds, or other isotopes containing the aforementioned isotopes and / or other atoms, and their salts, are within the scope of this disclosure. Certain isotopically labeled compounds of this disclosure (e.g., those incorporating radioactive isotopes such as…) 3 H and 14 Compounds containing C can be used in drug and / or substrate tissue distribution analysis. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H) substitution can provide certain therapeutic advantages arising from greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure can generally be prepared by performing the procedures disclosed in the examples and preparations described herein, by replacing the non-isotopically labeled reagent with an readily available isotopically labeled reagent.

[0239] Using PROTAC technology (Schapira M. et al., Nat. Rev. Drug Discov. 2019, 18(12) Modifications to compounds of formula (I) or other formulas, embodiments thereof, aspects thereof, or portions thereof, as described in (949-963) are also covered within this disclosure. Specifically, PROTAC technology designs bifunctional small molecules, one end of which is a compound of formula (I) or other formulas, embodiments thereof, aspects thereof, or portions thereof, or a metabolite thereof, and the other end of which is linked to a ligand of an E3 ubiquitin ligase via a linker chain to form a target-induced protein degradation complex. Because this degradation is catalytic, effective degradation can be achieved at lower doses. Compounds of formula (I) or other formulas, embodiments thereof, aspects thereof, or portions thereof, or a metabolite thereof, can be linked to a ligand of an E3 ubiquitin ligase via a linker arm (e.g., a long-chain ethylene glycol of length 2-10, a long-chain propylene glycol of length 2-10, or a long-chain aliphatic alkane of length 2-10), such as thalidomide analogues.

[0240] The disclosed compounds can be formulated with conventional carriers and excipients, which will be selected according to common practice. Tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and will generally be isotonic when intended for delivery by non-oral administration. Formulations optionally contain excipients, such as those listed in "Handbook of Pharmaceutical Excipients" (1986), and include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextrin), hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0241] Subsequently, as used herein, the term "pharmaceutically acceptable carrier" means any material or substance formulated together with the active ingredient to facilitate its administration or dispersal to the therapeutic locus (e.g., by dissolving, dispersing, or diffusing the composition) and / or to facilitate its storage, transport, or disposal without impairing its effectiveness. Pharmaceutically acceptable carriers can be solids or liquids or gases compressed to form liquids; for example, the compositions disclosed herein can suitably be used as concentrates, emulsions, solutions, granules, powders, sprays, aerosols, suspensions, ointments, creams, tablets, pills, or powders.

[0242] Drug carriers suitable for use in the pharmaceutical compositions and formulations thereof are well known to those skilled in the art, and there are no particular limitations on their selection within this disclosure. They may also include additives such as wetting agents, dispersants, binders, adhesives, emulsifiers, solvents, coatings, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (e.g., sugars or sodium chloride), etc., provided that they are consistent with pharmaceutical practice, for example, carriers and additives that do not cause permanent harm to mammals. The pharmaceutical compositions of this disclosure can be prepared in any known manner, for example by uniformly mixing the active ingredient with a selected carrier material and (where appropriate) other additives (such as surfactants) in one or more steps, coating with them, and / or milling, or by micronization, for example, to obtain compositions in the form of microspheres typically having a diameter of about 1 gm to 10 gm, i.e., for the manufacture of microcapsules for the controlled or sustained release of the active ingredient.

[0243] Suitable surfactants (also called emulsifiers) for use in the pharmaceutical compositions disclosed herein are nonionic, cationic, and / or anionic materials with good emulsifying, dispersing, and / or wetting properties. Suitable anionic surfactants include water-soluble soaps and water-soluble synthetic surfactants. Suitable soaps are higher fatty acids (C... 10 -C 22Alkali metal or alkaline earth metal salts, unsubstituted or substituted ammonium salts, such as sodium or potassium salts of oleic acid or stearic acid, or sodium or potassium salts of mixtures of natural fatty acids obtainable from coconut oil or tallow. Synthetic surfactants include sodium or calcium salts of polyacrylic acid; fatty sulfonates and sulfates; sulfonated benzimidazole derivatives and alkyl aryl sulfonates. Fatty sulfonates or sulfates are generally in the following forms: alkali metal or alkaline earth metal salts, unsubstituted ammonium salts, or ammonium salts substituted with alkyl or acyl groups having 8 to 22 carbon atoms, such as sodium or calcium salts of lignin sulfonate or dodecyl sulfonate, or mixtures of alkali metal or alkaline earth metal salts of fatty alcohol sulfates, sulfate esters, or sulfonates obtained from natural fatty acids (such as sodium lauryl sulfate) and sulfonic acids of fatty alcohol / ethylene oxide adducts. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylaryl sulfonates are sodium, calcium, or alkanolamine salts of dodecylbenzenesulfonic acid or dibutyl-naphthalenesulfonic acid or naphthalene-sulfonic acid / formaldehyde condensation products. Corresponding phosphates (e.g., salts of phosphate esters) and adducts of nonylphenol with ethylene oxide and / or propylene oxide, or phospholipids, are also suitable. Suitable phospholipids for this purpose are cephalin or lecithin-type natural phospholipids (derived from animal or plant cells) or synthetic phospholipids, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, lysophosphatidylcholine, cardiolipin, dioctylphosphatidylcholine, dipalmitoylphosphatidylcholine, and mixtures thereof.

[0244] Suitable nonionic surfactants include alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in their molecules, polyethoxylated and polypropoxylated derivatives of alkyl aromatic sulfonates and dialkyl sulfosuccinates, such as aliphatic and cyclic aliphatic alcohols, saturated and unsaturated fatty acids, and polyethylene glycol ether derivatives of alkylphenols, 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. Other suitable nonionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, or ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, wherein the adduct contains 20 to 250 glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds typically contain 1 to 5 glycol units per propylene glycol unit. Representative examples of nonionic surfactants include nonylphenol-polyethoxyethanol, castor oil polyglycolic acid ether, polypropylene oxide / ethylene oxide adducts, 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.

[0245] Suitable cationic surfactants include quaternary ammonium salts, particularly halides, in which four hydrocarbon groups are optionally substituted with halogens, phenyl groups, substituted phenyl groups, or hydroxyl groups; for example, containing at least one C 8-22 Quaternary ammonium salts containing alkyl groups (e.g., cetyl, lauryl, palmityl, myristyl, oleyl, etc.) as N-substituents and unsubstituted or halogenated lower alkyl groups, benzyl and / or hydroxy-lower alkyl groups as other substituents.

[0246] More detailed descriptions of surfactants suitable for this purpose can be found in, for example, McCutcheon's Detergents and Emulsifiers Annual (MC Publishing Crop., Ridgewood, New Jersey, 1981), Tensid-Taschenbucw, 2nd edition (Hanser Verlag, Vienna, 1981), and Encyclopaedia of Surfactants (Chemical Publishing Co., New York, 1981).

[0247] The disclosed compounds and their pharmaceutically acceptable salts (hereinafter collectively referred to as the active ingredients) may be administered via any route suitable for the disease to be treated, including oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). Preferred routes of administration may vary depending on, for example, the recipient's disease.

[0248] Although the active ingredient may be administered alone, it is preferably presented as a pharmaceutical formulation. Formulations disclosed herein for veterinary and human use comprise at least one active ingredient as described above, along with one or more pharmaceutically acceptable carriers and optionally other therapeutic components. One or more carriers are preferably “acceptable” in the sense of compatibility with the other components of the formulation and harmlessness to the recipient. 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. Formulations can be conveniently presented in unit dose form and can be prepared by any method well known in the pharmaceutical field. Such methods include the step of associating the active ingredient with a carrier constituting one or more adjuvant components. Generally, formulations are prepared by homogeneously and tightly associating the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then (if necessary) shaping the product.

[0249] Formulations of this disclosure suitable for oral administration may be presented as discrete units, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be presented as pills, granules, or pastes.

[0250] Tablets can be prepared by compression or molding, optionally having one or more excipients. Compressed tablets can be prepared by compressing an active ingredient (such as powder or granules) in a free-flowing form in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or indented and may be formulated to provide a slow or controlled release of the active ingredient therein. For injection into the eye or other external tissues (e.g., mouth and skin), the formulation is optionally administered as a topical ointment or cream containing, for example, 0.075% to 20% w / w (including increments of 0.1% w / w in the range between 0.1% and 20% (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 as an ointment, the active ingredient may be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w polyols, such as alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations may desirably contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogues.

[0251] The oil phase of the emulsion disclosed herein can be composed of known ingredients in a known manner. Although the phase may contain only an emulsifier (also referred to as an emulsifier), it desirablely includes at least one emulsifier in a mixture with fats or oils, or in a mixture with both fats and oils. Optionally, a hydrophilic emulsifier is incorporated together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oils and fats. In summary, one or more emulsifiers, with or without one or more stabilizers, constitute a so-called emulsified wax, and the wax, together with oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the cream formulation.

[0252] The selection of a suitable oil or fat for the formulation is based on achieving the desired cosmetic properties, as the active compound has extremely low solubility in most oils that may be used in pharmaceutical emulsion formulations. Therefore, the cream should optionally be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight-chain or branched mono- or dialkyl esters, such as di-isohexadiate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or blends of branched esters, known as Crodamol CAP, are preferred. Depending on the desired properties, these alkyl esters may be used alone or in combination. Alternatively, high-melting-point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, may be used.

[0253] Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent of the active ingredient. The active ingredient is optionally present in such formulations at a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w. Formulations suitable for topical application in the mouth include rhomboid lozenges containing the active ingredient in a flavoring matrix (usually sucrose and gum arabic or tragacanth); soft lozenges containing the active ingredient in an inert matrix (such as gelatin and glycerin) or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0254] Formulations for rectal administration may be presented as suppositories having a suitable matrix comprising, for example, cocoa butter or salicylates. Formulations suitable for nasal administration (where the carrier is solid) include coarse powders with particle sizes, for example, in the range of 20 to 500 micrometers (including increments of 5 micrometers for particle sizes in the range of 20 to 500 micrometers, such as 30 micrometers, 35 micrometers, etc.), administered by inhalation of nasal smoke, for example, by rapid inhalation through the nasal passage via a container of powder that is kept close to the nose. Suitable formulations for administration as, for example, nasal sprays or nasal drops (where the carrier is liquid) 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 together with other therapeutic agents.

[0255] Preparations suitable for vaginal application may be in the form of pessaries, tampons, creams, gels, pastes, foams, or sprays, and in addition to the active ingredient, may contain a suitable carrier such as those known in the art.

[0256] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Formulations may be available in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored under lyophilized (freeze-dried) conditions, requiring the addition of a sterile liquid carrier (e.g., water for injection) only shortly before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the previously described types.

[0257] Preferred unit-dose formulations are those containing the active ingredient at the daily dose or sub-daily dose or an appropriate fraction thereof as listed above.

[0258] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations disclosed herein may contain other agents conventional in the field of the type of formulation discussed, such as flavoring agents for those formulations suitable for oral administration.

[0259] The compounds disclosed herein can be used to provide controlled-release pharmaceutical formulations (“controlled-release formulations”) containing one or more of the disclosed compounds as active ingredients, wherein the release of the active ingredient can be controlled and modulated to allow for less frequent dosing or to improve the pharmacokinetic or toxicological characteristics of a given disclosed compound. Controlled-release formulations suitable for oral administration (where discrete units comprise one or more of the disclosed compounds) can be prepared according to conventional methods.

[0260] Additional components may be included to control the duration of action of the active ingredient in the composition. Therefore, controlled-release compositions can be achieved by selecting appropriate polymeric carriers (e.g., polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate, etc.). Drug release rates and durations of action can also be controlled by encapsulating the active ingredient in particles (e.g., microcapsules) of polymeric substances (such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate, and other polymers mentioned above). Such methods include colloidal drug delivery systems such as liposomes, microspheres, microemulsions, nanoparticles, nanocapsules, etc. Depending on the route of administration, the drug composition may require protective coating. Suitable drug forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for their ad hoc preparation. Therefore, typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, and mixtures thereof.

[0261] Given that when several active ingredients are used in combination, they do not necessarily produce their combined therapeutic effect simultaneously and directly in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing two ingredients in separate but adjacent storage containers or compartments. Therefore, in the latter case, each active ingredient can be formulated for a different route of administration than the other ingredient; for example, one may be in the form of an oral or parenteral formulation, while the other may be in the form of an ampoule or aerosol for intravenous injection.

[0262] Another embodiment of this disclosure relates to various prodrug or "prodrug" forms of the compounds of this disclosure. It may be desirable to formulate the compounds of this disclosure in the form of chemical substances that, in themselves, have no significant biological activity but will undergo normal bodily functions when delivered to animals, mammals, or humans. Especially A chemical reaction catalyzed by an enzyme present in the stomach or serum, which has the effect of releasing a compound as defined herein. Therefore, the term "prodrug" refers to a substance that, in the stomach or serum, is present in the stomach or serum. body Inside These substances are transformed into active pharmaceutical ingredients.

[0263] The prodrug of the disclosed compound may have any form suitable for the formulation user; for example, esters are a common, non-limiting form of prodrug. However, in this case, the prodrug may have to be in a form where its covalent bonds are present in the target. locus The enzyme acts to cleave the form of the substance. For example, the C-C covalent bond can be formed by the target. locus One or more enzymes selectively cleave the prodrug at the site, and therefore it can be used in prodrug forms other than those that can be easily hydrolyzed in vitro. Especially Esters, amides, etc. The counterparts of the active pharmaceutical ingredient in prodrugs can have different structures, such as amino acid or peptide structures, alkyl chains, sugar moieties, and other structures as known in the art.

[0264] For the purposes of this disclosure, the term "therapeuticly suitable prodrug" is defined herein as "when in contact with tissues of an animal, mammal, or human to which a prodrug has been administered, in a manner such as..." In the body Compounds modified in a manner that converts them into their therapeutically active form, whether by a single bioconversion or by multiple bioconversions, without excessive toxicity, irritation, or allergic reactions, and achieves the desired therapeutic outcome.

[0265] More specifically, as used herein, the term "prodrug" refers to an inactive or significantly less active derivative of a compound, such as those represented by the structural formulas described herein, which undergoes spontaneous or enzymatic conversion in vivo 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).

[0266] The compounds disclosed herein can be prepared simultaneously using a series of chemical reactions well known to those skilled in the art, which together constitute a method for preparing said compounds and are further illustrated. The methods described further are intended to be illustrative only and are in no way intended to limit the scope of this disclosure.

[0267] Example General Synthesis The abbreviations that may be used in this specification, especially in the schemes and examples, are as follows: AIBN - azobisisobutyronitrile, aq - aqueous solution, ACN - acetonitrile, Ac2O - acetic anhydride, AcOH - Acetic acid, AcCl-acetyl chloride, B2Pin2-bis(pinacol)diboron, BF3.OEt2-boron trifluoride diethyl ether, BINAP-(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Bn-benzyl, Boc- Uncle Butyloxycarbonyl, Boc2O-dicarbonate Uncle Butyl ester, BrettPhos-2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, BrettPhos Pd G3-[(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate, t BuOH - Uncle Butanol, Bz-benzoyl, CDI-1,1'-carbonyldiimidazole, Conc-concentrated, mCPBA- between Chloroperoxybenzoic acid, CMBP-(tributylphosphine)acetonitrile, Cu(OAc)2-copper(II)acetate, d-t, DAST-diethylaminosulfuric trifluoride, DBU-1,8-diazabicyclo[5.4.0]undec-7-ene, DCM-dichloromethane, DCE-1,2-dichloroethane, DIAD-diisopropyl azodicarboxylate, DIPEA - Diisopropylethylamine, DMAN , N -Dimethylacetamide, DMAP- N , N - Dimethylpyridine-4-amine, DMEM - Duchene modified Eagle medium, DMF - N , N -Dimethylformamide, DMF-DMA- N , N-II Methylformamide dimethyl acetal, DMP-Dies Martin periodoyl acetal, DMS-dimethyl sulfoxide, DMSO-dimethyl sulfoxide, DMSO- d 6 - Deuterated dimethyl sulfoxide, DPPA - diphenylphosphoazide, DPPF - 1,1'-ferrocenediyl-bis(diphenylphosphine), EDA - ethyl diazonium, EDC - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Et3N - triethylamine, Et3SiH - triethylsilane, EtOH - ethanol, EtOAc - Ethyl acetate, Et₂O - diethyl ether, Eq. - equivalent, FA - formic acid, g - gram, h - hour, HATU - O-(7-azabenzotriazol-1-yl)- N , N , N ', N' -Tetramethylurea hexafluorophosphate, HCl - Hydrogen chloride, HEPES - 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, HMPA - hexamethylphosphoramide, HPLC - High performance liquid chromatography (HPLC), IPA-2-propanol, KHMDS-bis(trimethylsilyl)aminopotassium, LAH-lithium aluminum hydride, LiHMDS-bis(trimethylsilyl)aminolithium, LDA-diisopropylaminolithium, LG - Leaving group, L - liter, LC / MS - liquid chromatography / mass spectrometry, Me - methyl, Me3SI - trimethylsulfonium iodide, MeI - iodomethane, MeOH - methanol, MsCl - methanesulfonyl chloride, min - minutes, mg - milligrams, mL - milliliters, m / z - mass-to-charge ratio, NaOAc - sodium acetate, NBS - N - Bromosuccinimide, n-BuLi- n-Butyllithium, NHS- N-Hydroxysuccinimide, Pd(amphos)Cl2-Bis(di) UncleButyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), PCy3-tricyclohexylphosphine, Pd(PPh3)2Cl2-bis(triphenylphosphine)dichloropalladium(II), Pd(PPh3)4-tetra(triphenylphosphine)palladium, Pd2(dba3)3 - Tris(dibenzylacetone)dipalladium, Pd(dppf)Cl2 - (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride, Pd(dppf)Cl2.DCM-(1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride, a complex with DCM, Pd(OAc)2-palladium(II) acetate, PG - protecting group, PMB - p-methoxybenzyl, PPh3-triphenylphosphine, ppm - parts per million, Pet ether - Petroleum ether, phosphomolybdic acid in PMA-EtOH, p-TSA-p-toluenesulfonic acid, Py-pyridine, Raney Ni - Raney nickel, Rf - retention factor, RLU - relative optical unit, RT - Room temperature, sat - saturated, SCX - strong cation exchange, SFC - supercritical fluid chromatography, S-phos - 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, TBAF - tetracycline just Butyl ammonium fluoride, TBN - nitrous acid Uncle Butyl ester, t-Bu-tert-butyl, t-BuOH-tert-butanol, t-BuONO-tert-butyl nitrite, TEA-triethylamine, THF - Tetrahydrofuran, THP-tetrahydropyran, TFA - Trifluoroacetic acid, TFAA - trifluoroacetic anhydride, TLC - thin-layer chromatography, TMS - trimethylsilyl, TMSN3 - trimethylsilyl azide, TMSI - trimethylsilyl iodide, T3P - propanephosphonic anhydride, TPP - triphenylphosphine, UPLC - ultra-high performance liquid chromatography, UV - ultraviolet light, Xanthphos - 4,5-Bis(diphenylphosphine)-9,9-dimethyloxanthracene, XPhos-2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, XPhos-Pd-G2-chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), ZnEt2-diethylzinc.

[0268] The compounds of the present invention can be prepared according to the general procedure outlined in Scheme 1.

[0269] Option 1: J is a protecting group (-OPG); L and Y are independent of: -N= or -C(H)=; A. Choose from the following groups: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0270] All other variables are as described in the compounds of this invention and their embodiments and formulas.

[0271] Alternatively, the compounds of the present invention can be synthesized according to Scheme 2.

[0272] Option 2: L and Y are independent of: -N= or -C(H)=.

[0273] A. Choose from the following groups: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0274] All other variables are as described in the compounds of this invention and their embodiments and formulas.

[0275] Alternatively, the compounds of the present invention can be synthesized according to Scheme 3.

[0276] Option 3: L and Y are independent of: -N= or -C(H)=.

[0277] X can choose from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) C1-C6 alkyl groups, (v) C1-C6 haloalkyl, (vi) -OZ 1 ,as well as (vii) -NZ 3 Z 4 .

[0278] A. Choose from the following groups: (a) Halogen, (b) Cyano group, (c) C1-C6 alkyl groups, (d) C3-C6 cycloalkyl groups, (e) C1-C6 haloalkyl groups, (f) -OZ 1 ,as well as (g) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups, and -OZ. 1 A group that is formed.

[0279] All other variables are as described in the compounds of this invention and their embodiments and formulas.

[0280] Alternatively, the compounds of the present invention can be synthesized according to Scheme 4.

[0281] Option 4 Variables L, Y, A, R a and R z As described in the compounds, embodiments, and formulas of the present invention.

[0282] Alternatively, the compounds of the present invention can be synthesized according to Scheme 5.

[0283] Option 5 variable R a and R z As described in the compounds, embodiments, and formulas of the present invention.

[0284] The general embodiments described above should be considered as non-limiting examples. It should be understood that the compounds of the present invention can be obtained by other methods known to those skilled in the art.

[0285] Table 1: The structures of the compounds disclosed herein and their respective compound numbers.

[0286] These embodiments are provided for illustrative purposes and should in no way be construed as limiting the scope of this disclosure.

[0287] Part A: Experimental Chemistry Procedures All starting materials not explicitly described are commercially available (details of suppliers (e.g., Acros, Avocado, Aldrich, Fluka, FluoroChem, MatrixScientific, Maybridge, Merck, Sigma, etc.) can be found in, for example, the SciFinder® database), or their synthesis has been previously described in professional literature (experimental guidelines can be found in, for example, the Reaxys® database or the SciFinder® database), or can be prepared using conventional methods known to those skilled in the art.

[0288] If desired, the reaction is carried out under an inert atmosphere (primarily argon and N2). The equivalent number of reagents, the amount of solvent used, and the reaction temperature and time may vary slightly between different reactions carried out by similar methods. Post-treatment and purification methods are tailored to the characteristic properties of each compound and may vary slightly for similar methods. The yields of the prepared compounds have not been optimized. The indication “equivalent” (“eq.” or “eq or “equiv.”) means molar equivalent, “RT” or “rt” means room temperature (23 ± 7 °C), “M” indicates concentration in mol / L, “sol.” means solution, and “conc.” means concentrated. Solvent mixing ratios are usually stated as volume / volume ratios. To conduct the reaction under microwave radiation, a CEM microwave (Discover SP) system was used (heating rate: 2°C–6°C / sec; temperature: 30°C–300°C with volume-independent infrared (IR) and fiber optic (FO) temperature measurements of 80°C–300°C; pressure: 0–435 psi, ActiVent™ technology; power: 0–300 W; magnetron frequency: 2450 MHz; reaction agitation: electromagnetic stirring; air cooling: ≥ 25 psi (20 L / min flow rate); system control: Synergy™ software). 1 Key analytical characterization was performed on all exemplary compounds and selected intermediates by 1H-NMR spectroscopy and / or mass spectrometry (MS, for m / z of [M+H]+ and / or [MH]-). In some cases, additional analyses were performed, such as when regioisomers and / or diastereomers may / are formed during the reaction. 13C10 NMR and NOE (nuclear overhauser effect) NMR experiments were conducted. The analytical instruments used were, for example, a BRUKER AVANCE 400 MHz (Topspin software) or VARIAN MR 400 MHz (VNMRJ software) for NMR analysis. For LC / MS analysis, instruments such as Acquity UPLC Class H, mass spectrometry with Acquity SQD2 detector (ESI); Acquity UPLC, mass spectrometry with Quatro premier XE detector (ESI); Acquity UPLC, mass spectrometry with Waters Xevo TQ-S detector (ESI / ESCI); or Alliance Waters 2695, mass spectrometry with Quattromicro™ (ESCI) multimode ionization were used. For example, analytical HPLC measurements were performed on an Alliance Waters 2695. For example, analytical SFC can be performed on PIC solution (software: SFC PIC Lab online), WATERS-X5 (MASSLYNX software), or WATERS-UPC2 (Empower). Preparative HPLC separations can be performed on Waters 2545 (Empower software), Gilson (Trilution software), or Shimadzu (LC Solution software). Preparative SFC separations can be performed on Waters Thar SFC-80 (Chromscope software), Waters Thar SFC-150 (Chromscope software), Waters Thar SFC-200 (Chromscope software), or PIC SFC-175 (SFC PIC Lab online software). If the stereochemistry is known, the structure of the example compound containing the stereocenter is plotted and named using absolute stereochemistry. In cases where the absolute stereochemistry is unknown, the compound can be a racemic mixture, a mixture of diastereomers, a pure diastereomer with unknown stereochemistry, or a pure enantiomer with unknown stereochemistry. Dia 1 and Dia 2 indicate that the diastereomer has been separated but its stereochemistry is unknown. En 1 and En 2 indicate that two enantiomers have been separated, but their absolute configurations are unknown. The absence of a suffix after the compound code indicates that the compound containing a stereocenter was obtained as either a racemic mixture or a mixture of diastereomers, unless the chemical name of the compound specifies the exact stereochemistry.The LC / MS analyses mentioned in the experimental section were also performed on an Alliance 15 Waters 2695 HPLC (equipped with a PDA detector) connected to a Waters Quattromicro (ESCI, multimode ionization) mass spectrometer, or on a Waters H-Class Acquity UPLC connected to a QDa or SQD2 mass spectrometer. Separation was performed using Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) columns, Acquity BEH C18 (1.7 μm, 2.1 x 100 mm) columns, or X-Bridge C18 (3.5 μm, 4.6 x 75 mm) columns, at a constant temperature of 30–35 °C, with the PDA acquisition wavelength set in the range of 210–400 nm (acquisition software: MassLynx). Elution was performed using the methods described in the table below. For methods L1, L2, L4, L6, and L7, solvent A: 0.05% LC-MS grade FA in milliQ water. Solvent B: LC-MS grade ACN. Column temperature = 35°C. For method L3, solvent A: 5 mM NH4HCO3 in milliQ water. Solvent B: LC-MS grade ACN. Column temperature = 35°C. For method L5, solvent A: 0.05% LC-MS grade TFA in milliQ water. Solvent B: LC-MS grade TFA in ACN. Column temperature = 35°C. For method L8, solvent A: 10 mM NH4HCO3 in milliQ water. Solvent B: LC-MS grade ACN. Column temperature = 35°C.

[0289] The SFC analyses mentioned in the experimental section were performed on a WATERS Acquity UPLC (Empower-3 software) equipped with an Acquity PDA and Acquity QDa detector. Separations were performed using the columns and conditions described in the table below.

[0290] The preparative HPLC purifications mentioned in this experimental section were performed on Waters 2545 (Empower software, 2996 PDA detector, 2707 autosampler), Gilson (Trilution software, 171 DAD detector, GX-271 autosampler), or Shimadzu (LC Solution software, CMB-20A detector, SIL-10AP autosampler). Separations were performed using the columns and solvents described in the table below. Gradient systems were used for each individual compound using the solvents mentioned in the table. Detection wavelengths were fixed at 210 and 254 nm.

[0291] The preparative SFC purification described in this experimental section was performed using the following system: a Thar SCF-200 (Chromscope software) equipped with a UV / PDA detector and a modified agent flow injection mode. Separation was performed using a column, and the conditions described in the table below were followed. The detection wavelength was fixed at 224 nm.

[0292] Example 1: Synthesis of N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide (compound number 3) Step 1: A solution of 1-methoxy-2-methyl-3-nitrobenzene (20.0 g, 119.64 mmol) in chloroform (200 mL) was treated at room temperature with AIBN (3.929 mg, 23.92 mmol) and NBS (23.45 g, 177.99 mmol). The reaction mixture was stirred at 75 °C for 16 h and the reaction was monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, Rf: 0.45, detection: UV). The reaction mixture was cooled to room temperature, diluted with H2O (500 mL) and extracted with DCM (2 x 400 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a brown gel (30.0 g), which was ground with pentane to give 2-(bromomethyl)-1-methoxy-3-nitrobenzene (23.0 g) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ ppm: 7.53-7.55 (dd, 1H), 7.40-7.44 (t, 1H), 7.14-7.16 (d, 1H), 4.83 (s, 2H), 3.98 (s, 3H).

[0293] Step 2:A solution of ethyl 2-cyanoacetate (21.21 g, 187.75 mmol) in THF (1700 mL) was cooled to 0 °C, treated with LiHMDS (188 mL, 187.75 mmol), and stirred at 0 °C for 30 min. This was followed by treatment with a solution of 2-(bromomethyl)-1-methoxy-3-nitrobenzene (23.0 g, 93.87 mmol) in THF (600 mL). The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.40, detection: UV). The reaction mixture was quenched at 0 °C with an aqueous solution of NH4Cl (2.0 L), and the product was extracted with EtOAc (3 x 750.0 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, and concentrated to give the crude product (35 g, LC / MS: 20%). The crude product was purified by silica gel column chromatography using 15% EtOAc in petroleum ether as the eluent. The collected fraction was concentrated under reduced pressure to give ethyl 2-cyano-3-(2-methoxy-6-nitrophenyl)propionate (20.0 g, LC / MS: 95%) as a brown liquid. (LC / MS; m / z 279.2 [M+H]) + ).

[0294] Step 3: A solution of ethyl 2-cyano-3-(2-methoxy-6-nitrophenyl)propionate (20 g, 71.87 mmol) in acetic acid (200.0 mL) was treated with Fe powder (20.1 g, 359.37 mmol) at 100 °C and stirred at 100 °C for 2 h. The reaction progress was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.26, detection: UV). The reaction mixture was diluted with EtOAc, filtered through a diatomaceous earth mat, and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 solution (3 x 300 mL), brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to give a brown solid (15 g, LC / MS: 50%). The crude product was ground together with pentane to give 7.5 g (LC / MS: 72%) of 5-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxynitrile as a grayish-white solid. (LC / MS; m / z 203.3 [M+H]) + ).

[0295] Step 4:A solution of 5-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxynitrile (7.50 g, 37.09 mmol) in MeOH (195 mL) was treated at 0 °C with NiCl2·6H2O (5.29 g, 22.25 mmol), (Boc)2O (10.22 mL, 44.50 mmol), and NaBH4 (8.14 g, 222.53 mmol). The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.50, detection: UV). The resulting solution was concentrated, diluted with EtOAc (300 mL), and filtered through a diatomaceous earth mat. The filtrate was washed with H2O (200 mL) and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a crude product (7.5 g, LC / MS: 45%). The crude product was ground with petroleum ether to give tert-butyl ((5-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as a grayish-white solid (5.0 g, LC / MS: 60%). (LC / MS; m / z 307.4 [M+H]) + ).

[0296] Step 5:A solution of ((5-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate tert-butyl ester (5.0 g, 16.32 mmol) in 1,4-dioxane (65.0 mL) was treated at room temperature with 1-iodo-4-(trifluoromethyl)benzene (8.87 g, 32.64 mmol), potassium carbonate (6.75 g, 48.96 mmol), CuI (621 mg, 3.26 mmol), and (±)-trans-1,2-diaminocyclohexane (464 mg, 3.26 mmol). The reaction mixture was stirred in a sealed tube at 120 °C for 16 h. The progress of the reaction mixture was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.63, detection: UV). The resulting solution was diluted with H₂O (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product (9.0 g, LC / MS: 34%). The crude product was purified by column chromatography using silica gel and 10% EtOAc in petroleum ether as the eluent to give tert-butyl ((5-methoxy-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (2.7 g, LC / MS: 90%) as a grayish-white solid. (LC / MS; m / z 451.4 [M+H]) + ).

[0297] Step 6: A solution of tert-butyl ((5-methoxy-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (2.7 g, 5.99 mmol) in THF (20 mL) was cooled to 0 °C and treated with a 1 M BH3·THF complex (26.0 mL, 26.64 mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 3 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.54, detection: UV). The reaction mixture was cooled to 0 °C and quenched with an aqueous solution of NH4Cl (80 mL), filtered through a diatomaceous earth mat, and the filtrate was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was then ground with n-pentane to give tert-butyl ((5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (2.0 g, LC / MS: 96%) as a grayish-white solid. (LC / MS; m / z 437.4 [M+H]) + ).

[0298] Step 7: A solution of tert-butyl ((5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (2.0 g, 4.58 mmol) in DCM (20.0 mL) was treated with BBr3 (23 mL, 22.91 mmol, 1 M solution in DCM) at 0 °C. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.03, detection: UV). The resulting solution was cooled to 0 °C, quenched with saturated sodium bicarbonate, and extracted with 20% IPA in chloroform (5 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (1.5 g, LC / MS: 81%). The crude product was ground together with n-pentane to give 3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-5-ol (1.1 g, LC / MS: 86%) as a dark brown solid. (LC / MS; m / z 323.3 [M+H)) + ).

[0299] Step 8: A solution of tert-butyl ((5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (1.1 g, 3.41 mmol) in DCM (11 mL) was treated at 0 °C with TEA (0.70 mL, 5.11 mmol) and (Boc)₂O (0.74 mL, 3.24 mmol). The reaction mixture was stirred at 0 °C for 2 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.24, detection: UV). The resulting solution was diluted with H₂O (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product (1.2 g, LC / MS: 84%). The crude product was purified by silica gel column chromatography using 25% EtOAc in petroleum ether as the eluent to give tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (900 mg, LC / MS: 99%) as a yellow solid. (LC / MS; m / z 423.2 [M+H)) + ).

[0300] Step 9:A solution of tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)carbamate (650 mg, 1.53 mmol) in DMSO (6.5 mL) was treated with potassium phosphate (979 mg, 4.61 mmol) and 3-iodopyridine (630 mg, 3.07 mmol). The reaction mixture was degassed by bubbling argon for 10 min and then treated with CuI (29 mg, 0.154 mmol) and pyridinecarboxylic acid (38 mg, 0.308 mmol) at room temperature. The reaction mixture was stirred at 120 °C under microwave irradiation for 1 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.35, detection: UV). The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (80 mL), dried over Na₂SO₄, and concentrated to give a crude product (800 mg, LC / MS: 49%). The crude product was purified by rapid chromatography using a 24 g silica column and 20% EtOAc in petroleum ether as the eluent to give tert-butyl ((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)carbamate (Int-1) (400 mg, LC / MS: 97%) as a grayish-white solid. (LC / MS; m / z 500.2 [M+H)) + ).

[0301] Step 10: A solution of Int-1 (380 mg, 0.761 mmol) in DCM (10.0 mL) was treated with TFA (1.5 mL) at 0 °C and stirred for 2 h. The reaction progress was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.03, detection: UV). The reaction mixture was concentrated, and the residue was ground with diethyl ether. The solid was dried under vacuum to give (5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methylamine (285 mg, LC / MS: 95%) as a brown gel. (LC / MS; m / z 400.4 [M+H]) + ).

[0302] Step 11:A solution of (5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methylamine (100 mg, 0.250 mmol) in DCM (4.5 mL) was treated at 0 °C under a nitrogen atmosphere with a solution of TEA (38 mg, 0.376 mmol) in DCM (0.25 mL) and a solution of acryloyl chloride (23 mg, 0.250 mmol) in DCM (0.25 mL) and stirred for 30 min. The reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.32; detection: UV). The reaction mixture was diluted with ice-cold water (10 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a brown gel (85 mg, LC / MS: 86%). The crude product was purified by preparative HPLC method H1, and the fraction was concentrated under reduced pressure to give N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide (compound number 3) (44.8 mg, LC / MS: 99.5%) as a grayish-white solid. (LC / MS; m / z 454.4 [M+H)) + ).

[0303] The following compounds were prepared in a manner similar to that of compound number 3 (using appropriate reagents and purification methods known to those skilled in the art): compound number 1 (using propionyl chloride in step 11) and compound number 2 (using methanesulfonyl chloride in step 11).

[0304] Example 2: Synthesis of N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide (compound number 4) Step 1:A solution of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (5 g, 31.14 mmol) in ACN (100 mL) was treated at 0 °C with Et3N (6.3 g, 62.28 mmol) and benzoyl chloride (8.7 g, 62.28 mmol). The reaction mixture was stirred at 0 °C for 2 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.5, detection: UV). The resulting reaction mixture was concentrated under reduced pressure, and the residue was ground together with ACN (50 mL) and dried under reduced pressure to give 6-(chloromethyl)pyrimidine-2,4-diester of dibenzoic acid (7 g, LC / MS: 98%). (LC / MS; m / z 503.2 [M+H]) + ).

[0305] Step 2: A solution of Int-1 (2 g, 4.73 mmol) in DMF (10 mL) was treated with NaH (0.379 g, 9.47 mmol) at 0 °C and stirred for 30 min. A solution of 6-(chloromethyl)pyrimidine-2,4-diester of dibenzoic acid (1.74 g, 4.73 mmol) in DMF (5 mL) was added at 0 °C, and the mixture was stirred at 80 °C for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.12, detection: UV). The resulting solution was cooled to 0 °C and quenched with ice-cold H2O (30 mL). The resulting precipitate was filtered and dried to give the crude product (2.5 g, LC / MS: 20%). The crude product was purified by rapid chromatography using a silica column and 5% MeOH in DCM as the eluent to give tert-butyl ((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (300 mg, LC / MS: 71%) as a light brown solid. (LC / MS; m / z 547.4 [M+H)) + ).

[0306] Step 3:A solution of tert-butyl carbamate (350 mg, 0.640 mmol) in DCM (5.0 mL) was treated with TFA (1.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and monitored by TLC (10% MeOH in DCM, Rf: 0.05, detection: UV). The resulting solution was concentrated, and the residue was ground together with diethyl ether. The solid was dried under reduced pressure to give 6-(((3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl)oxy)methyl)pyrimidine-2,4(1H,3H)-dione (250 mg, LC / MS: 74%). (LC / MS; m / z 447.4 [M+H]) + ).

[0307] Step 4: A solution of 6-(((3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl)oxy)methyl)pyrimidin-2,4(1H,3H)-dione TFA salt (110 mg, 0.246 mmol) in 1,4-dioxane (4.0 mL) was treated at 0 °C under a nitrogen atmosphere with a solution of NaHCO3 (82 mg, 0.986 mmol) in H2O (0.5 mL) and a solution of acryloyl chloride (22.30 mg, 0.246 mmol) in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 0 °C for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM; Rf: 0.32; detection: UV). The resulting solution was diluted with ice-cold H2O (20 mL) and extracted with DCM (2 x 15 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a crude product (95 mg, LC / MS: 63%). The crude product was purified by preparative HPLC using H₂, and the collected fractions were concentrated and lyophilized to give N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide (compound number 4) (17.4 mg, LC / MS: 99%) as a light brown solid. (LC / MS; m / z 501.4 [M+H)) + ).

[0308] The following compounds were prepared in a manner similar to that of compound number 4 (using appropriate reagents and purification methods known to those skilled in the art): compound number 5 (using propionyl chloride and Et3N in DCM in step 4), compound number 6, compound number 7 (using propionyl chloride and Et3N in DCM in step 4), compound number 8 (using methanesulfonyl chloride in step 4), compound number 9 (using methanesulfonyl chloride in step 4), and compound number 14.

[0309] Racemic compound 6 (220 mg) was purified by preparative SFC method K1 to obtain compound 6-En1 (66 mg) and compound 6-En2 (63 mg), each as a grayish-white solid. The chiral purity of each enantiomer was assessed by analytical SFC method S3: compound 6-En1 (99.4% ee) and compound 6-En2 (92% ee).

[0310] The following single enantiomers were isolated in a manner similar to that of compound number 6-En1 and compound number 6-En2 (using appropriate purification methods known to those skilled in the art): compound number 14-En1 (99.9% ee) and compound number 14-En2 (99.8% ee).

[0311] Example 3: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide (compound number 10) Step 1: A solution of (2-formylpyridin-3-yl)carbamate tert-butyl ester (3.0 g, 13.49 mmol) in DCM (60 mL) was treated with (ethoxycarbonylmethylene)triphenylphosphine (19.39 g, 26.99 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, Rf: 0.35; detection: UV). The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 80 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a brown gel (5.0 g, LC / MS: 57%). The crude product was purified by rapid chromatography using an 80 g silica column and 15% EtOAc in petroleum ether as the eluent to give (E)-3-(3-((tert-butoxycarbonyl)amino)pyridin-2-yl)ethyl acrylate (3.0 g, LC / MS: 99%) as a light brown semi-solid. (LC / MS; m / z 293.3 [M+H]) + ).

[0312] Step 2: A solution of (E)-3-(3-((tert-Butoxycarbonyl)amino)pyridin-2-yl)acrylate (3.0 g, 10.27 mmol) in EtOH (60 mL) was treated with 10% Pd / C (1.5 g) at room temperature. The reaction mixture was stirred in an H2 gas chamber at room temperature for 2 h. The reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.40; detection: UV). The reaction mixture was filtered through a diatomaceous earth filter and washed with EtOH (100 mL). The filtrate was concentrated under reduced pressure to give 3-(3-((tert-Butoxycarbonyl)amino)pyridin-2-yl)propionate (2.8 g, LC / MS: 99%) as a colorless gel. (LC / MS; m / z 295.4 [M+H]) + ).

[0313] Step 3: A solution of ethyl 3-(3-((tert-butoxycarbonyl)amino)pyridin-2-yl)propionate (2.8 g, 9.52 mmol) in DCM (28 mL) was treated with TFA (14 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.20; detection: UV). The reaction mixture was concentrated under reduced pressure and the residue was diluted with saturated aqueous NaHCO3 solution (50 mL) (pH 7–8) and extracted with 10% MeOH in DCM (6 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3,4-dihydro-1,5-naphthyl-2(1H)-one (1.4 g, LC / MS: 99%) as a white solid. (LC / MS; m / z 149.2 [M+H]) + ).

[0314] Step 4:A solution of 3,4-dihydro-1,5-naphthidium-2(1H)-one (2.0 g, 13.51 mmol) in DMF (20 mL) was treated with NaH (0.6 g, 27.02 mmol, 60%) at 0 °C, and the mixture was stirred at room temperature for 30 min. Benzyl chloride (1.7 g, 13.51 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 4 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.42; detection: UV). The resulting solution was quenched with cooled water (100 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude product (3.0 g, LC / MS: 80%). The crude product was purified by rapid chromatography using an 80 g column (silica) and 2% MeOH in DCM as the eluent to give 2.6 g (LC / MS: 82%), a pale yellow solid, as 1-benzyl-3,4-dihydro-1,5-naphthidium-2(1H)-one. (LC / MS; m / z 239.2 [M+H]) + ).

[0315] Step 5: A solution of 1-benzyl-3,4-dihydro-1,5-naphthidium-2(1H)-one (2.6 g, 10.92 mmol) in THF (52 mL) was treated with LiHMDS (1.0 M in THF) (22 mL, 21.84 mmol) at -78 °C. Ethyl chloroformate (1.18 mL, 12.01 mmol) was added at -78 °C, and the reaction mixture was stirred at -78 °C for 30 min. The reaction was monitored by TLC (mobile phase: 70% EtOAc in petroleum ether, Rf: 0.37, detection: UV). The reaction mixture was heated to room temperature, quenched with saturated aqueous NH4Cl solution (100 mL), and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a brown gel (3.0 g, LC / MS: 63%). The crude product was purified by rapid chromatography using an 80 g silica gel column and 50% EtOAc in petroleum ether as the eluent to give ethyl 1-benzyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyl-3-carboxylate (2.5 g, LC / MS: 76%) as a pale yellow solid. (LC / MS; m / z 311.0 [M+H]) + ).

[0316] Step 6:A solution of ethyl 1-benzyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyl-3-carboxylate (2.5 g, 10.50 mmol) in THF (25 mL) was treated with 2M BH3·DMS in THF (20 mL, 52.52 mmol) at 0 °C. The reaction mixture was heated to 70 °C and stirred for 90 min. The reaction was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.52, detection: UV). The reaction mixture was cooled to 0 °C and quenched with MeOH (30 mL). The reaction mixture was heated to 70 °C and stirred for 6 h, and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.13, detection: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a brown gel (2.5 g, LC / MS: 77%). The crude product was purified by rapid chromatography using an 80 g silica gel column and 10% MeOH in DCM as the eluent to give a light brown gel (1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methanol (Int-2) (1.5 g, LC / MS: 87%). (LC / MS; m / z 255.3 [M+H]) + ).

[0317] Step 7: A solution of Int-2 (1.5 g, 5.90 mmol) in THF (30 mL) was treated at 0 °C with phthalimide (1.3 g, 8.85 mmol), TPP (2.3 g, 8.85 mmol), and DIAD (1.73 mL, 8.85 mmol). The reaction mixture was heated to 70 °C and stirred for 16 h, and monitored by TLC (mobile phase: 5% MeOH in DCM; Rf: 0.52; detection: UV). The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (2 x 80 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude product (5.0 g, LC / MS: 48%). The crude product was purified by reversed-phase chromatography using a 120 g C18 column and 20% ACN in H2O as the eluent to give 2-((1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isoindoline-1,3-dione (1.0 g, LC / MS: 82%) as a light brown solid. (LC / MS; m / z 384.0 [M+H])+ ).

[0318] Step 8: A solution of 2-((1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isoindoline-1,3-dione (1.0 g, 2.61 mmol) in MeOH (1.0 mL) was treated at room temperature with ammonium formate (1.07 g, 16.97 mmol) and 10% Pd / C (1.5 g). The reaction mixture was stirred at 70 °C for 16 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.33, detection: UV). The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, and washed with MeOH (150 mL). The filtrate was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give a brown gel (800 mg, LC / MS: 35%). The crude product was purified by reversed-phase column chromatography using a 40 g C18 column and 40% ACN in H2O as the eluent to give 2-((1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isoindoline-1,3-dione (270 mg, LC / MS: 94%) as a light brown solid. (LC / MS; m / z 294.3 [M+H)) + ).

[0319] Step 9:A solution of 2-((1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isoindoline-1,3-dione (260 mg, 0.64 mmol) in 1,4-dioxane (6 mL) was treated with Cs₂CO₃ (720.99 mg, 2.21 mmol). The reaction mixture was degassed by bubbling argon for 5 min, then Pd₂(dba)₃ (48.75 mg, 0.053 mmol), X-Phos (50.68 mg, 0.106 mmol), and 1-iodo-4-(trifluoromethyl)benzene (289.64 mg, 1.06 mmol) were added, and the reaction mixture was heated to 100 °C for 1 h by microwave irradiation. The reaction was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.39, detection: UV). The reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give a crude product (500 mg, LC / MS: 39%). The crude product was purified by rapid chromatography using a 24 g silica gel column and 50% EtOAc in petroleum ether as the eluent to give a pale brown gel-like 2-((1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isoindoline-1,3-dione (190 mg, LC / MS: 98%). (LC / MS; m / z 437.3 [M+H]) + ).

[0320] Step 10: A solution of 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)isoindoline-1,3-dione (190 mg, 0.43 mmol) in EtOH (4 mL) was treated with hydrazine hydrate (0.21 mL, 4.34 mmol). The reaction mixture was stirred at 80 °C for 2 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.10; detection: UV). The reaction mixture was cooled to room temperature, filtered, washed with EtOH (20 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with ACN (15 mL), filtered, and washed with ACN (10 mL). The filtrate was concentrated under reduced pressure to give a yellow gel-like substance, (120 mg, LC / MS: 96%), of (4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methylamine (LC / MS: m / z 308.3 [M+H)). + ).

[0321] Step 11: A solution of (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methylamine (110 mg, 0.35 mmol) in DCM (5.0 mL) was cooled to 0 °C and treated under a nitrogen atmosphere with a solution of TEA (0.25 mL, 1.79 mmol) and acryloyl chloride (0.029 mL, 0.35 mmol) in DCM (2.0 mL). The reaction mixture was stirred at 0 °C for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.54; detection: UV). The reaction mixture was diluted with H₂O (40 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a pale yellow gel (150 mg, LC / MS: 81%). The crude product was purified by preparative HPLC using H3, and the collected fractions were concentrated under reduced pressure and lyophilized to give N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)acrylamide (compound number 10) as a white solid (36.5 mg, LC / MS: 99.2%). (LC / MS; m / z 362.5 [M+H)) + Chiral SFC purification: Compound 10 (308 mg) was purified by preparative SFC method K2 to obtain compound 10-En1 (109 mg) and compound 10-En2 (80 mg), each as a grayish-white solid. The chiral purity of each enantiomer was assessed by analytical SFC method S1: compound 10-En1 (99.9% ee) and compound 10-En2 (99.7% ee).

[0322] The following compounds were prepared in a manner similar to that of compound number 10 (using appropriate reagents and purification methods known to those skilled in the art): compound number 12 (acetyl chloride was used in step 11).

[0323] The following single enantiomers were isolated in a manner similar to that of compound 10-En1 and compound 10-En2 (using appropriate purification methods known to those skilled in the art): compound 12-En1 (99.9% ee), compound 12-En2 (99.2% ee), compound 15-En1 (96% ee), and compound 15-En2 (99.6% ee).

[0324] Example 4: Synthesis of 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetic acid (compound number 13) Step 1: A solution of Int-2 (1.0 g, 3.932 mmol) in DCM (18 mL) was treated at 0 °C with a solution of Et3N (1.644 mL, 11.796 mmol) and methanesulfonyl chloride (0.493 g, 4.325 mmol) in DCM (2 mL). The reaction mixture was stirred at 0 °C for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.45, detection: UV). The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give methyl methanesulfonic acid (1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl) as a light brown semi-solid (1.2 g, LC / MS: 93%). (LC / MS; m / z 333.5 [M+H]) + ).

[0325] Step 2: A solution of methyl methanesulfonate (1.2 g, 3.610 mmol) in DMF (20 mL) was treated at room temperature with Et3N (0.753 mL, 5.415 mmol) and tetrabutylammonium cyanide (1.161 g, 4.332 mmol). The reaction mixture was stirred at 90 °C for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 50, detection: UV). The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown semi-solid (2.1 g, LC / MS: 76%). The crude product was purified by column chromatography (silica gel) using 5% MeOH in DCM as the eluent. The pure fraction was concentrated under reduced pressure to give 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetonitrile (1.5 g, LC / MS: 78%) as a brown semi-solid. (LC / MS; m / z 264.2 [M+H]) + ).

[0326] Step 3: Freshly prepared HCl gas was bubbled through a solution of 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetonitrile (1.0 g, 3.797 mmol) in MeOH (20 mL) for 30 min at 0 °C. The reaction mixture was then stirred at 75 °C for 16 h and monitored by TLC (mobile phase: 100% EtOAc, Rf: 50, detection: UV). The reaction mixture was concentrated and quenched with a saturated NaHCO3 (50 mL) aqueous solution, and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give methyl 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetate (630 mg, LC / MS: 70%) as a brown semi-solid. (LC / MS; m / z 297.3 [M+H]) + ).

[0327] Step 4: A solution of methyl 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetate (600 mg, 2.024 mmol) in MeOH (15 mL) was treated at room temperature with ammonium formate (829.821 mg, 13.159 mmol) and 10% Pd / C (600 mg). The reaction mixture was stirred at 80 °C for 16 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.27, detection: UV). The reaction mixture was filtered through a diatomaceous earth mat and washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give methyl 2-(1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetate (380 mg, LC / MS: 61%) as a pale brown semi-solid. (LC / MS; m / z 207.1 [M+H]) + ).

[0328] Step 5:A solution of methyl 2-(1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetate (350 mg, 1.697 mmol) in 1,4-dioxane (12 mL) was treated with Cs₂CO₃ (2530.243 mg, 5.940 mmol) and degassed by bubbling argon for 5 min. Pd₂(dba)₃ (77.699 mg, 0.085 mmol), X-Phos (80.897 mg, 0.170 mmol), and 1-iodo-4-(trifluoromethyl)benzene (738.564 mg, 2.715 mmol) were added, and the mixture was heated to 100 °C for 1 h by microwave irradiation. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.50, detection: UV). The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give a crude product (1.2 g, LC / MS: 30%). The crude product was purified by column chromatography (silica gel) using 3% MeOH in DCM as the eluent. The purified fraction was concentrated under reduced pressure to give methyl 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidium-3-yl)acetate (390 mg, LC / MS: 66%) as a pale brown semi-solid. (LC / MS; m / z 351.3 [M+H]) + ).

[0329] Step 6:A stirred solution of methyl 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetate (380 mg, 1.085 mmol) in THF (4 mL) and water (4 mL) was treated with lithium hydroxide hydrate (91.029 mg, 2.169 mmol) at room temperature for 16 h. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.16, detection: UV). The reaction mixture was concentrated, diluted with water (1 mL), acidified with formic acid (3 drops, pH 2–3), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to give a brown semi-solid (365 mg, LC / MS: 64%). The crude product was purified by preparative HPLC using H2, and the pure fraction was concentrated under reduced pressure to give 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acetic acid (compound number 13) (115 mg, LC / MS: 98%) as a white solid. (LC / MS; m / z 337.3 [M+H)) + ).

[0330] Example 5: Synthesis of 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthidine 1-oxide (compound number 16) The stirred solution of compound 12 (200 mg, 0.573 mmol) in DCM (8 mL) was cooled to 0 °C and treated with m-CPBA (118.28 mg, 0.687 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.53; detection: UV). The reaction mixture was diluted with H₂O (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a pale brown semi-solid (LC / MS: 73%). The crude product was purified by preparative HPLC using H4, and the pure fraction was concentrated under reduced pressure to give 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthidine 1-oxide (compound number 16) (35 mg, LC / MS: 99%) as a grayish-white solid. (LC / MS; m / z 366.2 [M+H)) + ).

[0331] Example 6: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide (compound number 17) Step 1: A solution of titanium tetrachloride (14.365 mL, 131.485 mmol) in CCl4 (20 mL) was treated with THF (300 mL) at 0 °C and stirred for 15 min. After 15 min, a solution of 3-nitropyridine-2-carboxaldehyde (10 g, 65.742 mmol) in THF (100 mL) and diethyl malonate (10.029 mL, 65.742 mmol) in THF (100 mL) were added at 0 °C and stirred for 5 min. After 5 min, a solution of pyridine (21.199 mL, 262.969 mmol) in THF (100 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature under a N2 atmosphere for 16 h. The reaction progress was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.58, detection: UV). The reaction mixture was quenched with ice-cold water (600 mL) and extracted with EtOAc (2 × 600 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (500 mL) and brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to give a brown liquid (24.5 g). The crude product was purified by rapid column chromatography (silica) using a gradient of 0-100% EtOAc in hexane as the eluent. The purified fraction was concentrated under reduced pressure to give diethyl 2-((3-nitropyridin-2-yl)methylene)malonate (20.9 g, LC / MS: 96%) as a light brown gel. (LC / MS; m / z 295.1 [M+H]) + ).

[0332] Step 2:A solution of diethyl imidazole 2-((3-nitropyridin-2-yl)methylene)malonate (20 g, 67.96 mmol) in MeOH (200 mL) was fractionally treated with NaBH4 (5 g, 135 mmol) at 0 °C. The reaction mixture was heated to 25 °C and stirred for 3 h under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h and the reaction progress was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether; Rf: 0.63; detection: UV). The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and concentrated under reduced pressure. The remaining aqueous mixture was extracted with EtOAc (2 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give a light brown gel (20 g, LC / MS: 67%). The crude product was purified by column chromatography using silica gel and 40% ethyl acetate in petroleum ether as the eluent to give diethyl 2-((3-nitropyridin-2-yl)methyl)malonate (13 g, LC / MS: 93%) as a light brown liquid. (LC / MS; m / z 297.2 [M+H]) + ).

[0333] Step 3: A solution of diethyl 2-((3-nitropyridin-2-yl)methyl)malonate (13 g, 43.87 mmol) in AcOH (130 mL) was treated with iron powder (12.2 g, 219.38 mmol) at room temperature. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether; Rf: 0.12; detection: UV). The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth mat, and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure, and the residue was alkalized with a saturated aqueous solution of NaHCO3 (pH approximately 8) and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give ethyl 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyl-3-carboxylate (6 g, LC / MS: 99%) as a white solid. (LC / MS; m / z 221.2 [M+H]) + ).

[0334] Step 4:A solution of ethyl 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyl-3-carboxylate (6 g, 27.24 mmol) in THF (60 mL) was treated at 0 °C with BH3·THF (1.0 M in THF, 81 mL, 81.73 mmol). The reaction mixture was stirred at room temperature for 24 h and monitored by TLC (mobile phase: 100% EtOAc, Rf = 0.67, detection: UV). The reaction mixture was cooled to 0 °C, quenched dropwise with MeOH (100 mL), and stirred at 70 °C under a nitrogen atmosphere for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a pale brown semi-solid (7 g). The crude product was purified by column chromatography (silica gel) using 10% MeOH as the eluent in DCM to give (1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methanol (3.5 g, LC / MS: 96%) as a light brown solid. (LC / MS; m / z 165.0 [M+H]) + ).

[0335] Step 5: A solution of (1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methanol (3.5 g, 21.31 mmol) in 1,4-dioxane (50 mL) was treated at room temperature with 1-iodo-4-(trifluoromethyl)benzene (8.6 g, 31.97 mmol) and NaOtBu (6.1 g, 63.94 mmol). The reaction mixture was degassed by bubbling nitrogen for 10 min, and then Pd2(dba)3 (0.97 g, 1.06 mmol) and XPhos (1.01 g, 2.13 mmol) were added at room temperature. The reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.5, detection: UV). The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth pad, and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a brown liquid (4 g, LC / MS: 70%). The crude product was purified by column chromatography using silica gel (40 g) and 5% MeOH in DCM as eluent to give (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methanol (Int-3) (2.8 g, LC / MS: 98%) as a brown solid. (LC / MS; m / z 309.2 [M+H)) + ).

[0336] Step 6:A solution of Int-3 (1 g, 3.24 mmol) in DCM (15 mL) was treated at 0 °C with Et3N (1.35 mL, 9.73 mmol) and methanesulfonyl chloride (0.31 mL, 3.89 mmol). The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 100% EtOAc in petroleum ether; Rf: 0.38; detection: UV). The reaction mixture was cooled to 0 °C, quenched with water (30 mL), and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure to give methyl methanesulfonic acid (1.2 g, LC / MS: 91%) as a brown gel. (LC / MS; m / z 387.2 [M+H]) + ).

[0337] Step 7: A solution of methyl (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methanesulfonic acid (1.2 g, 3.10 mmol) in DMF (12 mL) and H₂O (4 mL) was treated with NaN₃ (0.76 g, 11.68 mmol) at room temperature. The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 16 h. The reaction progress was monitored by TLC (mobile phase: 100% EtOAc; Rf: 0.48; detection: UV). The reaction mixture was cooled to 0 °C, quenched with ice water (100 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give 3-(azidomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidine (1 g, LC / MS: 82%) as a brown gel. (LC / MS; m / z 334.2 [M+H]) + ).

[0338] Step 8:A solution of 3-(azidomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidine (1 g, 3.00 mmol) in MeOH (10 mL) was treated with 10% Pd / C (700 mg) under hydrogen (gas bag) and stirred at room temperature for 3 h. The reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM; Rf: 0.07; detection: UV). The reaction mixture was filtered through a diatomaceous earth pad and washed with EtOAc (100 mL), and the filtrate was concentrated under reduced pressure to give (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidine-3-yl)methylamine (750 mg, LC / MS: 78%) as a brown gel. (LC / MS; m / z 308.1 [M+H]) + ).

[0339] Step 9: A solution of (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methylamine (250 mg, 0.81 mmol) in DCM (4 mL) was treated at 0 °C with a solution of Et3N (0.28 mL, 2.03 mmol) and propionyl chloride (75 mg, 0.81 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 1 h and the reaction progress was monitored by TLC (mobile phase: 10% MeOH in DCM; Rf: 0.5; detection: UV). The reaction mixture was diluted with DCM (50 mL), washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a yellow gel (260 mg, LC / MS: 73%). The crude product was purified by preparative HPLC method H5, and the collected fractions were concentrated under reduced pressure and lyophilized to give N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)methyl)propionamide (compound number 17) (35 mg, LC / MS: 96%) as a grayish-white solid. (LC / MS; m / z 364.3 [M+H)) + Chiral SFC purification: Compound 17 (75 mg) was purified by preparative SFC method K3 to obtain compound 17-En1 (27 mg) and compound 17-En2 (22 mg), each as a pale yellow solid. The chiral purity of each enantiomer was assessed by analytical SFC method S4: compound 17-En1 (99.8% ee) and compound 17-En2 (99% ee).

[0340] The following compounds were prepared in a manner similar to that of compound 17 (using appropriate reagents and purification methods known to those skilled in the art): compound 18 (using cyclopropanecarboxylic acid, HATU, and DIPEA in DMF in step 9), compound 19 (using MsCl in step 9), compound 21 (using 6-methoxy-3-nitropyridine-2-carboxaldehyde in step 1 and acryloyl chloride in step 9), compound 22 (using 6-methoxy-3-nitropyridine-2-carboxaldehyde in step 1 and AcCl in step 9), compound 25 (using oxetane-3-one, NaCNBH3, and AcOH in DCE in step 9), compound 28 (using (S)-5-oxopyrrolidine-2-carboxylic acid, HATU, and DIPEA in DMF in step 9), and compound 29 (using (R) in DMF in step 9). Compound 30 (using 1-methyl-1H-imidazol-5-carboxylic acid, HATU, and DIPEA in DMF in step 9), Compound 31 (using 4-chlorobutyryl chloride in step 9, followed by KotBu cyclization in THF), Compound 34 (using acetic acid-2,2,2-d3 anhydride, TEA, and DMAP in step 9), Compound 35 (using 2-phenylacetyl chloride in step 9), Compound 38 (using 3,3,3-trifluoropropionyl chloride in step 9), Compound 39 (using isobutyric acid, HATU, and DIPEA in DMF in step 9), Compound 40 (using benzoyl chloride in step 9), Compound 43 (using methylcarbamoyl chloride in step 9), and Compound 53 (using 2-bromo-5-(trifluoromethyl)pyridine in step 5).

[0341] The following single enantiomers were isolated in a manner similar to that of compounds 17-En1 and 17-En2 (using appropriate purification methods known to those skilled in the art): compound 22-En1 (99.8% ee), compound 22-En2 (99.4% ee), compound 34-En1 (99.8% ee), compound 34-En2 (98% ee), compound 38-En1 (99.4% ee), and compound 38-En2 (94% ee).

[0342] Example 7: Synthesis of (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthid-3-yl)acrylic acid (compound number 20) Step 1:A solution of Int-3 (500 mg, 1.62 mmol) in DCM (10 mL) was treated with DMP (1.37 g, 3.24 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether; Rf: 0.49; detection: PMA staining). The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (2 x 40 mL). The combined organic layers were washed with sodium thiosulfate aqueous solution (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthidine-3-carboxaldehyde (500 mg, LC / MS: 37%) as a brown gel (LC / MS; m / z 307.3 [M+H...

Claims

1. A compound of formula I: I, Or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein: Z is chosen freely = N-, = N + The group consisting of - and =C-; Q 1 =N- or =CX 1 -; Q 2 =N- or =CX 2 -; Q 3 =N- or =CX 3 -; X 1 X 2 and X 3 Choose independently from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) C1-C6 alkyl groups, (v) C1-C6 haloalkyl, (vi) -OZ 1 ,as well as (vii) -NZ 3 Z 4 ; When Z is equal to C-, R 1 Choose from the following groups: (i) Hydrogen, (ii) Halogens, (iii) Unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from Z. 1 The group formed (iv) C1-C6 haloalkyl groups, (v) -OZ 1 ,as well as (vi) -NZ 3 Z 4 ; When Z is =N- or =N + - At that time, R 1 -O - Or it may not exist; R 2 Choose from the following groups: (i) Hydrogen, (ii) C1-C6 alkyl groups, (iii) -(CH2)n -R 3a , (iv) -O-(CH2) n -R 3a , (v) unsubstituted or substituted C2-C6alkenyl, wherein one or more substituents are independently selected from the group consisting of: i. hydrogen, ii. unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of:

1. halogen, 2. hydroxy, 3. cyano, 4. -OZ 1 , 5. -SZ 1 , 6. -NZ 3 Z 4 , 7. -C(=O)Z 2 8. -C(=0)OH, 9. -C(=O)OZ 2 , 10. -C(=O)NZ 3 Z 4 , 11. -NZ 5 C(=O)Z 2 , 12. -NZ 5 C(=O)OZ 2 , 13. -NZ 5 C(=O)NZ 3 Z 4 , 14. -S(=O)2Z 8 , 15. -S(=O)2NZ 3 Z 4 , 16. -S(=O)(=NZ 6 )Z 2 , 17. -S(=Z 6 )(=NZ 7 )Z 2 , 18. -S(=O)(=NZ 6 )NZ 3 Z 4 , 19. -NZ 5 S(=O)2Z 2 , 20. -NZ 5 S(=O)2NZ 3 Z 4 , 21. -NZ 5 S(=O)(=NZ 6 )Z 2 , 22. -NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and 23. -NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , iii. -C(=O)Z 2 iv. -C(=O)OZ 2 , v. -C(=O)NZ 3 Z 4 , vi. -S(=0)2Z 8 , vii. -S(=0)2NZ 3 Z 4 , viii. -S(=0)(=NZ 6 )Z 2 , ix. -S(=Z 6 )(=NZ 7 ) 2 , x. -S(=0)(=NZ 6 )NZ 3 Z 4 , and (vi) -(CH2)-NR 3a R 3b ; n is 0 or 1; R 3a selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted Ci-C6alkyl, wherein one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) -OZ 1 , (d) -SZ 1 , (e) -NZ 3 Z 4 , (f) -C(=O)Z 2 (g) -C(=0)OH, (h) -C(=0)OZ 2 , (i) -C(=O)NZ 3 Z 4 , (j) -NZ 5 C(=O)Z 2 , (k) -NZ 5 C(=O)OZ 2 , (l) -NZ 5 C(=O)NZ 3 Z 4 , (m) -S(=0)2Z 8 , (n) -S(=0)2NZ 3 Z 4 , (o) -S(=0)(=NZ 6 )Z 2 , (p) -S(=Z 6 )(=NZ 7 )Z 2 , (q) -S(=0)(=NZ 6 )NZ 3 Z 4 , (r) -NZ 5 S(=O)2Z 2 , (s) -NZ 5 S(=O)2NZ 3 Z 4 , (t) -NZ 5 S(=O)(=NZ 6 )Z 2 , (u) -NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and (v) -NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 , (iii) -C(=O)Z 2 , (iv) -C(=0)0Z 2 , (v) -C(=0)NZ 3 Z 4 , (vi) -S(=0)2Z 8 , (vii) -S(=0)2NZ 3 Z 4 , (viii) -S(=0)(=NZ 6 )Z 2 , (ix) -S(=Z 6 )(=NZ 7 ) 2 , (x) -S(=0)(=NZ 6 )NZ 3 Z 4 , and (xi) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, C2-C8alkenyl, and Ci-C6alkyl, and zero or more heterocycle carbons can be oxidized to form C=0; R 3b selected from the group consisting of hydrogen and Ci-C6alkyl; R 4 selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted Ci-C6alkyl, wherein one or more substituents are independently selected from the group consisting of: (a) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) Ci-C6alkyl, (4) C3-C6cycloalkyl, (5) Ci-C6haloalkyl, (6) -OZ 1 , (7) C2-C6alkenyl, and (8) C2-C6alkynyl, (b) unsubstituted or substituted C3-C6cycloalkyl, wherein zero or more cycloalkyl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) Ci-C6alkyl, (4) C3-C6cycloalkyl, (5) Ci-C6haloalkyl, and (6) -OZ 1 , (c) C2-C6alkynyl, and (d) unsubstituted or substituted 3- to 6-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, cyano, C2-C8alkenyl, and Ci-C6alkyl, (xiv) unsubstituted or substituted C6-Ci8-aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: 10 (xiv) unsubstituted or substituted C6-Ci8-aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) Ci-C6alkyl, (d) C3-C6cycloalkyl, (e) Ci-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form (xv) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein zero or more heteroaryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) Ci-C6alkyl, (d) C3-C6cycloalkyl, (e) Ci-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form (xvi) unsubstituted or substituted C3-C6cycloalkyl, wherein zero or more cycloalkyl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) Ci-C6alkyl, (d) C3-C6cycloalkyl, (e) Ci-C6haloalkyl, and (f) -OZ 1 , (xvii) unsubstituted or substituted 3- to 6-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) Ci-C6alkyl, (d) C3-C6cycloalkyl, (e) Ci-C6haloalkyl, and (f) -OZ 1 , (xviii) -S(=0)2Z 2 and (xix) -C(=0)Z 2 ; each Z is independently selected from the group consisting of: 1 is independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted Ci-C6alkyl, wherein one or more substituents are independently selected from the group consisting of: a. cyano, b. -S(=0)2Z 8 , c. C3-C8cycloalkyl, d. -C(=0)OH, e. -S(=O)2Z 8 , f. -NZ 3 Z 4 , g. halogen, h. unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl and C2-C6alkenyl, and zero or more heterocycle carbons can be oxidized to form C=0, i. unsubstituted or substituted 3- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl and C2-C6alkenyl, and zero or more heteroaryl carbons can be oxidized to form C=0, and j. unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and cyano, (iii) unsubstituted or substituted C2-C6alkenyl, wherein one or more substituents are independently selected from the group consisting of: a. cyano, b. -S(=0)2Z 8 , c. halogen, and d. unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of: i. cyano, ii. -S(=0)2Z 8 , iii. C3-C8cycloalkyl, iv. -C(=0)OH, v. -S(=0)2Z 8 , vi. -NZ 3 Z 4 , vii. halogen, viii. unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl and C2-C6alkenyl, and zero or more heterocycle carbons can be oxidized to form C=0, ix. unsubstituted or substituted 3- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl and C2-C6alkenyl, and zero or more heteroaryl carbons can be oxidized to form C=0, and x. unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, C1-C6haloalkyl, cyano, -S(=0)2Z 8 , -NZ 3 Z 4 and unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl, and C2-C6alkenyl, and zero or more heterocycle carbons can be oxidized to form C=0, (iv) C2-C6alkynyl, (v) C3-C6cycloalkyl, (vi) C3-C6cycloalkenyl, (vii) unsubstituted or substituted C3-C8cycloalkyl, wherein zero or more cycloalkyl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, -S(=0)2Z 8 , -NZ 3 Z 4 , and 4- to 8-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, (viii) Unsubstituted or substituted C6-C 10 Aryl group, wherein zero or more aryl carbons can be oxidized to form C=O, and one or more substituents are independently selected from the group consisting of halogens, cyano groups, and unsubstituted or substituted C1-C6 alkyl groups, wherein one or more substituents are independently selected from the group consisting of halogens, cyano groups, and -S(=O)2Z. 8 -NZ 3 Z 4 The group consists of 4 to 8-membered heterocycles, in which zero or more heterocyclic carbons can be oxidized to form C=O. (ix) unsubstituted or substituted 3- to 8-membered heteroaryl, wherein zero or more heteroaryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl and C2-C6alkenyl, and (x) unsubstituted or substituted 3- to 8-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, C1-C6alkyl and C2-C6alkenyl; each Z is independently selected from the group consisting of: 2 is independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of C2-C6alkenyl, cyano, -C(=0)OH, -S(=0)2Z 8 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, (iii) unsubstituted or substituted C2-C6alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, -S(=0)2Z 8 , halogen, and unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, -S(=0)2Z 8 , -NZ 3 Z 4 , and 4- to 8-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, (iv) C2-C6alkynyl, (v) C3-C6cycloalkyl, and (vi) C3-C6cycloalkenyl; each Z is independently selected from the group consisting of: 3 is independently selected from the group consisting of: (i) unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of C2-C6alkenyl, cyano, -C(=0)OH, -S(=0)2Z 8 , halogen, -N(unsubstituted or substituted C1-C6alkyl)Z 4 , -N(unsubstituted or substituted C2-C6alkenyl)Z 4 , -N(unsubstituted or substituted C2-C6alkynyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkenyl)Z 4 , and 4- to 8-membered heterocyclic ring, wherein zero or more heterocyclic carbons can be oxidized to form C=0, (ii) unsubstituted or substituted C2-C6-alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, -S(=0)2Z 8 , halogen and unsubstituted or substituted C1-C6-alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, -S(=0)2Z 8 , -N(unsubstituted or substituted C1-C6-alkyl)Z 4 , -N(unsubstituted or substituted C2-C6-alkenyl)Z 4 , -N(unsubstituted or substituted C2-C6-alkynyl)Z 4 , -N(unsubstituted or substituted C3-C6-cycloalkyl)Z 4 , -N(unsubstituted or substituted C3-C6-cycloalkenyl)Z 4 and 4- to 8-membered heterocyclic ring, wherein zero or more heterocyclic carbons can be oxidized to form C=0, (iii) unsubstituted or substituted C2-C6alkynyl, wherein one or more substituents are independently selected from the group consisting of cyano, -S(=0)2Z 8 , halogen and unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, OZ 1 , -S(=0)2Z 8 , -N(unsubstituted or substituted C1-C6alkyl)Z 4 , -N(unsubstituted or substituted C2-C6alkenyl)Z 4 , -N(unsubstituted or substituted C2-C6alkynyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkenyl)Z 4 and 4- to 8-membered heterocycle, wherein zero or more heterocyclic carbons can be oxidized to form C=0, (iv) unsubstituted or substituted C3-C6cycloalkyl, wherein zero or more cycloalkyl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, -S(=0)2Z 8 , -N(unsubstituted or substituted C1-C6alkyl)Z 4 , -N(unsubstituted or substituted C2-C6alkenyl)Z 4 , -N(unsubstituted or substituted C2-C6alkynyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkenyl)Z 4 and 4- to 8-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0, and (v) unsubstituted or substituted C3-C6-cycloalkenyl, wherein zero or more cycloalkenyl carbons can be oxidized to form C=0 and one or more substituents are independently selected from the group consisting of halogen, cyano and unsubstituted or substituted C1-C6-alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, -S(=0)2Z 8 , -N(unsubstituted or substituted C1-C6-alkyl)Z 4 , -N(unsubstituted or substituted C2-C6-alkenyl)Z 4 , -N(unsubstituted or substituted C2-C6-alkynyl)Z 4 , -N(unsubstituted or substituted C3-C6-cycloalkyl)Z 4 , -N(unsubstituted or substituted C3-C6-cycloalkenyl)Z 4 and 4- to 8-membered heterocycle, wherein zero or more heterocycle carbons can be oxidized to form C=0; each Z 4 , Z 5 , Z 6 and Z 7 is independently selected from the group consisting of (i) hydrogen, (ii) C1-C6alkyl, and (iii) C3-C6cycloalkyl; each Z is independently selected from the group consisting of: 8 is independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano and C1-C6alkyl, (iii) unsubstituted or substituted C2-C6alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of -N(unsubstituted or substituted C1-C6alkyl)Z 4 , -N(unsubstituted or substituted C2-C6alkenyl)Z 4 , -N(unsubstituted or substituted C2-C6alkynyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkyl)Z 4 , -N(unsubstituted or substituted C3-C6cycloalkenyl)Z 4 and 4- to 8-membered heterocycle, wherein zero or more heterocyclic carbons can be oxidized to form C=0, (iv) halogen, and (v) hydroxyl.

2. The compound of claim 1, having Formula II: II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

3. The compound of claim 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 , Q 2 , and Q 3 are =CX 1 -, =CX 2 -, and =CX 3 -, respectively.

4. The compound of claim 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 5. The compound of claim 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

6. The compound of claim 1, having Formula III: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. III, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

7. The compound of claim 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 , Q 2 , and Q 3 are =CX 1 -, =CX 2 -, and =CX 3 -, respectively.

8. The compound of claim 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 9. The compound of claim 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

10. The compound of claim 1 having Formula IV: IV, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

11. The compound of claim 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 , X 2 , and X 3 are independently selected from the group consisting of -H, -OH, substituted or unsubstituted C1-C6alkyl, and -O-methyl.

12. The compound of claim 10 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 13. The compound of claim 10 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is Ci haloalkyl.

14. The compound of claim 1 having Formula V: V， or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

15. The compound of claim 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 , X 2 , and X 3 are independently selected from the group consisting of -H, -OH, and -O-methyl.

16. The compound of claim 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 17. The compound of claim 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

18. The compound of claim 1 having Formula VI: VI, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

19. The compound of claim 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 20. The compound of claim 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

21. The compound of claim 1 having Formula VII: VII, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

22. The compound of claim 21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 23. The compound of claim 21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

24. The compound of claim 1 having Formula VIII: VIII, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

25. The compound of claim 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 , Q 2 , and Q 3 are =CX 1 -, =CX 2 -, and =CX 3 -, respectively.

26. The compound of claim 24 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 27. The compound of claim 24 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

28. The compound of claim 1 having Formula IX: IX, or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

29. The compound of claim 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q 1 , Q 2 , and Q 3 are =CX 1 -, =CX 2 -, and =CX 3 -, respectively.

30. The compound of claim 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is unsubstituted or substituted C6-C 10 aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of: (a) halogen, (b) cyano, (c) C1-C6alkyl, (d) C3-C6cycloalkyl, (e) C1-C6haloalkyl, (f) -OZ 1 and (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 10 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents are independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6haloalkyl, and -OZ 1 (g) unsubstituted or substituted C6-Ci8aryl, wherein zero or more aryl carbons can be oxidized to form 31. The compound of claim 28 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 4 is substituted C6aryl, wherein zero or more aryl carbons can be oxidized to form C=0, and one or more substituents is C1haloalkyl.

32. A compound of Formula X: X， or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein: Z is selected from the group consisting of =N-, =N + - and =C-; X 1 is selected from the group consisting of -H, -0(Ci-C6alkyl), substituted or unsubstituted Ci-C6alkyl, and -OH; when Z is =N- or =N + - R 1 is -O - or is absent; when Z is =C-, R 1 is -OR 6 or unsubstituted or substituted C2-C6alkyl, wherein one or more substituents are independently selected from the group consisting of R 6 ; R 2 selected from the group consisting of: (i) -OR 3 , (ii) unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of R 3 and the group consisting of (iii) unsubstituted or substituted C2-C6alkenyl, wherein one or more substituents are independently selected from the group consisting of R 4 consisting of R R 3 selected from the group consisting of: (i) unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of R 4 consisting of R 4 consisting of R 4 consisting of R 4 consisting of R 4 consisting of R < (ii) -C(=O)R 4 and (iii) -NHR 4 ; R 4 is selected from the group consisting of: (i) -C(=O)R 5 , (ii) -S(=0)2R 5 , (iii) -OH, and (iv) an unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6alkyl, and zero or more heterocycle carbons can be oxidized to form C=O; R 5 selected from the group consisting of: (i) -C1-C6alkyl, (ii) -C2-C6alkenyl, (iii) -O(C1-C6alkyl), (iv) -NH-C1-C6alkyl, (v) -OH, and (vi) unsubstituted or substituted C3-C6cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C1-C6alkyl, and zero or more cycloalkyl carbons can be oxidized to form C=O; R 6 selected from the group consisting of: (i) unsubstituted or substituted C1-C6alkyl, wherein one or more substituents are independently selected from the group consisting of R 6 (ii) and R 6 (iii) consisting of, (ii) Unsubstituted or substituted 3- to 6-membered heteroaryl groups, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heteroaryl carbons can be oxidized to form C=O, and (iii) An unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C1-C6 alkyl groups, and zero or more heterocyclic carbons may be oxidized to form C=O.

33. The compound of claim 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X 1 is selected from the group consisting of -H, -OH, substituted or unsubstituted C1-C6alkyl (e.g., methyl), and -O-methyl.

34. The compound of claim 32 or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein Z is =N-.

35. The compound of claim 32 or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, wherein Z is =C-.

36. The compound of claim 32 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 2 is C1alkyl substituted with one R 3 substituent, and the one R 3 substituent is -NHR 4 .

37. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; (R)- or (S)-N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)acrylamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)propionamide; N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-yl)methyl)methanesulfonamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acrylamide; N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide; 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetic acid; N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide; (R)- or (S)-N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide; (R)- or (S)-methyl ((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)carbamate; 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide; (R)- or (S)-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)propionamide; N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)cyclopropanecarboxamide; N-(methylsulfamoyl)-1-[1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,5-naphthyridin-3- yl]methanamine; (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylic acid; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acrylamide; N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide; (R)-or (S)-N-((6-methoxy-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((6-hydroxy-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; 2-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)oxy)acetic acid; and N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)oxetan- 3 -amine.

38. A compound, or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-((5-((2-oxo-l,2-dihydropyridin-4-yl)methoxy)-l-(4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroquinolin-3-yl)methyl)acrylamide; (R)-N-((5-((2-oxo-l,2-dihydropyridin-4-yl)methoxy)-l-(4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroquinolin-3-yl)methyl)acrylamide; (S)-N-((5-((2-oxo-l,2-dihydropyridin-4-yl)methoxy)-l-(4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroquinolin-3-yl)methyl)acrylamide; N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acrylamide; (R)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acrylamide; (S)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acrylamide; N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide; (R)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide; (S)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide; N-((5-((3-methyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-l-(4- (trifluoromethyl)phenyl)-l,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide; (R)-N-((5-((3-methyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-l-(4- (trifluoromethyl)phenyl)-l,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide; (S)-N-((5-((3-methyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-l-(4- (trifluoromethyl)phenyl)-l,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide; Methyl-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)carbamate; (R)-methyl-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)carbamate; (S)-methyl-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)carbamate; N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)propionamide; (R)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)propionamide; (S)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)propionamide; N-((6-methoxy-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (R)-N-((6-methoxy-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; and (S)-N-((6-methoxy-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide.

39. A compound, or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (R)-or (S)-N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((5-oxo-l-(4-(trifluoromethyl)phenyl)-l,2,3,4,5,6-hexahydro-l,6-naphthyridin-3- yl)methyl)acetamide; (2S)-5-oxo-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)pyrrolidine-2-carboxamide; (2R)-5-oxo-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)pyrrolidine-2-carboxamide; 1-methyl-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)-lH-imidazole-5-carboxamide; 1 -((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-6-carboxamide; N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide; N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acrylamide; N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)- acetamide-2,2,2-d3; (R)-or (S)-N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide-2,2,2-d3; 2-phenyl-N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide; N-acryloyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- methyl)glycine; N-acetyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- methyl)glycine; 3,3,3-trifluoro-N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)propanamide; (R)-or (S)-3,3,3-trifluoro-N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)propanamide; N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)- isobutyramide; N-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)- benzamide; 1 -(4-(1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1 -yl)- prop-2-en-1 -one; N-((6-(trifluoromethyl)-1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthy- ridin-3-yl)methyl)acetamide; 1 -methyl-3-((1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)urea; N-((7-bromo-1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide; N-((6-amino-1 -(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide; N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- methyl)acetamide; N-((3-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (R)- or (S)-N-((3-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((5-methyl-6-oxo-l-(4-(trifluoromethyl)phenyl)-l,2,3,4,5,6-hexahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((7-amino-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; N-((7-fluoro-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; N-((7-chloro-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; N-((6-(dimethylamino)-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((l-(5-(trifluoromethyl)pyridin-2-yl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; N-((6-methyl-5-oxo-l-(4-(trifluoromethyl)phenyl)-l,2,3,4,5,6-hexahydro-l,6- naphthyridin-3-yl)methyl)acetamide; N-((6-ethyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7- yl)methyl)acetamide; N-((6-cyclopropyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin- 3-yl)methyl)acetamide; N-((6-cyano-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-l,5- naphthyridine-2-carboxamide; N-((6-(difluoromethoxy)-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((6-(difluoromethyl)-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; N-((6-bromo-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; and N-((6-ethynyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide.

40. A compound, or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (R)-N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (S)-N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide- 2,2,2-d3; (R)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide- 2,2,2-d3; (S)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide- 2,2,2-d3; 3,3,3-trifluoro-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)propanamide; (R)-3,3,3-trifluoro-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)propanamide; (S)-3,3,3-trifluoro-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)propanamide; N-((3-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (R)-N-((3-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; and (S)-N-((3-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide.

41. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide; (R)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide; (S)-N-((l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)acetamide; N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5-naphthyridin-3- yl)methyl)acetamide; (R)-N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide; and (S)-N-((6-methyl-l-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro-l,5- naphthyridin-3-yl)methyl)acetamide.

42. A pharmaceutical composition comprising a compound of any one of claims 1-41, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.

43. A compound of any one of claims 1-41, or a pharmaceutical composition of claim 42, for use as a medicament.

44. A compound of any one of claims 1-41 or a pharmaceutical composition of claim 42 for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder in an animal, a mammal, or a human.

45. The compound of claim 44, or the pharmaceutical composition of claim 44, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from the group consisting of cancer, fibrosis, and a YAP / TAZ-TEAD activation-mediated congenital disorder.

46. The compound of claim 44, or the pharmaceutical composition of claim 44, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from the group consisting of 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, mesothelioma, and / or sarcoma.

47. The compound of claim 44, or the pharmaceutical composition of claim 44, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblast, adenocarcinoma, angiosarcoma, astrocytic, granulocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, biliary duct cancer, bronchus lung cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplasia (dysdifferentiation and metaplasia), embryonal carcinoma, endometrial carcinoma, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, 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, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung carcinoma, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal carcinoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach carcinoma, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumor, uterine cancer, and Wilms’ tumor.

48. A method for preventing or treating a YAP / TAZ-TEAD activation-mediated disorder in an animal, a mammal, or a human, the method comprising administering to the animal, mammal, or human in need of such prevention or treatment an effective dose of a compound of any one of claims 1-41.

49. The method of treating or preventing a YAP / TAZ-TEAD activation-mediated disorder of claim 48, further comprising administering one or more additional 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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