Indoles, indazoles, and related analogues for inhibiting YAP / TAZ-TEAD

Abstract

The present disclosure relates to novel compounds, for use as medicaments, more particularly for the prevention or treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription, and even more particularly for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to methods for the prevention or treatment of said diseases, comprising the use of the novel compounds.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 293,537, filed December 23, 2021, which is incorporated by reference in its entirety.

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

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

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

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

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

[0007] In Drosophila, loss of function of Hippo or Warts kinases (MST1 / 2 or LATS1 / 2 in mammals) or overexpression of Yorkie (Drosophila homologs of YAP and TAZ) results in dramatic overgrowth of the cuticle as a result of dysregulated cell proliferation and resistance to apoptosis, which in turn increases organ size. In mice, overexpression of YAP, loss of MST1 / 2 or LATS1 / 2 kinase activity, or deletion of NF2 results in upregulation of TEAD target genes and progenitor cell proliferation, resulting in overgrowth of the liver and heart, and ultimately cancer formation in the liver, small intestine, and skin. In contrast, a serine to alanine mutation at position 94 of YAP, i.e., it is unable to bind TEAD and does not form tumors (Zhao et al., 2008, Genes Dev 22, 1962-1971). Similarly, dominant-negative TEAD mutants unable to bind DNA overcome YAP-driven liver tumorigenesis. In addition, NF2 mutant hepatocellular carcinomas were largely suppressed by heterozygous deletion of Yap (Zhang et al., 2010, Dev Cell 19, 27-38). Finally, verteporfin, a small molecule that inhibits YAP-TEAD binding, significantly suppressed the tumorigenic activity of YAP in these models (Liu-Chittenden et al., 2012, Genes Dev 26, 1300-1305).

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

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

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

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

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

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

[0014] However, there remains a great need for new alternative or better therapies for the prevention or treatment of diseases mediated by YAP / TAZ-TEAD activation, such as cancer and fibrosis, among other potential indications. Therapies with better efficacy, fewer side effects, greater activity, less toxicity, or better pharmacokinetic or dynamic properties, or a combination thereof, would be highly welcomed.

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

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

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

[0018] In some aspects, the compounds described herein can be used to treat and / or prevent Hippo-mediated disorders in animals, mammals, and humans, more specifically acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, hemangiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, and more particularly, acute myeloid leukemia, acute myelogenous ... disease, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germinal cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma , hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphatic endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT positive The present invention may be used for the treatment and / or prevention of: non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, 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, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

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

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

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

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

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

[0024] The term "treatment" or "treating" as used herein is intended to refer to the administration of a compound or composition to a subject for the purpose of producing a therapeutic or prophylactic effect via inhibition of YAP / TAZ-TEAD transcription. Treating includes reversing the progression, alleviating, mitigating, inhibiting, reducing the severity, or preventing a disease, disorder, or condition, or one or more symptoms of a disease, disorder, or condition mediated via such YAP / TAZ-TEAD transcription. A "therapeutic effect" refers to eradicating, alleviating, reversing, alleviating, inhibiting, or reducing the severity of the underlying disorder being treated. A therapeutic effect is also achieved by eradicating or alleviating one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is seen in the patient, even if the patient suffers from the underlying disorder in some embodiments. With regard to a prophylactic effect, in some embodiments, the composition is administered to a patient at risk of developing a particular disease, or to a patient who reports one or more of the physiological symptoms of the disease, even if the patient has not been diagnosed with the disease.

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

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

[0027] The term "composition," as used herein, is intended to encompass a product containing therapeutically effective amounts of the specified ingredients, as well as any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts.

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

[0029] It should be noted that the term "comprising" used in the claims should not be construed as being limited to the meaning recited thereafter and does not exclude other elements or steps.

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

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

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

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

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

[0035] Protected compounds may also exhibit modified and possibly optimized properties in vitro and in vivo, such as passing through cell membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with the desired therapeutic effect may be called prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, which is released upon conversion of the prodrug in vivo. The active prodrug may be absorbed more efficiently than the parent drug, so that the prodrug may have higher efficacy than the parent drug in vivo. The protecting group is removed either in vitro in the case of chemical intermediates, or in vivo in the case of prodrugs. For chemical intermediates, it is not particularly important that the resulting product after deprotection is physiologically acceptable, e.g., alcohol, but in general, it is more desirable if the product is pharmacologically harmless.

[0036] As used herein, "alkyl" or "C 1~18 The term "alkyl" refers to a C 1 ~C 18 It means a straight-chain, secondary or tertiary, linear, branched or straight-chain hydrocarbon. Examples include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl- 2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl. In certain embodiments, the term alkyl refers to any of the C 1 -C 2 -C ...1~12 Alkyl(C 1~12 More specifically, C 1~9 Alkyl(C 1~9 Hydrocarbons), and more specifically, C 1~6 Alkyl(C 1~6 Hydrocarbons).

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

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

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

[0040] As used herein, "cycloalkyl" or "C 3~18 The term "cycloalkyl" means, unless otherwise specified, C 3~10 Monocyclic or C 7~18 It refers to a monovalent group of saturated hydrocarbons having 3 to 18 carbon atoms, consisting of or including polycyclic saturated hydrocarbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl, and the like. In certain embodiments, the term cycloalkyl refers to any of the C cycloalkyl, ... 3~12 Cycloalkyl (saturated cyclic C 3~12 More specifically, C 3~9 Cycloalkyl (saturated cyclic C 3~9 Hydrocarbons), and more specifically, C 3~6 Cycloalkyl (saturated cyclic C 3~6 For the avoidance of doubt, a fused system of a cycloalkyl ring with a heterocycle is considered to be heterocycle, regardless of which ring is attached to the core structure. A fused system of a cycloalkyl ring with an aryl ring is considered to be aryl, regardless of which ring is attached to the core structure. A fused system of a cycloalkyl ring with a heteroaryl ring is considered to be heteroaryl, regardless of which ring is attached to the core structure.

[0041] As used herein, "alkenyl" or "C 2~18 The term "alkenyl" refers to a C alkyl group having at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond. 2 ~C 18 It is a straight chain, secondary or tertiary, linear, branched or straight chain hydrocarbon. Examples are ethylene or vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), and 5-hexenyl (-CH 2 CH 2CH 2 CH 2 CH=CH 2 The double bond may be in a cis or trans configuration. In certain embodiments, the term alkenyl refers to a C alkyl group having at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond, as further defined herein above. 2~12 Alkenyl (C 2~12 More specifically, C 2~9 Alkenyl (C 2~9 Hydrocarbons), and more specifically, C 2~6 Alkenyl (C 2~6 Hydrocarbons).

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

[0043] As used herein, the term "cycloalkenyl" refers to an alkyl group having 5 to 18 carbon atoms, with at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond, and 5~10 Monocyclic or C 7~18 It refers to a non-aromatic hydrocarbon group consisting of or containing polycyclic hydrocarbons. Examples include cyclopentenyl (-C 5 H 7 ), cyclopentenylpropylene, methylcyclohexenylene, and cyclohexenyl (-C 6 H 9 The double bond may be in a cis or trans configuration. In certain embodiments, the term cycloalkenyl refers to a C cycloalkenyl having at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond, as further defined herein above. 5~12 Cycloalkenyl (ring C 5~12 More specifically, C 5~9 Cycloalkenyl (ring C5~9 Hydrocarbons), and more specifically, C 5~6 Cycloalkenyl (ring C 5~6 For the avoidance of doubt, a fused cycloalkenyl ring with a heterocyclic ring is considered to be a heterocyclic ring, regardless of which ring is attached to the core structure. A fused cycloalkenyl ring with an aryl ring is considered to be an aryl ring, regardless of which ring is attached to the core structure. A fused cycloalkenyl ring with a heteroaryl ring is considered to be a heteroaryl ring, regardless of which ring is attached to the core structure.

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

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

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

[0047] As used herein, the term "alkylene" refers to any alkyl group having 1 to 18 carbon atoms, more specifically, C 1~12 , C 1~9 , or C 1~6 Alkylene refers to a saturated branched or straight-chain hydrocarbon group of 10 carbon atoms (10 carbon atoms) with two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Exemplary alkylenes include methylene (-CH 2 -), 1,2-ethyl (-CH 2 CH 2 -), 1,3-propyl (-CH2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), but are not limited to these.

[0048] As used herein, the term "alkenylene" refers to an alkyl group having 2 to 18 carbon atoms (more specifically, C 2~12 , C 2~9 , or C 2~6 It refers to a branched or straight-chain hydrocarbon of 10,000 carbon atoms (1,000 alkane carbon atoms) having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.

[0049] As used herein, the term "alkynylene" refers to an alkynylene having 2 to 18 carbon atoms (more specifically, C 2~12 , C 2~9 , or C 2~6 Alkyne refers to a branched or straight-chain hydrocarbon of 10,000 carbon atoms (1,000 alkoxycarbonyl) having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0067] The term "heteroaryl" refers to an aromatic ring system of 5-18 atoms containing at least one N, O, S, or P, containing one or two rings that can be fused together or covalently bonded, each ring typically containing 5-6 atoms, where at least one of the rings is aromatic, where the N and S heteroatoms can be optionally oxidized, and the N heteroatom can be optionally quaternized, and where at least one carbon atom of the heteroaryl can be oxidized to form at least one C=O. A fused system of a heteroaryl ring with a cycloalkyl ring or a cycloalkenyl ring or a cycloalkynyl ring is considered heteroaryl, regardless of the ring that is attached to the core structure. A fused system of a heteroaryl ring with a heterocycle is considered heteroaryl, regardless of the ring that is attached to the core structure. A fused system of a heteroaryl ring with an aryl ring is considered heteroaryl, regardless of the ring that is attached to the core structure.Non-limiting examples of such heteroaryls include triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thiazole, thiazolyl ... eno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl In some embodiments, the heteroaryl group is selected from the group including pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl, and thiazolyl, in some embodiments, the heteroaryl group is selected from the group including pyridyl, pyrazinyl, pyrimidinyl, indolyl, and benzimidazolyl.

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

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

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

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

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

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

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

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

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

[0077] The term "heterocyclyl-heteroalkyl" or "heterocycle-heteroalkyl" as a group or part of a group refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl. The heterocyclyl-heteroalkyl or heterocycle-heteroalkyl group can contain 6 to 20 atoms, e.g., the heteroalkyl portion can contain 1 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms. In some embodiments, the heterocyclyl-heteroalkyl or heterocycle-heteroalkyl can be heterocyclyl-O-alkyl, heterocyclylalkyl-O-alkyl, heterocyclyl-NH-alkyl, heterocyclyl-N(alkyl) 2 , heterocyclylalkyl-NH-alkyl, heterocyclylalkyl-N-(alkyl) 2 , heterocyclyl-S-alkyl, and heterocyclylalkyl-S-alkyl.

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

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

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

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

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

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

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

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

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

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

[0088] The term “alkylthio” as a group or part of a group refers to a group of the formula —SR b In the formula, R b is alkyl as defined hereinabove. Non-limiting examples of alkylthio groups include methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0102] As used herein, the term "optionally containing one or more heteroatoms, said heteroatoms being selected from the group consisting of O, S, and N" refers to a group in which one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, and thus includes, inter alia, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, heteroarylheteroalkynyl, depending on the group referred to. Thus, depending on the group referred to, the term includes, by way of example, alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-heteroalkyl, heterocyclyl-heteroalkyl, heteroaryl-alkoxy, heterocyclyl-alkoxy, among others. Thus, by way of example, the term "alkyl optionally containing one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N" refers to heteroalkyl and means an alkyl containing one or more heteroatoms in the hydrocarbon chain, while the heteroatoms may be located at the beginning of the hydrocarbon chain, within the hydrocarbon chain, or at the end of the hydrocarbon chain. Examples of heteroalkyl include methoxy, methylthio, ethoxy, propoxy, CH, among many other examples. 3 -O-CH 2 -, CH 3 -S-CH 2 -, CH 3 -CH 2 -O-CH 2 -, CH 3 -NH-, (CH 3 ) 2 -N-, (CH 3 ) 2 -CH 2 -NH-CH 2 -CH 2-. Thus, as an example, the term "aryl alkylene optionally containing one or more heteroatoms in the alkylene chain, said heteroatoms being selected from the group consisting of O, S, and N" refers to aryl hetero alkylene and means an aryl alkylene containing one or more heteroatoms in the hydrocarbon chain, while the heteroatoms may be located at the beginning of the hydrocarbon chain, within the hydrocarbon chain, or at the end of the hydrocarbon chain. Thus, "aryl hetero alkylene" includes aryloxy, aryl alkoxy, aryl-alkyl-NH-, and the like, examples of which include phenyloxy, benzyloxy, aryl-CH, among many other examples. 2 -S-CH 2 -, aryl-CH 2 -O-CH 2 -, aryl-NH-CH 2 The same applies to "heteroalkenylene," "heteroalkynylene," and other terms used herein when they refer to "optionally containing one or more heteroatoms, said heteroatoms being selected from the group consisting of O, S, and N atoms."

[0103] As used herein, the term relating to a chemical group "wherein two or more hydrogen atoms adjacent to a carbon atom or heteroatom of said group are optionally available together to form =O or =S" refers to a group in which two or more hydrogen atoms adjacent to a carbon atom or heteroatom of said group are optionally available together to form =O or =S. As an example, the term refers to "alkyl, where two or more hydrogen atoms adjacent to a carbon atom or heteroatom of said alkyl are optionally available together to form =O or =S," and includes, among other examples, CH 3 -C(O)-CH 2 -, CH 3 -C(O)-, CH 3 -C(S)-CH 2 -, CH 3 -S(O) 2 -CH 2 - and (CH 3 ) 2 -CH 2-C(O)-CH 2 -CH 2 -- are some examples.

[0104] The combination of the group "optionally containing one or more heteroatoms, said heteroatoms being selected from the group consisting of O, S, and N" and "optionally two or more hydrogen atoms adjacent to carbon atoms or heteroatoms of said group are available together to form =O or =S" can combine the two aspects described herein above, and when the group is referred to as alkyl, can be used, among other examples, as CH 3 -C(O)O-, CH 3 -C(O)O-CH 2 -, CH 3 -NH-C(O)-, CH 3 -C(O)-NH-, CH 3 -NH-C(O)-CH 2 -, CH 3 -NH-C(S)-CH 2 -, CH 3 -NH-C(S)-NH-CH 2 -, CH 3 -NH-S(O) 2 - and CH 3 -NH-S(O) 2 -NH-CH 2 -- are some examples.

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

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

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

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

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

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

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

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

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

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

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

[0116] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , (c)C 2 ~C 6 Alkynyl, and (d) Unsubstituted or substituted C 3 ~C 6 Heterocycles, where one or more of the substituents are halogen, cyano, C 2 ~C 8 Alkenyl, and C 1 ~C 6 independently selected from the group consisting of alkyl, (iii) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of: (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of: (v) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vi) Unsubstituted or substituted C 3 ~C 6 Heterocycles, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vii)-S(=O) 2 Z 2 , and (viii) -C(=O)Z 2 ; Y 1 =CR 2 selected from the group consisting of -, ═N-, and -C(═O)-; However, this is subject to the following conditions: (i)Y 1 GA=CR 2 - or =N- and R 4 In the absence of [ka] represents a double bond, or (ii) Y 1 is -C(=O)- and R 4 is hydrogen and C 1 ~C 6 When selected from the group consisting of alkyl, [ka] represents a single bond; R 2 is selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) n -NR 5a R 5b ; n is 0 or 1; R 5a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g) -C(=O)Z 2 , (h) C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O) 2 Z 8 , (o)-S(=O) 2 New Zealand 3 Z 4 , (p)-S(=O)(=NZ 6 )Z 2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 , (r)-S(=O)(=NZ 6 )NZ 3 Z 4 , (s)-NZ 5 S(=O) 2 Z 2 , (t)-NZ 5 S(=O) 2 New Zealand 3 Z 4 , (u)-NZ 5 S(=O)(=NZ 6 )Z 2 , (v)-N.Z. 5 S(=NZ 6 )(=NZ 7 )Z 2 , and (w)-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) 2 Z 8 , (vii)-S(=O) 2 New Zealand 3 Z 4 , (viii)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R 5b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; R 3 and R 4are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) p -NR 6a R 6b ; p is 0 or 1; R 6a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g) -C(=O)Z 2 , (h) C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O) 2 Z 8 , (o)-S(=O) 2 New Zealand 3 Z 4 , (p)-S(=O)(=NZ 6)Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ 6 )NZ 3 Z 4 、 (s)-NZ 5 S(=O) 2 Z 2 、 (t)-NZ 5 S(=O) 2 NZ 3 Z 4 、 (u)-NZ 5 S(=O)(=NZ 6 )Z 2 、 (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、 (w)-NZ 5 S(=O)(=NZ 6 )NZ 3 Z 4 、and (x)C 2 ~C 6 alkenyl, (iii)-C(=O)Z 2 、 (iv)-C(=O)OZ 2 、 (v)-C(=O)NZ 3 Z 4 、 (vi)-S(=O) 2 Z 8 、 (vii)-S(=O) 2 NZ 3 Z 4 、 (viii)-S(=O)(=NZ 6 )Z 2 、 (xi)-S(=Z 6 )(=NZ 7 )Z 2 、as well as (x)-S(=O)(=NZ6 )NZ 3 Z 4 ; R 6b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 Alkyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , C 3 ~C 8 Cycloalkyl, --C(=O)OH -S(=O) 2 Z 8 , -N.Z. 3 Z 4 , 4-8 membered heterocycles, 5-9 membered heteroaryls, and unsubstituted or substituted aryls (wherein one or more of the substituents is halogen, C 1 ~C 6 haloalkyl and cyano; (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, (vii) C1 ~C 6 Haloalkyl, (viii) Unsubstituted or substituted 4- to 8-membered heterocycles, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl and C 2 ~C 6 alkenyl, and (ix) unsubstituted or substituted aryl, where one or more of the substituents is halogen, cyano, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is halogen, cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4-8 membered heterocycles; each Z 2 are independently selected from the group consisting of: (I C 1 ~C 6 Alkyl, (ii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iii) C 2 ~C 6 Alkynyl, (iv) C 3 ~C 6 Cycloalkyl, (v) C 3 ~C 6 Cycloalkenyl, and (vi) C 1 ~C 6Haloalkyl; each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 Alkyl, where one or more of the substituents is C 2 ~C 6 Alkenyl, cyano, -C(=O)OH, -S(=O) 2 Z 8 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is -NZ 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 4 , Z 5 , Z 6 , and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii) C 3 ~C 6 Cycloalkyl; each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 Alkyl, where one or more of the substituents are halogen, cyano and C 1 ~C 6 independently selected from the group consisting of alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is -NZ 3 Z 4 and 4- to 8-membered heterocycles, (iv) halogens, and (v) hydroxy; X is =N- and =CR 7a - selected from the group consisting of; X 1 =N- and =CR 7b - selected from the group consisting of; X 2 =N- and =CR 7c - selected from the group consisting of; X 3 =N- and =CR 7d - selected from the group consisting of; R 7a , R 7b , R 7c , and R 7d is hydrogen, halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OZ 1 and -(CH 2 ) q -NR 6a R 6b independently selected from the group consisting of: q is 0 or 1.

[0117] In another embodiment, the present disclosure provides a compound of formula II: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , (c)C 2 ~C 6 Alkynyl, (iii) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of: (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6Haloalkyl, and -OZ 1 are independently selected from the group consisting of (v) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vi) Unsubstituted or substituted C 3 ~C 6 Heterocycle, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vii)-S(=O) 2 Z 2 , and (viii) -C(=O)Z 2 ; Y 1 =CR 2 selected from the group consisting of -, ═N-, and -C(═O)-; However, this is subject to the following conditions: (i)Y 1 GA=CR 2 - or =N- and R 4 In the absence of [ka] represents a double bond, or (ii) Y 1 is -C(=O)- and R 4 is hydrogen and C 1 ~C 6 When selected from the group consisting of alkyl, [ka] represents a single bond; R 2 is selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) n -NR 5a R 5b ; n is 0 or 1; R 5a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g) -C(=O)Z 2 , (h) -C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 、 (m)-NZ 5 C(=O)NZ 3 With 4 、 (n)-S(=O) 2 With 8 、 (o)-S(=O) 2 NT 3 With 4 、 (p)-S(=O)(=NZ) 6 )Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ) 6 )NZ 3 With 4 、 (s)-NZ 5 S(=O) 2 With 2 、 (t)-NZ 5 S(=O) 2 NT 3 With 4 、 (u)-NZ 5 S(=O)(=NZ) 6 )Z 2 、 (in)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、2. (w)-NZ 5 S(=O)(=NZ) 6 )NZ 3 With 4 、 (iii)-C(=O)Z 2 、 (iv)-C(=O)OZ 2 、 (v)-C(=O)NZ 3 With 4 、 (vi)-S(=O) 2 With 8 、 (vii)-S(=O) 2 New Zealand 3 Z 4 , (viii)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R 5b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; R 3 and R 4 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) p -NR 6a R 6b ; p is 0 or 1; R 6a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g) -C(=O)Z 2 , (h) C(=O)OH, (i)-C(=O)OZ2 、 (j)-C(=O)NZ 3 With 4 、 (k)-NZ 5 C(=O)Z 2 、 (l)-NZ 5 C(=O)OZ 2 、 (m)-NZ 5 C(=O)NZ 3 With 4 、 (n)-S(=O) 2 With 8 、 (o)-S(=O) 2 NT 3 With 4 、 (p)-S(=O)(=NZ) 6 )Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ) 6 )NZ 3 With 4 、 (s)-NZ 5 S(=O) 2 With 2 、 (t)-NZ 5 S(=O) 2 NT 3 With 4 、 (u)-NZ 5 S(=O)(=NZ) 6 )Z 2 、 (in)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、2. (w)-NZ 5 S(=O)(=NZ) 6 )NZ 3 With 4 、 (iii)-C(=O)Z 2 、 (iv)-C(=O)OZ2 , (v)-C(=O)NZ 3 Z 4 , (vi) -S(=O) 2 Z 8 , (vii)-S(=O) 2 New Zealand 3 Z 4 , (viii)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R 6b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 2 are independently selected from the group consisting of: (I C 1 ~C 6 Alkyl, (ii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iii) C 2 ~C 6 Alkynyl, (iv) C 3 ~C 6 Cycloalkyl, (v) C 3 ~C 6 Cycloalkenyl, and (vi) C 1 ~C 6 Haloalkyl; each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 4 , Z 5 , Z 6 , and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii) C 3 ~C 6 Cycloalkyl; each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is -NZ 3 Z 4 and 4- to 8-membered heterocycles, (iv) halogens, and (v) hydroxy; X is =N- and =CR 7a - selected from the group consisting of; X 1 =N- and =CR 7b- selected from the group consisting of; X 2 =N- and =CR 7c - selected from the group consisting of; X 3 =N- and =CR 7d - selected from the group consisting of; R 7a , R 7b , R 7c , and R 7d is hydrogen, halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OZ 1 and -NZ 3 Z 4 are independently selected from the group consisting of:

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

[0119] In another embodiment, the disclosure provides a compound of formula III, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 2 is -(CH 2 ) n -NR 5a R 5b and; R 3 is hydrogen and C 1 ~C 6 alkyl.

[0120] In another embodiment, the disclosure provides a compound of formula III, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 5a is -C(=O)Z 2 and R 5b is hydrogen.

[0121] In another embodiment, the disclosure provides a compound of formula III, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 2 is hydrogen and C 1 ~C 6 is selected from the group consisting of alkyl, R 3 is -(CH 2 ) p -NR 6a R 6b It is.

[0122] In another embodiment, the disclosure provides a compound of formula III, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 6a is -C(=O)Z 2 and R 6b is hydrogen.

[0123] In another embodiment, the present disclosure provides a compound of formula IV: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 1 , R 3 , X, X 1 , X 2 , and X 3 is as defined in relation to formula I or II.

[0124] In another embodiment, the disclosure provides a compound of formula IV, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 3 is -(CH 2 ) p-NR 6a R 6b It is.

[0125] In another embodiment, the disclosure provides a compound of formula IV, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 6a is -C(=O)Z 2 and -S(=O) 2 Z 8 selected from the group consisting of; R 6b is hydrogen.

[0126] In another embodiment, the present disclosure provides a compound of formula V: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 1 , R 3 , X, X 1 , X 2 , and X 3 is as defined in relation to formula I or II.

[0127] In another embodiment, the disclosure provides a compound of formula V, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein R 3 is -(CH 2 ) p -NR 6a R 6b It is.

[0128] In another embodiment, the disclosure provides a compound of formula V, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 6a is -C(=O)Z 2 selected from the group consisting of; R 6b is hydrogen.

[0129] In another embodiment, the disclosure provides a compound of any one of formulas I-V, or a stereoisomer, tautomer, pharma-ceutically acceptable salt, or solvate thereof, wherein R 1 is unsubstituted or substituted C 6 ~C 10 aryl, where one or more of the substituents are halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and -OZ 1 are independently selected from the group consisting of:

[0130] In another embodiment, the disclosure provides a compound of any one of formulas I-V, or a stereoisomer, tautomer, pharma-ceutically acceptable salt, or solvate thereof, wherein: X is -CR 7a = and; X 1 -CR 7b = and; X 2 -CR 7c = and; X 3 -CR 7d =.

[0131] In another embodiment, the disclosure provides a compound of formula I, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-[[5-(cyanomethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[rac-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[(3S)-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[(3R)-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-phenoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[6-(cyclopropoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(3-methyl-2,6-dioxo-pyrimidin-4-yl)oxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-benzyloxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(1H-pyrazol-3-ylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[1-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-c]pyridin-3-yl]methyl]prop-2-enamide; N-[[5-prop-2-ynoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(cyclopropylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(cyclopropylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]methanesulfonamide; 2-[[[1-[4-(trifluoromethyl)phenyl]indazol-3-yl]amino]methyl]prop-2-enoic acid; N-[[5-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[6-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; and N-[[1-(4,4-difluorocyclohexyl)indazol-3-yl]methyl]prop-2-enamide.

[0132] In another embodiment, the disclosure provides a compound of formula II, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acrylamide; N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acetamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)propionamide; N-(1-phenyl-1H-indol-3-yl)acrylamide; N-(1-(4-isopropylphenyl)-1H-indol-3-yl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)acrylamide; N-(1-(4-chlorophenyl)-1H-indol-3-yl)acrylamide; N-(1-(3-chlorophenyl)-1H-indol-3-yl)acrylamide; N-(1-([1,1'-biphenyl]-4-yl)-1H-indol-3-yl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)propionamide; N-((1-(3-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide; N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acrylamide; N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acetamide; and N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)propionamide.

[0133] In another embodiment, the present disclosure provides a compound of formula VI: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 8 is selected from the group consisting of: (i) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , (c)C 2 ~C 6 Alkynyl, (ii) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (iii) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (iv) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (v) Unsubstituted or substituted C 3 ~C 6 Heterocycles, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vi) -S(=O) 2 Z 2 , and (vii) -C(=O)Z 2 ; X is -N(R 11 )-; or X is absent; R 11 is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; R9 is selected from the group consisting of: [ka] R 12 is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , and (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , and (iii) C 1 ~C 6 Haloalkyl; R 10 is -(CH 2 ) q -C(=O)R 13 and; q is 0, 1, or 2; R 13 -OH, OZ 1 , and -N.Z. 3 Z 4 selected from the group consisting of; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 2 are independently selected from the group consisting of: (I C 1 ~C 6 Alkyl, (ii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iii) C 2 ~C 6 Alkynyl, (iv) C 3 ~C 6 Cycloalkyl, (v) C 3 ~C 6 Cycloalkenyl, and (vi) C 1 ~C 6 Haloalkyl; each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; and each Z 4 are independently selected from the group consisting of (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii) C 3 ~C 6 Cycloalkyl.

[0134] In another embodiment, the disclosure provides a compound of formula VI, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of: 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetic acid; N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetamide; 2-(6-phenyl-8-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl)acetic acid; 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetic acid; and N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetamide.

[0135] Preferred or specific descriptions (features) and embodiments of the compounds of the present disclosure are described herein below. Each of the descriptions, aspects, and embodiments of the present disclosure defined may be combined with any other description, aspect, and / or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as being preferred, specific, or advantageous may be combined with any other feature or description indicated as being preferred, specific, or advantageous. The present disclosure is particularly expressed herein by any one or more of the following numbered descriptions and embodiments, or any combination with any other description, aspect, and / or embodiment (not numbered).

[0136] Embodiment 1. A compound of formula I: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , (c)C 2 ~C 6 Alkynyl, and (d) Unsubstituted or substituted C 3 ~C 6 Heterocycles, where one or more of the substituents are halogen, cyano, C 2 ~C 8 Alkenyl, and C 1 ~C 6 independently selected from the group consisting of alkyl, (iii) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of (v) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vi) Unsubstituted or substituted C 3 ~C 6 Heterocycles, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vii)-S(=O) 2 Z 2 , and (viii) -C(=O)Z 2 ; Y 1 =CR 2 selected from the group consisting of -, ═N-, and -C(═O)-; However, this is subject to the following conditions: (i)Y 1 GA=CR 2 - or =N- and R 4 In the absence of [ka] represents a double bond, or (ii) Y 1 is -C(=O)- and R 4 is hydrogen and C 1 ~C 6 When selected from the group consisting of alkyl, [ka] represents a single bond; R 2is selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) n -NR 5a R 5b ; n is 0 or 1; R 5a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g) -C(=O)Z 2 , (h) C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O) 2 Z 8 , (o)-S(=O) 2 New Zealand 3 Z 4 , (p)-S(=O)(=NZ 6 )Z2 , (q)-S(=Z 6 )(=NZ 7 )Z 2 , (r)-S(=O)(=NZ 6 )NZ 3 Z 4 , (s)-NZ 5 S(=O) 2 Z 2 , (t)-NZ 5 S(=O) 2 NZ 3 Z 4 , (u)-NZ 5 S(=O)(=NZ 6 )Z 2 , (v)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 , and (w)-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) 2 Z 8 , (vii)-S(=O) 2 NZ 3 Z 4 , (viii)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R5b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; R 3 and R 4 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) p -NR 6a R 6b ; p is 0 or 1; R 6a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g) -C(=O)Z 2 , (h) C(=O)OH, (i)-C(=O)OZ 2 , (j)-C(=O)NZ 3 Z 4 , (k)-NZ 5 C(=O)Z 2 , (l)-NZ 5 C(=O)OZ 2 , (m)-NZ 5 C(=O)NZ 3 Z 4 , (n)-S(=O) 2 Z 8、 (o)-S(=O) 2 NT 3 With 4 、 (p)-S(=O)(=NZ) 6 )Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ) 6 )NZ 3 With 4 、 (s)-NZ 5 S(=O) 2 With 2 、 (t)-NZ 5 S(=O) 2 NT 3 With 4 、 (u)-NZ 5 S(=O)(=NZ) 6 )Z 2 、 (in)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、 (w)-NZ 5 S(=O)(=NZ) 6 )NZ 3 With 4 、2. (x)C 2 ~C 6 Alkenil (iii)-C(=O)Z 2 、 (iv)-C(=O)OZ 2 、 (v)-C(=O)NZ 3 With 4 、 (vi)-S(=O) 2 With 8 、 (vii)-S(=O) 2 NT 3 With 4 、 (viii)-S(=O)(=NZ) 6 )Z 2, (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R 6b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 Alkyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , C 3 ~C 8 Cycloalkyl, --C(=O)OH -S(=O) 2 Z 8 , -N.Z. 3 Z 4 , 4-8 membered heterocycles, 5-9 membered heteroaryls, and unsubstituted or substituted aryls (wherein one or more of the substituents is halogen, C 1 ~C 6 haloalkyl and cyano; (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, (vii) C 1 ~C 6 Haloalkyl, (viii) Unsubstituted or substituted 4- to 8-membered heterocycles, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl and C 2 ~C 6 alkenyl, and (ix) unsubstituted or substituted aryl, where one or more of the substituents is halogen, cyano, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is halogen, cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles; each Z 2 are independently selected from the group consisting of: (I C 1 ~C 6 Alkyl, (ii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iii) C 2 ~C 6 Alkynyl, (iv) C 3 ~C 6 Cycloalkyl, (v) C 3 ~C 6 Cycloalkenyl, and (vi) C 1 ~C 6 Haloalkyl; each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 Alkyl, where one or more of the substituents is C 2 ~C 6 Alkenyl, cyano, -C(=O)OH, -S(=O) 2 Z 8 , halogen, -NZ 3 Z 4 and 4- to 8-membered heterocycles, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 4 , Z 5 , Z 6 , and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii) C 3 ~C 6 Cycloalkyl; each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 Alkyl, where one or more of the substituents are halogen, cyano and C 1 ~C 6 independently selected from the group consisting of alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is -NZ 3 Z 4 and 4- to 8-membered heterocycles, (iv) halogens, and (v) hydroxy; X is =N- and =CR 7a - selected from the group consisting of; X 1 =N- and =CR 7b - selected from the group consisting of; X 2 =N- and =CR 7c - selected from the group consisting of; X 3 =N- and =CR 7d - selected from the group consisting of; R 7a , R 7b , R 7c , and R 7d is hydrogen, halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OZ 1 and -(CH2 ) q -NR 6a R 6b independently selected from the group consisting of: The compound, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein q is 0 or 1.

[0137] Embodiment 2. A compound of formula II: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , (c)C 2 ~C 6 Alkynyl, (iii) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of: (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents is halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Haloalkyl, and -OZ 1 are independently selected from the group consisting of: (v) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vi) Unsubstituted or substituted C 3 ~C 6 Heterocycles, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vii)-S(=O) 2 Z 2 , and (viii) -C(=O)Z 2 ; Y 1 =CR 2 selected from the group consisting of -, ═N-, and -C(═O)-; However, this is subject to the following conditions: (i)Y 1 GA=CR 2 - or =N- and R 4 In the absence of [ka] represents a double bond, or (ii) Y 1 is -C(=O)- and R 4 is hydrogen and C 1 ~C 6 When selected from the group consisting of alkyl, [ka] represents a single bond; R 2 is selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) n -NR 5a R 5b ; n is 0 or 1; R 5a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 , (e)-SZ 1 , (f)-NZ 3 Z 4 , (g)-C(=O)Z 2 、 (h)-C(=O)OH, (i)-C(=O)OZ 2 、 (j)-C(=O)NZ 3 With 4 、 (k)-NZ 5 C(=O)Z 2 、 (l)-NZ 5 C(=O)OZ 2 、 (m)-NZ 5 C(=O)NZ 3 With 4 、 (n)-S(=O) 2 With 8 、 (o)-S(=O) 2 NT 3 With 4 、 (p)-S(=O)(=NZ) 6 )Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ) 6 )NZ 3 With 4 、 (s)-NZ 5 S(=O) 2 With 2 、 (t)-NZ 5 S(=O) 2 NT 3 With 4 、 (u)-NZ 5 S(=O)(=NZ) 6 )Z 2 、 (in)-NZ 5 S(=NZ 6 )(=NZ 7 )Z 2 、2. (w)-NZ 5 S(=O)(=NZ) 6 )NZ 3Z 4 , (iii) -C(=O)Z 2 , (iv) -C(=O)OZ 2 , (v)-C(=O)NZ 3 Z 4 , (vi) -S(=O) 2 Z 8 , (vii)-S(=O) 2 New Zealand 3 Z 4 , (viii)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R 5b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; R 3 and R 4 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii)-(CH 2 ) p -NR 6a R 6b ; p is 0 or 1; R 6a is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) hydroxy, (c) Cyano, (d)-OZ 1 、 (e)-SZ 1 、 (f)-NZ 3 Z 4 、 (g)-C(=O)Z 2 、 (h)C(=O)OH、 (i)-C(=O)OZ 2 、 (j)-C(=O)NZ 3 Z 4 、 (k)-NZ 5 C(=O)Z 2 、 (l)-NZ 5 C(=O)OZ 2 、 (m)-NZ 5 C(=O)NZ 3 Z 4 、 (n)-S(=O) 2 Z 8 、 (o)-S(=O) 2 NZ 3 Z 4 、 (p)-S(=O)(=NZ 6 )Z 2 、 (q)-S(=Z 6 )(=NZ 7 )Z 2 、 (r)-S(=O)(=NZ 6 )NZ 3 Z 4 、 (s)-NZ 5 S(=O) 2 Z 2 、 (t)-NZ 5 S(=O) 2 NZ 3 Z 4 、 (u)-NZ 5 S(=O)(=NZ 6 )Z 2 、 (v)-NZ 5 S(=NZ6 )(=NZ 7 )Z 2 , and (w)-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) 2 Z 8 , (vii)-S(=O) 2 New Zealand 3 Z 4 , (viii)-S(=O)(=NZ 6 )Z 2 , (xi)-S(=Z 6 )(=NZ 7 )Z 2 , and (x)-S(=O)(=NZ 6 )NZ 3 Z 4 ; R 6b is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z.3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 2 are independently selected from the group consisting of: (I C 1 ~C 6 Alkyl, (ii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iii) C 2 ~C 6 Alkynyl, (iv) C 3 ~C 6 Cycloalkyl, (v) C 3 ~C 6 Cycloalkenyl, and (vi) C 1 ~C 6 Haloalkyl; each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 4 , Z 5 , Z 6 , and Z 7 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii) C 3 ~C 6 Cycloalkyl; each Z 8 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is -NZ 3 Z4 and 4- to 8-membered heterocycles, (iv) halogens, and (v) hydroxy; X is =N- and =CR 7a - selected from the group consisting of; X 1 =N- and =CR 7b - selected from the group consisting of; X 2 =N- and =CR 7c - selected from the group consisting of; X 3 =N- and =CR 7d - selected from the group consisting of; R 7a , R 7b , R 7c , and R 7d is hydrogen, halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, -OZ 1 and -NZ 3 Z 4 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

[0138] Embodiment 3. A compound of formula III: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0139] Embodiment 4. R 2 is -(CH 2 ) n -NR 5a R 5b and; R 3 is hydrogen and C 1 ~C6 The compound according to any one of embodiments 1 to 3, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, selected from the group consisting of alkyl.

[0140] Embodiment 5.R 5a is -C(=O)Z 2 and R 5b The compound of any one of embodiments 1-4, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: is hydrogen.

[0141] Embodiment 6. R 2 is hydrogen and C 1 ~C 6 is selected from the group consisting of alkyl, R 3 is -(CH 2 ) p -NR 6a R 6b 6. The compound of any one of embodiments 1-5, wherein:

[0142] Embodiment 7.R 6a is -C(=O)Z 2 and R 6b The compound of any one of embodiments 1-6, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: is hydrogen.

[0143] Embodiment 8. A compound of formula IV: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0144] Embodiment 9.R 3 is -(CH 2 ) p -NR 6a R6b or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0145] Embodiment 10. R 6a is -C(=O)Z 2 and -S(=O) 2 Z 8 selected from the group consisting of; R 6b The compound of any one of embodiments 1, 2, 8, or 9, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

[0146] Embodiment 11. A compound of formula V: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0147] Embodiment 12.R 3 is -(CH 2 ) p -NR 6a R 6b 12. The compound of any one of embodiments 1, 2, or 11, wherein:

[0148] Embodiment 13. R 6a is -C(=O)Z 2 selected from the group consisting of; R 6b The compound of any one of embodiments 1, 2, 11, or 12, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

[0149] Embodiment 14.R 1 is unsubstituted or substituted C 6 ~C10 aryl, where one or more of the substituents are halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and -OZ 1 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

[0150] EMBODIMENT 15. X is -CR 7a = and; X 1 -CR 7b = and; X 2 -CR 7c = and; X 3 -CR 7d 15. The compound of any one of embodiments 1, 2, or 11-14, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

[0151] Embodiment 16. N-[[5-(cyanomethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[rac-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[(3S)-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[(3R)-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-phenoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[6-(cyclopropoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(3-methyl-2,6-dioxo-pyrimidin-4-yl)oxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-benzyloxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(1H-pyrazol-3-ylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[1-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-c]pyridin-3-yl]methyl]prop-2-enamide; N-[[5-prop-2-ynoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(cyclopropylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(cyclopropylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]methanesulfonamide; 2-[[[1-[4-(trifluoromethyl)phenyl]indazol-3-yl]amino]methyl]prop-2-enoic acid; N-[[5-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[6-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; and N-[[1-(4,4-difluorocyclohexyl)indazol-3-yl]methyl]prop-2-enamide, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0152] EMBODIMENT 17. N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acrylamide; N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acetamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)propionamide; N-(1-phenyl-1H-indol-3-yl)acrylamide; N-(1-(4-isopropylphenyl)-1H-indol-3-yl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)acrylamide; N-(1-(4-chlorophenyl)-1H-indol-3-yl)acrylamide; N-(1-(3-chlorophenyl)-1H-indol-3-yl)acrylamide; N-(1-([1,1'-biphenyl]-4-yl)-1H-indol-3-yl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)propionamide; N-((1-(3-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide; N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acrylamide; N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acetamide; and N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)propionamide, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0153] Embodiment 18. A compound of formula VI: [ka] or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 8 is selected from the group consisting of: (i) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , (c)C 2 ~C 6 Alkynyl, (ii) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (iii) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C6 Haloalkyl, and (f)-OZ 1 , (iv) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (v) Unsubstituted or substituted C 3 ~C 6 Heterocycle, where one or more substituents are independently selected from the group consisting of: (a) halogens, (b) cyano, (c)C 1 ~C 6 Alkyl, (d) C 3 ~C 6 Cycloalkyl, (e)C 1 ~C 6 Haloalkyl, and (f)-OZ 1 , (vi) -S(=O) 2 Z 2 , and (vii) -C(=O)Z 2 ; X is -N(R 11 )-; or X is absent; R 11 is hydrogen and C 1 ~C 6 selected from the group consisting of alkyl; R 9 is selected from the group consisting of: [ka] R 12 is selected from the group consisting of: (i) hydrogen, (ii) Unsubstituted or substituted C 1 ~C 6 alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C 6 ~C 10 Aryl, where one or more of the substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, (6)-OZ 1 , (7) C 2 ~C 6 Alkenyl, and (8) C 2 ~C 6 Alkynyl, (b) Unsubstituted or substituted C 3 ~C 6 cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , and (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) Halogen, (2) Cyano, (3) C 1 ~C 6 Alkyl, (4) C 3 ~C 6 Cycloalkyl, (5) C 1 ~C 6 Haloalkyl, and (6)-OZ 1 , and (iii) C 1 ~C 6 Haloalkyl; R 10 is -(CH 2 ) q -C(=O)R 13 and; q is 0, 1, or 2; R 13 -OH, OZ 1 , and -N.Z. 3 Z 4 selected from the group consisting of; each Z 1 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; each Z 2 are independently selected from the group consisting of: (I C 1 ~C 6 Alkyl, (ii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8 , halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iii) C 2 ~C 6 Alkynyl, (iv) C 3 ~C 6 Cycloalkyl, (v) C 3 ~C 6 Cycloalkenyl, and (vi) C 1 ~C 6 Haloalkyl; each Z 3 are independently selected from the group consisting of: (i) hydrogen, (ii) C 1 ~C 6 Alkyl, (iii) Unsubstituted or substituted C 2 ~C 6 alkenyl, where one or more of the substituents is cyano, -S(=O) 2 Z 8, halogen, and unsubstituted or substituted C 1 ~C 6 Alkyl (wherein one or more of the substituents is cyano, -S(=O) 2 Z 8 , -N.Z. 3 Z 4 and 4- to 8-membered heterocycles, (iv) C 2 ~C 6 Alkynyl, (v) C 3 ~C 6 Cycloalkyl, (vi) C 3 ~C 6 Cycloalkenyl, and (vii) C 1 ~C 6 Haloalkyl; and each Z 4 are independently selected from the group consisting of (i) hydrogen, (ii) C 1 ~C 6 Alkyl, and (iii) C 3 ~C 6 Cycloalkyl, the compound, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0154] EMBODIMENT 19. 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetic acid; N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetamide; 2-(6-phenyl-8-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl)acetic acid; 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetic acid; and N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetamide, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

[0155] Embodiment 20. A compound as set forth in Table 1.

[0156] Embodiment 21. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 20, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

[0157] Embodiment 22. A compound according to any one of embodiments 1 to 20, or a pharmaceutical composition according to claim 21, for use as a medicament.

[0158] Embodiment 23. A compound according to any one of embodiments 1 to 20, or a pharmaceutical composition according to embodiment 21, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder in an animal, mammal, or human.

[0159] Embodiment 24. A compound according to any one of embodiments 1 to 20, or a pharmaceutical composition according to embodiment 21, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder selected from the group consisting of cancer, fibrosis, and YAP / TAZ-TEAD activation-mediated congenital disorder.

[0160] Embodiment 25. A compound according to any one of embodiments 1 to 20, or a pharmaceutical composition according to embodiment 21, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer, and prostate cancer, mesothelioma, and / or sarcoma.

[0161] Embodiment 26. Acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia) normal and metastatic), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germinal cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphoendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma) and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma A compound according to any one of embodiments 1 to 20, or a pharmaceutical composition according to embodiment 21, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder selected from: myocardial infarction, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0162] Embodiment 27. A method for the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal, or human, comprising administering an effective amount of a compound according to any one of embodiments 1 to 20 to said animal, mammal, or human in need of such prevention or treatment.

[0163] Embodiment 28. A method for treating or preventing a YAP / TAZ-TEAD activation mediated disorder as described in embodiment 27 in combination with one or more other medicinal agents selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor, in a patient in need thereof.

[0164] Further, in general, the present disclosure relates to compounds of the formulae described herein, and embodiments, descriptions, and aspects thereof that are useful as biologically active agents or as diagnostic agents. Any of the uses described with respect to the present disclosure may be limited to non-medical, non-therapeutic, non-diagnostic, or exclusively in vitro or in association with cells separate from an animal.

[0165] The compounds of the present disclosure are small molecule YAP / TAZ-TEAD inhibitors. Small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers including, but not limited to, lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer, and prostate cancer, mesothelioma, and / or sarcoma. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers characterized by squamous cell carcinoma of the lung, cervix, ovary, head and neck, esophagus, and / or skin. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers arising from tissues of neuroectodermal origin, such as ependymomas, meningiomas, schwannomas, peripheral nerve sheet tumors, and / or neuroblastomas. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating vascular cancers such as epithelioid hemangioendothelioma, or for treating supratentorial ependymoma or porodenoma. In some embodiments, the solid tumor has a gain-of-function gene amplification, gene fusion, or activating mutation in the YAP1 or WWTR1 (TAZ) genes. In some embodiments, the solid tumor has a loss-of-function mutation or deletion in the NF2, LATS1 / 2, BAP1, FAT1, SAV1, and / or MST1 / 2 genes. In some embodiments, the solid tumor has a gain-of-function mutation in the GNAQ and / or GNA11 genes, for example, in uveal melanoma. In some embodiments, the solid tumor is characterized by constitutive nuclear localization of YAP and / or TAZ. In some embodiments, the solid tumor is characterized by overexpression of YAP / TAZ-TEAD signature genes, including but not limited to CTGF, CYR61, AMOTL2, and / or ANKRD1.

[0166] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating cancers that have developed resistance to previous treatments, including, for example, treating cancers that have developed resistance to chemotherapy or targeted therapies. In some embodiments, this may include treatment of cancers that have developed resistance to inhibitors of receptor tyrosine kinases such as EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canetinib, cetuximab) or AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), inhibitors of components of the RAS-MAPK signaling cascade, including inhibitors of RAS itself (AMG510, MRTX849, BI1701963, ARS1620, etc.), inhibitors of B-RAF (sorafenib tosylate, dabrafenib, vemurafenib, regorafenib), or inhibitors of MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0167] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in combination with other agents used to treat cancer, either co-administered or sequentially administered, including inhibitors or monoclonal antibodies targeting receptor tyrosine kinases such as EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canetinib, cetuximab) or inhibitors or monoclonal antibodies of AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), RAS-MAPK inhibitors including inhibitors of RAS itself. This may include concomitant treatment with inhibitors or monoclonal antibodies against components of the signal transduction cascade (such as AMG510, MRTX849, BI1701963, ARS1620), inhibitors or monoclonal antibodies of B-RAF (sorafenib tosylate, dabrafenib, vemurafenib, regorafenib), or inhibitors or monoclonal antibodies of MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0168] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating metastatic cancers. In some cases, the metastatic cancer is selected from metastatic uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma.

[0169] In some embodiments, the cancer being treated may be malignant pleural mesothelioma or lung cancer.

[0170] In some embodiments, the compounds of the present disclosure are useful in the treatment of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, and the like. Cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, Liposarcoma, Lung cancer, Lymphatic endothelial sarcoma, Lymphangiosarcoma, Lymphoblastic leukemia, Lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), Malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, Lymphoid malignancies of T-cell or B-cell origin, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Mesothelioma, Multiple myeloma, Myeloid leukemia, Myeloma, Myxosarcoma, Neuroblastoma, NUT midline carcinoma (NMC), Non-small cell lung cancer , oligodendroglioma, oral cancer, osteogenic osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0171] Malignant pleural mesothelioma Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating malignant pleural mesothelioma as single agents or in combination with inhibitors such as pemetrexed disodium, raltitrexed, carboplatin, oxaliplatin, gemcitabine, doxorubicin, or monoclonal antibodies such as bevacizumab. Combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. Combination with cell therapy, e.g., chimeric antigen receptor (CAR) T therapy or CAR NK therapy, which may use mesothelin (MSLN) as an antigen. For example, combination with monoclonal antibodies that recognize mesothelin as an antigen, e.g., BMS-986148, BAY 94-9343, amatuximab, and / or LMB-100.

[0172] lung cancer Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating lung cancer as single agents or in combination with inhibitors such as afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, and / or oartuzumab, and in combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. In combination with cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, pemetrexed, afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, necitumumab, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, oartuzumab, pembrolizumab, atezolizumab, and / or nivolumab.

[0173] In some embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful, for example, for the treatment of congenital disorders. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ-binding motifs / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the congenital disease is characterized by a mutant Ga protein. In some embodiments, the mutant Ga protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the congenital disease is characterized by a loss-of-function mutation or deletion of 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.

[0174] In some embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating fibrotic disorders, such as, for example, fibrosis of the liver, lung, kidney, heart, or skin. In some embodiments, fibrosis may be treated in the context of non-alcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cirrhosis, idiopathic alveolar fibrosis, chronic kidney disease, and / or myocardial infarction injury.

[0175] The compounds of the present disclosure can inhibit YAP / TAZ-TEAD transcriptional activation. The compounds have been shown to inhibit YAP / TAZ-TEAD transcriptional activity in cell and animal models. The compounds have also been shown to have inhibitory effects on cancer cell lines that depend on YAP / TAZ-TEAD transcriptional activity and cancer growth in xenograft cancer models.

[0176] The compounds of the present disclosure can be optionally covalently bound to an insoluble matrix and used for affinity chromatography (separation according to the nature of the compound's groups, e.g., compounds with pendant aryls are useful for hydrophobic affinity separations).

[0177] When one or more derivatives of the formula as defined herein are used, - the active ingredient of the compound(s) may be administered to the animal or mammal (including humans) to be treated by any means known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intraarterially, parenterally or by catheterization; - a therapeutically effective amount of a pharmaceutical of compound(s), in particular for the treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription in humans and other mammals (e.g. cancer, fibrosis, and certain congenital disorders), is preferably an amount of a compound of the formulas, descriptions, aspects and embodiments as defined herein that inhibits YAP / TAZ-TEAD transcription, corresponds to an amount ensuring plasma levels capable of inhibiting YAP / TAZ-TEAD activation, and is between 1 μg / ml and 100 mg / ml.

[0178] The suitable dosage of the compound or composition of the present disclosure should be used to treat or prevent the target disease in the subject.According to the pathology to be treated and the condition of the patient, the above-mentioned effective amount can be divided into several sub-units per day, or can be administered at intervals of 2 or more days.

[0179] According to certain embodiments of the present disclosure, the compounds of the present disclosure may be used in combination with other therapeutic agents for the treatment or prevention of diseases mediated by the activity of YAP / TAZ-TEAD transcription in humans and other animals (e.g., cancer, fibrosis, and certain congenital disorders). Thus, the present disclosure provides (a) one or more compounds of the formulae and aspects, descriptions and embodiments herein; (b) relates to the use of a composition comprising as a biologically active agent one or more further therapeutic or prophylactic agents used for the prevention or treatment of cancer or fibrosis in the form of a combined pharmaceutical preparation for simultaneous, separate or sequential use.

[0180] The compounds or compositions can be administered simultaneously with, prior to, or subsequent to one or more additional therapeutic agents that are different from the compounds described herein and that may be useful, for example, as a combination therapy.

[0181] Examples of such additional therapeutic agents for use in combination include agents that are inhibitors of the following: EGFR inhibitors (e.g., afatinib, erlotinib, osimertinib, gefitinib, dacomitinib, neratinib, canetinib, cetuximab), AXL inhibitors (e.g., crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), Inhibitors of components of the RAS-MAPK signaling cascade, including inhibitors of RAS itself (e.g., AMG510, MRTX849, BI1701963, ARS1620), Inhibitors of B-RAF (e.g. sorafenib, tosylate, dabrafenib, vemurafenib, regorafenib) or MEK1 / 2 inhibitors (trametinib, selumetinib, cobimetinib, mirdametinib).

[0182] The pharmaceutical composition or combination preparation according to the present disclosure may contain the compound of the present disclosure over a wide range of content depending on the intended use and expected effect of the preparation. In general, the content of the derivative of the present disclosure in the combination preparation is within the range of 0.1-99.9% by weight, preferably 1-99% by weight, more preferably 5-95% by weight.

[0183] Those skilled in the art will also recognize that the compounds of the present disclosure can exist in many different protonation states, depending, inter alia, on the pH of their environment. Although the structural formulae provided herein represent the compounds in only one of several possible protonation states, it will be understood that these structures are merely exemplary and the present disclosure is not limited to any particular protonation state, and any and all protonation forms of the compounds are intended to be within the scope of the present disclosure.

[0184] As used herein, the term "pharmaceutically acceptable salts" refers to the therapeutically active non-toxic salt forms that the compounds of the formulas herein can form. Thus, the compounds of the present disclosure may optionally be used as salts of the compounds herein, e.g., Na + , Li + , K + , Ca 2+ , and Mg 2+ In particular, pharma- ceutically acceptable non-toxic salts containing: ##STR00011## Such salts may include those derived from the combination of suitable cations, such as alkali and alkaline earth metal ions, or ammonium and tetravalent amino ions, with an acidic anion moiety, typically a carboxylic acid. Compounds of the present disclosure may have multiple positive or negative charges. The net charge of compounds of the present disclosure may be either positive or negative. Any associated counterions are typically determined by the synthesis and / or isolation method by which the compounds are obtained. Exemplary counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, and the like, and mixtures thereof. It will be understood that the identity of any associated counterion is not a critical feature of the present disclosure, and the present disclosure encompasses compounds associated with any type of counterion. Furthermore, because compounds may exist in a variety of different forms, the present disclosure is intended to encompass not only the form of the compound associated with the counterion (e.g., dry salt), but also the form not associated with the counterion (e.g., aqueous or organic solution). Metal salts are typically prepared by reacting the metal hydroxide with a compound of the present disclosure. Examples of metal salts thus prepared include Li + , Na + , and K +There are salts containing the following: Less soluble metal salts can be precipitated from the solution of a more soluble salt by the addition of a suitable metal compound. In addition, salts can be formed from the acid addition of certain organic and inorganic acids to a basic center, typically an amine, or to an acidic group. Examples of such suitable acids include inorganic acids such as hydrohalogen acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, e.g., acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, and the like. Furthermore, this term also includes solvates, such as hydrates, alcoholates, etc., which the compounds of the formulae herein as well as their salts can form. Finally, it should be understood that the compositions herein include the compounds of the present disclosure in their non-ionized as well as zwitterionic forms, and in combination with a stoichiometric amount of water as hydrates.

[0185] Also included within the scope of this disclosure are salts of the parent compounds with one or more amino acids, particularly the naturally occurring amino acids found as protein components. The amino acids are typically those having side chains with basic or acidic groups, e.g., lysine, arginine, or glutamic acid, or neutral groups, e.g., glycine, serine, threonine, alanine, isoleucine, or leucine.

[0186] The compounds of the present disclosure also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the present disclosure include alkali metal (e.g., sodium), alkaline earth (e.g., magnesium), ammonium and NX. 4 + (Wherein, X is C 1 ~C 4Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of compounds containing a hydroxy group include salts of the anions of the above compounds, such as Na + and NX 4 + (wherein X is typically H or C 1 ~C 4 Examples of suitable salts include those with a suitable cation, such as an alkyl group (independently selected from the alkyl radicals). However, salts of acids or bases which are not physiologically acceptable may also be used, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the disclosure.

[0187] As used herein, and unless otherwise specified, the term "enantiomer" means each individual optically active form of a compound of the present disclosure having an optical purity or enantiomeric excess (as measured by standard methods in the art) of at least 80% (e.g., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0188] The term "isomer" as used herein refers to all possible isomeric forms, including tautomeric and stereochemical forms, that the compounds of the formulae herein may have (but not positional isomers). Typically, the structures shown herein only exemplify one tautomeric or resonance form of the compound, but the corresponding alternative structures are also contemplated. Unless otherwise stated, the chemical designation of the compound refers to a mixture of all possible stereochemical isomeric forms, including all diastereomers and enantiomers of the basic molecular structure (since the compounds of the formulae herein may have at least one chiral center), as well as stereochemically pure or enriched compounds. More specifically, the asymmetric centers may have either the R or S configuration, and the multiple bonds may have the cis or trans configuration.

[0189] The pure isomeric forms of the compounds are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term "stereoisomerically pure" or "chirally pure" refers to a compound having a stereoisomeric excess of at least about 80% (e.g., at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94%, and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in the same way, taking into account the enantiomeric excess and diastereomeric excess of the mixture in question, respectively.

[0190] Separation of stereoisomers is carried out by standard methods known to those skilled in the art. One enantiomer of the compounds of the present disclosure can be separated substantially free of its opposite enantiomer by methods such as the formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," by EL Eliel, McGraw Hill, (1962); Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302). Separation of isomers in a mixture can be achieved by any suitable method, including (1) forming ionic, diastereomeric salts with chiral compounds and separating them by fractional recrystallization or other methods, (2) forming diastereomeric compounds with chiral derivatization agents, separating the diastereomers and converting them to pure enantiomers, or (3) enantiomers can be directly separated under chiral conditions. In method (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base, such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), with an asymmetric compound having an acidic functional group, such as carboxylic acid and sulfonic acid. The diastereomeric salts can be induced to separate by fractional recrystallization or ionic chromatography. In the case of separation of optical isomers of amino compounds, diastereomeric salts can be formed by addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid. Alternatively, in method (2), the substrate to be resolved can be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing agents, such as menthyl derivatives, followed by separation and hydrolysis of the diastereomers to give the free enantiomerically enriched compounds.A method for determining the optical purity involves preparing a chiral ester, such as menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal and reverse phase chromatography according to the method for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96 / 15111). In method (3), the racemic mixture of the two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide-based chiral stationary phases include ChiralCeI™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Suitable eluents or mobile phases for use in combination with the polysaccharide chiral stationary phases include hexane modified with alcohols such as ethanol, isopropanol, etc. ("Chiral Liquid Chromatography" (1989) WJ Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513: 375-378).

[0191] The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of substituents on a ring moiety. The absolute stereochemical configuration of compounds of the formulae described herein can be readily determined by one skilled in the art using known methods such as, for example, X-ray diffraction.

[0192] The present disclosure also includes isotopically labeled compounds that are identical to the compounds recited in the formulas described herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds of the present disclosure and pharma- ceutically acceptable salts of the compounds, or those that contain the above isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, e.g., 3 H and 14 Compounds into which a radioactive isotope, such as C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium, i.e. 2Substitution with H may be preferred in some circumstances since it may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the disclosed formulae can generally be prepared by carrying out the procedures disclosed in the Examples and preparations described herein by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0193] Also included within the scope of the present disclosure is the modification of the compound of formula (I) or other formulas, embodiments, or aspects, or a portion thereof, or a metabolite thereof, using PROTAC technology (Schapira M. et al, Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, PROTAC technology designs a bifunctional small molecule in which one end is a compound of general formula (I) or other formulas, embodiments, or aspects, or a portion thereof, or a metabolite thereof, and the other end is linked to a ligand of E3 ubiquitin ligase via a linking chain to form a target-induced protein degradation complex. This degradation has a catalytic effect, so efficient degradation can be achieved by reducing the dosage. The compounds of general formula (I) or other formulas, embodiments, or aspects, or portions thereof, or metabolites thereof, can be linked to a ligand of an E3 ubiquitin ligase, such as, for example, a thalidomide analog, via a linker arm (e.g., long chain ethylene glycols of 2-10 in length, long chain propylene glycols of 2-10 in length, and long chain fatty alkanes of 2-10 in length).

[0194] The compounds of the present disclosure may be formulated using conventional carriers and excipients selected according to normal practice. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery other than oral administration. Formulations optionally contain excipients such as those described in "Handbook of Pharmaceutical Excipients" (1986), and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0195] As used herein, the term "pharmaceutical acceptable carrier" refers to any material or substance that is formulated to facilitate the application or delivery of the active ingredient to the site to be treated, for example by dissolving, dispersing, or diffusing the composition, and / or to facilitate storage, transportation, or handling without compromising its effectiveness. The pharmaceutical acceptable carrier may be a solid, or a liquid, or a gas compressed to form a liquid, for example, the composition of the present disclosure may be suitably used as a concentrate, emulsion, solution, granule, fine powder, spray, aerosol, suspension, ointment, cream, tablet, pellet, or powder.

[0196] Suitable pharmaceutical carriers for use in the above pharmaceutical compositions and their formulation are known to those skilled in the art and are not particularly limited to their selection within the scope of the present disclosure. They may also include additives such as wetting agents, dispersants, spreading agents, adhesives, emulsifiers, solvents, coatings, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride), etc., provided that they are compatible with pharmaceutical practice and, for example, are carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present disclosure may be prepared in any known manner, for example, by uniformly mixing, coating and / or grinding the active ingredient with the selected carrier material in a single step or multiple step procedure, and, if necessary, other additives such as surfactants may also be prepared, for example, by micronization, for the purpose of obtaining them in the form of fine particles, usually about 1 to 10 gm in diameter, i.e., for the production of microcapsules for controlled or sustained release of the active ingredient.

[0197] Suitable surfactants, also known as excretion enhancers or emulsifiers, for use in the pharmaceutical compositions of the present disclosure are nonionic, cationic and / or anionic materials with good emulsifying, dispersing and / or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surfactants. Suitable soaps include alkali or alkaline earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C 10 ~C 22), for example, sodium or potassium salts of oleic or stearic acid, or natural fatty acid mixtures obtained from coconut or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acid; fatty sulfonates and sulfates; sulfonated benzimidazole derivatives and alkylarylsulfonates. The fatty sulfonates or sulfates are usually in the form of alkali or alkaline earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with alkyl or acyl groups having 8 to 22 carbon atoms, for example, sodium or calcium salts of lignosulfonic or dodecylsulfonic acid, or mixtures of fatty alcohol sulfates obtained from natural fatty acids, alkali or alkaline earth metal salts of sulfate or sulfonate esters (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 alkylarylsulfonates are the sodium, calcium or alcoholamine salts of dodecylbenzenesulfonic acid or dibutyl-naphthalenesulfonic acid or naphthalene-sulfonic acid / formaldehyde condensation products. Also suitable are the corresponding phosphoric acids, such as the salts of phosphoric acid esters and the adducts of p-nonylphenol with ethylene and / or propylene oxide, or phospholipids. Suitable phospholipids for this purpose include natural (animal or plant cell derived) or synthetic phospholipids of the cephalin or lecithin type, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphosphatidyl-choline, and mixtures thereof.

[0198] Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, aliphatic alcohols, fatty acids, aliphatic amines or amides, alkyl arenesulfonates and dialkyl sulfosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon portion and 6 to 18 carbon atoms in the alkyl portion of the alkylphenol. Further suitable nonionic surfactants include water-soluble adducts of polyethylene oxide and polypropylene glycol, ethylene diamino polypropylene glycols containing 1 to 10 carbon atoms in the alkyl chain, which contain 20 to 250 ethylene glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants include nonylphenol-polyethoxyethanol, castor oil polyglycol ether, polypropylene / polyethylene oxide adduct, tributylphenoxypolyethoxyethanol, polyethylene glycol, and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose, and pentaerythritol are also suitable nonionic surfactants.

[0199] Suitable cationic surfactants include quaternary ammonium salts, particularly halides having four hydrocarbon groups, optionally substituted with halo, phenyl, substituted phenyl, or hydroxy; e.g., at least one C 8~22 Included are quaternary ammonium salts containing alkyl (eg, cetyl, lauryl, palmityl, myristyl, oleyl, etc.) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl, and / or hydroxy lower alkyl.

[0200] A more detailed description of surfactants suitable for this purpose can be found, for example, in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw", 2d ed. (Hanser Verlag, Vienna, 1981), and "Encyclopaedia of Surfactants" (Chemical Publishing Co., New York, 1981).

[0201] The compounds of the present disclosure and their pharma- ceutically acceptable salts (hereinafter collectively referred to as active ingredients) may be administered by any route appropriate to the condition being treated, with suitable routes including oral, rectal, nasal, topical (including ocular, buccal, and sublingual), intravaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural).The preferred route of administration may vary, for example, with the condition of the recipient.

[0202] Although it is contemplated that the active ingredient may be administered alone, it is preferred that the active ingredient is present as a pharmaceutical formulation. For both veterinary and human use, the formulations of the present disclosure include at least one active ingredient, as described above, together with one or more pharma- ceutically acceptable carriers, and therefore, optionally, other therapeutic ingredients. The carrier(s) are optimally "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. The formulations may conveniently be presented in unit dosage formulations and may be prepared by any of the methods known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0203] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0204] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of a moist powdered compound and an inert liquid diluent in a suitable machine. Tablets can be optionally coated or divided, and can be formulated to provide a sustained or controlled release of the active ingredient therein. For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w (including in 0.1% w / w increments of the active ingredient(s) ranging from 0.1% to 20% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, such as an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0205] The oil phase of the emulsion of the present disclosure can be composed of known ingredients in a known manner. The phase can simply comprise an emulsifier (otherwise known as a drainage promoter), but desirably comprises a mixture of at least one emulsifier with fat or oil, or with both fat and oil. Optionally, a hydrophilic emulsifier is comprised together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to comprise both oil and fat. Taken together, the emulsifier(s) with or without stabilizer(s) constitute the so-called emulsifying wax, which, together with oil and fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations.

[0206] Since the solubility of active compounds in most oils that may be used in pharmaceutical emulsion formulations is very low, the selection of suitable oils or fats for the formulation is based on whether they achieve the desired cosmetic properties. Therefore, creams must be non-oily, non-staining, and washable products, optionally with suitable compatibility to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters may be used, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, with the last three esters being preferred. These may be used alone or in combination, depending on the properties required. Alternatively, high melting point lipids such as white petrolatum and / or liquid paraffin, or other mineral oils may be used.

[0207] Formulations suitable for topical administration to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5-20%, advantageously 0.5-10%, particularly about 1.5% w / w. Formulations suitable for topical administration to the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0208] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or salicylic acid. Formulations suitable for nasal administration where the carrier is a solid include, for example, a coarse powder having a particle size in the range of 20 to 500 microns (including particle sizes in the range of 20 to 500 microns in 5 micron increments, such as 30 microns, 35 microns, etc.), which may be administered in the form of a snuff, for example by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Suitable formulations where the carrier is a liquid, for example to be administered as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.

[0209] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0210] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.The preparations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a frozen-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0211] Preferred unit dosage formulations are those containing a daily dose or daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0212] It will be understood that, in addition to the ingredients particularly mentioned above, the formulations of the present disclosure may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0213] The compounds of the present disclosure can be used to provide controlled release pharmaceutical formulations containing one or more compounds of the present disclosure as active ingredients ("controlled release formulations") in which the release of the active ingredient is controlled and regulated, allowing for less frequent administration or improved pharmacokinetic or toxicity profile of a given disclosed compound. Controlled release formulations adapted for oral administration in which discrete units contain one or more compounds of the present disclosure can be prepared according to conventional methods.

[0214] Additional components may be included to control the duration of action of the active ingredient in the composition. Thus, controlled release compositions can be achieved by selecting appropriate polymeric carriers, such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate, etc. The rate of drug release and duration of action can also be controlled by incorporating the active ingredient into particles, e.g., microcapsules, of polymeric materials, such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate, and other polymers mentioned above. Such methods include colloidal drug delivery systems, such as liposomes, microspheres, microemulsions, nanoparticles, nanocapsules, etc. Depending on the route of administration, the pharmaceutical composition may require a protective coating. Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for their extemporaneous preparation. Thus, typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, etc., and mixtures thereof.

[0215] Taking into account the fact that, when several active ingredients are used in combination, they do not necessarily directly produce a joint therapeutic effect in the treated mammal at the same time, the corresponding composition may be in the form of a medical kit or package containing the two components in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a manner suitable for a different administration route than the other components, for example, one of them may be in the form of an oral or parenteral preparation, while the other one may be in the form of an ampoule or aerosol for intravenous injection.

[0216] Another embodiment of the present disclosure relates to various precursor or "prodrug" forms of the compounds of the present disclosure. It may be desirable to formulate the compounds of the present disclosure in the form of chemical species that do not have biologically significant activity themselves, but when delivered to an animal, mammal, or human, undergo a chemical reaction catalyzed by the normal functions of the body of the fish, particularly enzymes present in the stomach or serum, where said chemical reaction has the effect of releasing the compound as defined herein. The term "prodrug" therefore relates to these species that are converted in vivo into the active pharmaceutical ingredient.

[0217] The prodrug of the compound of the present disclosure can have any form suitable for the formulator, for example, ester is a non-limiting common prodrug form. However, in this case, the prodrug may necessarily exist in a form in which the covalent bond is cleaved by the action of an enzyme present at the target site. For example, the CC covalent bond may be selectively cleaved by one or more enzymes at the target site, so that a prodrug in a form other than a readily hydrolyzable precursor, particularly ester, amide, etc., may be used. The counterpart of the active pharmaceutical ingredient in the prodrug may have a different structure, such as an amino acid or peptide structure, an alkyl chain, a saccharide moiety, and others known in the art.

[0218] For purposes of this disclosure, the term "therapeutically suitable prodrug" is defined herein as "a compound that has been modified in such a way that, upon contact with the tissues of an animal, mammal or human to which the prodrug has been administered, it is converted in vivo without undue toxicity, irritation, or allergic response into a therapeutically active form and is capable of achieving a desired therapeutic result, whether by single or multiple biological transformations."

[0219] More specifically, the term "prodrug" as used herein refers to an inactive or significantly less active derivative of a compound that is converted naturally or enzymatically in the body to release a pharmacologically active form of the compound, as represented by the structural formulas described herein.For a comprehensive review, reference is made to Rautio J.et al. ("Prodrugs: design and clinical applications" Nature Reviews Drug Discovery, 2008, doi:10.1038 / nrd2468).

[0220] The compounds of the present disclosure can be prepared using a series of chemical reactions known to those skilled in the art that together constitute and are further exemplified processes for preparing said compounds. The further described processes are meant to be merely exemplary and are not intended to limit the scope of the present disclosure.

[0221] Working Example General Synthesis Abbreviations that may be used herein, particularly in the schemes and examples, are as follows: AIBN - azobisisobutyronitrile, aq - aqueous solution, ACN - acetonitrile, Ac 2 O-Acetic anhydride, AcOH-Acetic acid, BF 3 .OEt 2 -Boron trifluoride diethyl ether, BINAP-(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Boc-tert-butyloxycarbonyl, Boc 2O-Di-tert-butyl dicarbonate, BrettPhos-2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, BrettPhos Pd G3-[(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, tBuOH-tert-butanol, Conc-concentrated, mCPBA-meta-chloroperoxybenzoic acid, CMBP-(tributylphosphoranylidene)acetonitrile, Cu(OAc) 2 -Copper(II) acetate, d-day, DCM-dichloromethane, DCE-1,2-dichloroethane, DIPEA-diisopropylethylamine, DMA-N,N-dimethylacetamide, DMAP-N,N-dimethylpyridin-4-amine, DMF-N,N-dimethylformamide, DMF-DMA-N,N-dimethylformamide dimethyl acetal, DMSO-dimethyl sulfoxide, DMSO-d 6 - Deuterated dimethyl sulfoxide, DPPA - Diphenylphosphoryl azide, EDA - Ethyl diazoacetate, EDC - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EtOH - Ethanol, EtOAc - Ethyl acetate, Et 2 O-Diethyl ether, Eq.-Equivalent, FA-Formic acid, h-Hour, HATU-O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HCl-Hydrogen chloride, HNO 3 -Nitric acid, H 2 O 2 -Hydrogen peroxide, HO(CH 2 O) n H-paraformaldehyde, HOAt-1-hydroxy-7-azabenzotriazole, HPLC-high performance liquid chromatography, IPA-2-propanol, LAH-lithium aluminum hydride, LG-leaving group, MeOH-methanol, min-minutes, NBS-N-bromosuccinimide, Pd(amphos)Cl 2-Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd(PPh 3 ) 2 Cl 2 -Bis(triphenylphosphine)palladium(II) dichloride, Pd(PPh 3 ) 4 -Tetrakis(triphenylphosphine)palladium, Pd 2 (dba) 3 - Tris(dibenzylideneacetone)dipalladium, Pd(dppf)Cl 2 -(1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, Pd(dppf)Cl 2 DCM-(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex with DCM, Pd(OAc) 2 -Palladium(II) acetate, PPh 3 -Triphenylphosphine, Pet Ether -Petroleum Ether, PFA -Paraformaldehyde, Pic-BH 3 -2-Picoline-borane complex, PhI(OAc) 2 -(Diacetoxyiodo)benzene, Raney Ni-Raney Nickel, RF-Retention factor, RT-Room temperature, sat-Saturated, SCX-Strong cation exchange, TBAF-Tetra-n-butylammonium fluoride, TBN-tert-Butyl nitrite, TEA-Triethylamine, THF-Tetrahydrofuran, THP-Tetrahydropyranyl, TFA-Trifluoroacetic acid, TFAA-Trifluoroacetic anhydride, TLC-Thin layer chromatography, TMS-Trimethylsilyl, TMSN 3 -Trimethylsilyl azide, T 3 P-Propanephosphonic anhydride, Xanthphos-4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, XPhos-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, XPhos-Pd-G2-chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), ZnEt 2-Diethylzinc.

[0222] Compounds of the present invention may be prepared according to the general procedures outlined in Scheme 1. Scheme 1: All variables are as described for the compounds of the invention and their embodiments and formulas. [ka]

[0223] In another embodiment, compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 2. Scheme 2: All variables are as described for the compounds of the invention and their embodiments and formulas. [ka]

[0224] Alternatively, compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 3. Scheme 3: All variables are as described for the compounds of the invention and their embodiments and formulas. [ka]

[0225] The general schemes described above should be considered as non-limiting examples, and it will be understood that compounds of the invention may be obtained via other methods known to those skilled in the art. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0226] These examples are provided to illustrate the disclosure and should not be construed in any way as limiting the scope of the disclosure.

[0227] Part A: Experimental Chemistry Procedures All starting materials not explicitly mentioned are either commercially available (details of suppliers such as, for example, Acros, Avocado, Aldrich, Fluka, FluoroChem, MatrixScientific, Maybridge, Merck, Sigma can be found, for example, in the SciFinder® database) or their synthesis has already been precisely described in the specialist literature (experimental guidelines can be found, for example, in the Reaxys® database or the SciFinder® database, respectively) or can be prepared using conventional methods known to the person skilled in the art.

[0228] If necessary, reactions are kept in an inert atmosphere (mostly argon and N 2 ) under. The equivalent number of reagents and the amount of solvent used as well as the reaction temperature and time can be slightly changed between different reactions carried out by similar methods. The work-up and purification methods were adapted according to the characteristic properties of each compound, but can be slightly changed for similar methods. The yield of the prepared compounds is not optimized.

[0229] The designation "equivalent" ("eq." or "eq" or "equiv.") means molar equivalent, "RT" or "rt" means room temperature T (23±7°C), "M" means concentration in mol / l, "sol." means solution, and "conc." means concentrated. Solvent mixture ratios are usually described as volume / volume ratios.

[0230] A CEM microwave (Discover SP) was used to carry out the reaction under microwave radiation (heating rate: 2-6°C / s; temperature: 30-300°C, volume independent infrared (IR) and fiber optic (FO) temperature measurement from 80-300°C; pressure: 0-435 psi, ActiVent™ technology; power: 0-300 W; magnetron frequency: 2450 MHz; reaction stirring: magnetic stirring; air cooling: ≥ 25 psi (20 L / min flow rate); system control: Synergy™ software).

[0231] 1 H-NMR spectroscopy and / or mass spectrometry (MS, [M+H] + and / or M.H.] - Primary analytical characterization was performed for all exemplary compounds and selected intermediates by m / z). In certain cases, e.g., regioisomers and / or diastereoisomers may / were formed during the reaction. 13 Additional analyses such as C NMR and NOE (Nuclear Overhauser Effect) NMR experiments were performed in some cases.

[0232] The analytical instruments used were, for example, BRUKER AVANCE 400MHz (Software Topspin) or VARIAN MR 400MHz (VNMRJ Sofware) machines for NMR analysis. For LC / MS analysis, for example, Acquity UPLC H-Class, Mass: Acquity SQD2 Detector (ESI), Acquity UPLC, Mass: Quatro premier XE Detector (ESI), Acquity UPLC, Mass: Waters Xevo TQ-S Detector (ESI / ESCI), or Alliance Waters 2695, Mass: Quattromicro™ (ESCI) multimode ionization was used. Analytical HPLC was measured, for example, with Alliance Waters 2695. Analytical SFC was performed, for example, with PIC Solutions (Software: SFC PIC Lab Online), WATERS-X5 (Software MASSLYNX), or WATERS-UPC2 (Empower).

[0233] Preparative HPLC was performed, for example, on a Waters 2545 (Software Empower), Gilson (Software Trilution), or Shimadzu (Software LC Solution). Preparative SFC was performed, for example, on a Waters Thar SFC-80 (Software Chromscope), Waters Thar SFC-150 (Software Chromscope), Waters Thar SFC-200 (Software Chromscope), or PIC SFC-175 (Software SFC PIC Lab Online).

[0234] The structures of exemplary compounds containing stereocenters are drawn and named with absolute stereochemistry, if known. When the absolute stereochemistry is unknown, the compound may be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia1 and Dia2 mean that the diastereomers were isolated but the stereochemistry is unknown. En1 and En2 mean that both enantiomers were isolated but the absolute configuration is unknown. If no suffix is ​​given after the compound code, it means that the compound containing a stereocenter was obtained as a racemic mixture or a mixture of diastereomers, respectively, unless the chemical name of the compound specifies the exact stereochemistry.

[0235] The LC / MS analyses mentioned in the experimental part were performed on an Alliance Waters 2695 HPLC (equipped with a PDA detector) connected to a mass spectrometer Waters Quattromicro (ESCI, multimode, ionization). Separation was performed using Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) column, Acquity BEH C18 (1.7 μm, 2.1 × 100 mm) column, or X-Bridge C18 (3.5 μm, 4.6 × 75 mm) columns thermostatted at 30-35 °C, and the PDA acquisition wavelength was set in the range of 210-400 nm (Acuisition Software: MassLynx). Elution was performed using the methods described in the table below. For methods L1, L6, and L7, solvent A: 0.1% LC-MS grade FA in milliQ water. Solvent B: 0.1% LC-MS grade FA in LC-MS grade ACN. For methods L2 and L3, solvent A: 0.05% LC-MS grade FA in milliQ water. Solvent B: 0.05% LC-MS grade FA in LC-MS grade ACN. For methods L4 and L8, solvent A: 0.05% LC-MS grade TFA in milliQ water. Solvent B: 0.05% LC-MS grade TFA in LC-MS grade ACN. For method L5, solvent A: 5 mM (NH 4 )HCO 3. Solvent B: LC-MS grade ACN. For method L9, Solvent A: 0.1% LC-MS grade TFA in milliQ water. Solvent B: LC-MS grade ACN. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0236] The UPLC analyses mentioned in the experimental part were carried out on an Acquity UPLC H-Class (equipped with a PDA detector) connected to a mass spectrometer Acquity TQ Detector (ESI / ESCI). Separation was performed using an Acquity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) or Acquity UPLC HSS C18 (1.8 μm, 2.1 × 50 mm) column thermostated at 40 °C and the PDA acquisition wavelength was set in the range of 190-420 nm. Elution was performed using the methods described in the table below. For methods U1 and U2, solvent A: 10 mM (NH 4 ) OAc. Solvent B: ACN (UPLC grade, Biosolve). For method U3, Solvent A: 0.1% FA in milliQ water (UPLC grade, Biosolve). Solvent B: ACN (UPLC grade, Biosolve). [Table 3]

[0237] Preparative HPLC purifications mentioned in this experimental part were performed on a Waters 2545 (Empower software, 2996 PDA detector, 2707 autosampler), Gilson (Software Trilution, 171 DAD detector, GX-271 autosampler), or Shimadzu (Software LC Solution, CMB-20A detector, SIL-10AP autosampler). Separations were performed using Luna C18 (5 μm, 21.2 × 250 mm; or 10 μm, 21.2 × 250 mm) columns, X-Bridge C18 (5 μm, 29 × 250 mm; 5 μm, 19 × 150 mm; or 10 μm, 19 × 150 mm) columns, X-Select C18 (5 μm, 19 × 150 mm; 5 μm, 19 × 250 mm; 5 μm, 25 × 150 mm; 10 μm, 25 × 150 mm; or 10 μm, 25 × 250 mm) columns, X-Select CSH Phenyl-Hexyl (5 μm, 19 × 150 mm; or 5 μm, 19 × 250 mm) columns, Synergi The analysis was carried out using a Polar-RP (5 μm, 21.2×250 mm) column, a Kromasil (5 μm, 19×150 mm) column, a YMC-Triart C18 (10 μm, 19×250 mm) column, or a SUNFIRE C18 (5 μm, 19×250 mm) column. Elution was carried out using the columns and solvents listed in the table below. A gradient system was employed for each individual compound using the solvents listed in the table. The detection wavelengths were fixed at 210 and 254 nm. [Table 4-1] [Table 4-2]

[0238] Example 1: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (Compound No. 001) [ka] Step 1: To a mixture of 3-(aminomethyl)-1H-indazole (100 mg, 0.65 mmol) in MeOH (4 mL), 1 M NaHCO 3 (1.3 mL, 1.29 mmol) in water, followed by Boc 2 0 (145 mg, 0.65 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was followed by LC / MS. The mixture was concentrated and H 2 The mixture was diluted with O and extracted with EtOAc. The combined organic layers were washed with brine and MgSO 4 The mixture was dried over hexane and concentrated under reduced pressure. The crude product was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 10-80% EtOAc in n-heptane as eluent to give tert-butyl (1H-indazol-3-ylmethyl)carbamate (75 mg, 47%). (LC / MS; m / z 246 [MH] - ).

[0239] Step 2: Add tert-butyl (1H-indazol-3-ylmethyl)carbamate (60 mg, 0.24 mmol), 4-iodobenzotrifluoride (44 μL, 0.30 mmol), K 3 PO 4 (132 mg, 0.60 mmol), 2-picolinic acid (4.0 mg, 0.032 mmol), and CuI (6.0 mg, 0.032 mmol). The vial was purged with argon gas and DMSO (1.5 mL) was added. The reaction mixture was stirred at 80 °C for 16 h (sealed tube). The progress of the reaction was followed by LC / MS. The mixture was diluted with EtOAc and filtered through a pad of Celite, washing with EtOAc. The filtrate was washed with saturated NH 4 Cl, NH 4 The solution was washed with Cl / NaOH (pH 8) solution and brine. 4The crude product was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 5-40% EtOAc in n-heptane as eluent to give tert-butyl ((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (60 mg, 63%) as a white solid. (LC / MS; m / z 336 [M+H-tBu] + ).

[0240] Step 3: A solution of tert-butyl ((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (60 mg, 0.15 mmol) in 1,4-dioxane (0.6 mL) was treated with HCl (4 M in 1,4-dioxane; 0.6 mL, 2.40 mmol). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was followed by LC / MS. The mixture was concentrated under reduced pressure to give (1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine hydrochloride (54 mg, 107%) as a white solid. The crude product was used in the next step without further purification.

[0241] Step 4: To a suspension of (1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine hydrochloride (30 mg, 0.092 mmol) in DCM (0.6 mL) was added TEA (51 μL, 0.37 mmol) followed by acryloyl chloride (10 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure and the residue was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 20-80% EtOAc in n-heptane as eluent to give N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (compound no. 001) (19 mg, 60%) as a white solid. (LC / MS; m / z 346 [M+H] + ).

[0242] The following compounds were prepared in a similar manner to Compound No. 001 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 002 (using propionyl chloride in step 4), Compound No. 003 (using mesyl chloride in step 4), Compound No. 004 (using 4-trifluoromethoxyphenyl iodide in step 2), Compound No. 005 (using 4-trifluoromethoxyphenyl iodide in step 2 and propionyl chloride in step 4), Compound No. 006 (using 4-trifluoromethoxyphenyl iodide in step 2 and mesyl chloride in step 4), Compound No. 057 (using cyanomethylsulfonyl chloride in step 4).

[0243] Example 2: Synthesis of N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acrylamide (Compound No. 020) [ka] Step 1: Methyl 1H-indole-3-carboxylate (1.0 g, 5.7 mmol), 1-iodo-4-(trifluoromethyl)benzene (3.87 g, 17.1 mmol), Cs in DMA (7 mL) 2 CO 3 (3.71 g, 11.4 mmol), and Cu 2 A solution of 2H2O (815 mg, 5.7 mmol) was stirred at 200 °C for 1 h (sealed tube; microwave irradiation). The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.5, TLC detection: UV. The reaction mixture was cooled to room temperature, diluted with EtOAc (80 mL) and purified by HCl. 2 The organic layer was washed with brine (40 mL) and anhydrous NaCl. 2 SO 4The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The crude product (1.2 g) was purified by normal phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-5% EtOAc in petroleum ether as eluent to give methyl 1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxylate (625 mg, 33%, LC / MS 96%) as an off-white solid. (LC / MS; m / z 320 [M+H] + ).

[0244] Step 2: MeOH (25 mL), THF (25 mL) and H 2 Methyl 1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxylate (2.5 g, 7.8 mmol) and LiOH.H 2 A solution of 2.62 g (62.4 mmol) of 1H-indole-3-carboxylic acid was stirred at 80° C. for 4 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 30% EtOAc in petroleum ether, RF: 0.5, TLC detection: UV. The reaction mixture was concentrated under reduced pressure and acidified with 2 M aqueous HCl (pH approx. 2) at 0° C. The precipitated solid was filtered and dried under vacuum to give 1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxylic acid (1.8 g, 73%, LC / MS 96%) as an off-white solid. (LC / MS; m / z 306 [M+H] + ).

[0245] Step 3: A solution of 1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxylic acid (1.3 g, 4.3 mmol) in THF (20 mL) was treated with DPPA (2.95 g, 10.75 mmol) and TEA (1.30 g, 12.9 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in tBuOH (25 mL) and the solution was stirred at 110° C. for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc in petroleum ether, RF: 0.76, TLC detection: UV. The reaction mixture was diluted with EtOAc (100 mL) and stirred at H 2The organic layer was washed with brine (50 mL) and anhydrous NaCl. 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The crude product (1.3 g) was purified by normal phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-7% EtOAc in petroleum ether to give tert-butyl (1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)carbamate (600 mg, 37%, LC / MS 97%) as an off-white solid. (LC / MS; m / z 377 [M+H] + ).

[0246] Step 4: A solution of tert-butyl (1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)carbamate (300 mg, 0.79 mmol) in DCM (7 mL) was treated with HCl (4 M in 1,4-dioxane) (2 mL) and stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc in petroleum ether, RF: 0.1, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give 1-(4-(trifluoromethyl)phenyl)-1H-indol-3-amine hydrochloride (150 mg, 24%, LC / MS 34%) as a pale yellow solid. (LC / MS; m / z 277 [M+H] + ). The product was used directly without further purification.

[0247] Step 5: 1-(4-(trifluoromethyl)phenyl)-1H-indol-3-amine hydrochloride (100 mg, 0.32 mmol, LC / MS 34%) and NaHCO in 1,4-dioxane (3 mL) and water (1 mL). 3 A solution of (54 mg, 0.63 mmol) was treated with a solution of acryloyl chloride (35 mg, 0.38 mmol) in 1,4-dioxane (2 mL) at 0° C. and stirred for 10 min. The progress of the reaction was monitored by TLC. TLC mobile phase: 30% EtOAc in petroleum ether, RF: 0.61, TLC detection: UV. The reaction mixture was diluted with DCM (10 mL) and diluted with H 2The organic layer was washed with brine (7 mL) and then with Na 2 SO 4 The mixture was dried over 100 ml of hexane and concentrated under reduced pressure. The crude product (110 mg, LC / MS 73%) was purified by preparative HPLC method H9. The collected fractions were lyophilized to give N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acrylamide (compound no. 022) (21 mg, 58%, LC / MS 99%) as an off-white solid. (LC / MS; m / z 331 [M+H] + ).

[0248] The following compound was prepared in a similar manner to Compound No. 020 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 021 (Ac in DCM in step 5) 2 O and DIPEA were used), Compound No. 022: Compound No. 023: Compound No. 024: Compound No. 025: Compound No. 026.

[0249] Example 3: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)acrylamide (Compound No. 027) [ka] Step 1: 1H-indole-3-carbaldehyde (1.0 g, 6.9 mmol) in 1,4-dioxane (10 ml), K 2 CO 3 A solution of (1.99 g, 14.49 mmol) and 1-iodo-4-(trifluoromethyl)benzene (3.75 g, 13.8 mmol) was degassed with argon for 10 min. The mixture was treated with CuI (262 mg, 1.38 mmol) and (±)-trans-1,2-diaminocyclohexane (157 mg, 1.38 mmol) and stirred at 120 °C for 16 h (sealed tube). The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.5, TLC detection: UV. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3 x 70 mL). The combined organic layers were washed with anhydrous Na 2 SO4 The mixture was dried over 100 ml of hexane and concentrated under reduced pressure. The crude product (1.2 g, LC / MS 78%) was purified by normal phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-5% EtOAc in petroleum ether to give 1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carbaldehyde (980 mg, 49%, LC / MS 99%) as an off-white solid. (LC / MS; m / z 290 [M+H] + ).

[0250] Step 2: EtOH (10mL) and H 2 1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carbaldehyde (250 mg, 0.9 mmol) in HO (1 mL), NH 2 OH.HCl (93 mg, 1.35 mmol) and Na 2 CO 3 A solution of (71 mg, 0.675 mmol) was stirred at 100° C. for 2 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.35, TLC detection: UV. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (2×50 mL). The organic layer was washed with anhydrous Na 2 SO 4 After drying over 100° C. and concentrating under reduced pressure, (E / Z)-1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carbaldehyde oxime (230 mg, 86%, LC / MS 36% and 62%) was obtained as an off-white solid. (LC / MS; m / z 305 [M+H] + ).

[0251] Step 3: (E / Z)-1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carbaldehyde oxime (230 mg, 0.75 mmol) and NiCl in MeOH (10 ml). 2 .6H 2 A solution of 2,4-dichlorophenyl ether (182 mg, 0.77 mmol) was dissolved in NaBH 4(319 mg, 8.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The progress of the reaction mixture was monitored by TLC. TLC mobile phase: 10% MeOH in DCM, RF: 0.6, TLC detection: UV. The reaction mixture was diluted with EtOAc (50 mL), stirred for 10 min, and filtered through a pad of Celite. The filtrate was diluted with H 2 20 mL and brine (2×25 mL). 2 SO 4 Drying over rt and concentration under reduced pressure gave (1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanamine (180 mg, 48%, LC / MS 57%) as a brown gum. (LC / MS; m / z 291 [M+H] + ).

[0252] Step 4: 1,4-dioxane (5 mL) and H 2 (1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanamine (90 mg, 0.31 mmol, LC / MS 57%) and NaHCO in 2H2O (1 mL). 3 A solution of (78 mg, 0.92 mmol) was cooled to 0° C. and treated with acryloyl chloride (28 mg, 0.31 mmol). The reaction mixture was stirred at 0° C. for 1 h. The progress of the reaction mixture was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.5, TLC detection: UV. The reaction mixture was diluted with DCM (30 mL) and diluted with H 2 The organic layer was washed with 2×O (15 mL) and brine (2×20 mL). 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure. The crude product (130 mg, LC / MS 38%) was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)acrylamide (compound no. 027) (21 mg, 34%, LC / MS 99%) as a white solid. (LC / MS; m / z 345 [M+H] + ).

[0253] Compound: Compound No. 028 (using propionyl chloride and TEA in DCM in step 4) was prepared in a similar manner to Compound No. 027 (using appropriate reagents and purification methods known to one of skill in the art).

[0254] Example 4: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2yl)methyl)acrylamide (Compound No. 029) [ka] Step 1: A solution of (1H-indol-2-yl)methanamine hydrochloride (2.0 g, 11 mmol), TEA (2.22 g, 22 mmol) and DMAP (67 mg, 0.55 mmol) in DCM (40 mL) was reacted with Boc 2 The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction mixture was monitored by TLC. TLC mobile phase: 60% EtOAc in petroleum ether, RF: 0.7, TLC detection: UV. The reaction mixture was diluted with DCM (30 mL) and diluted with H 2 The organic layer was washed with anhydrous NaO (20 mL). 2 SO 4 The crude product was purified by normal phase flash column chromatography using a 40 g column (silica) and a gradient of 0-10% EtOAc in petroleum ether as eluent to give tert-butyl ((1H-indol-2-yl)methyl)carbamate (Intermediate 1) (2.0 g, 74%, LC / MS 99%) as an off-white solid. (LC / MS; m / z 247 [M+H] + ).

[0255] Step 2: Intermediate 1 (1.0 g, 4.06 mmol), 1-iodo-4-(trifluoromethyl)benzene (2.23 g, 8.13 mmol), K in toluene (10 mL) 3 PO 4A solution of (1.73 g, 8.13 mmol), CuI (389 mg, 2.03 mmol) and trans-1,2-diaminocyclohexane (93 mg, 0.82 mmol) was stirred at 120° C. under nitrogen atmosphere for 16 h (sealed tube). The progress of the reaction mixture was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.33, TLC detection: UV. The reaction mixture was concentrated under reduced pressure. The crude product was purified by normal phase flash column chromatography using a 24 g column (silica) and a gradient of 10% EtOAc in petroleum ether as eluent to give tert-butyl ((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)carbamate (400 mg, 24%, LC / MS 95%) as an off-white solid. (LC / MS; m / z 391 [M+H] + ).

[0256] Steps 3-4: These steps were carried out in a similar manner as steps 4 and 5 for Compound No. 020 (using appropriate reagents and purification methods known to one skilled in the art). The starting material (400 mg, 1.02 mmol, LC / MS 95%) gave a crude product (385 mg, LC / MS 68%) which was purified by preparative HPLC method H5. The resulting fractions were lyophilized to give N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)acrylamide (Compound No. 029) (98 mg, 29%, LC / MS 99%) as an off-white solid. (LC / MS; m / z 345 [M+H] + ).

[0257] Compound: Compound No. 030 (using propionyl chloride and TEA in DCM in step 4) was prepared in a similar manner to Compound No. 029 (using appropriate reagents and purification methods known to one of skill in the art).

[0258] Example 5: Synthesis of N-((1-(4-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide (Compound No. 031) [ka] Step 1: Intermediate 1 (300 mg, 1.22 mmol, LC / MS 91%) in ACN (6 mL), K 2 CO 3 A solution of (336 mg, 2.44 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (232 mg, 0.975 mmol) was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 20% EtOAc in petroleum ether, RF: 0.5, TLC detection: UV. The reaction mixture was diluted with H 2 The mixture was diluted with 20 mL of EtOAc and extracted with 2×20 mL of EtOAc. The combined organic layers were 2 Wash with 20 mL of anhydrous NaCl. 2 SO 4 The crude product (450 mg, LC / MS 35%) was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 0-20% EtOAc in petroleum ether as eluent to give tert-butyl ((1-(4-trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)carbamate (120 mg, 16%, LC / MS 60%). (LC / MS; m / z 405 [M+H] + ).

[0259] Steps 2-3: These steps were carried out in a similar manner (using appropriate reagents and purification methods known to one skilled in the art) as steps 4 and 5 for Compound No. 020. The starting material (120 mg, 0.30 mmol, LC / MS 60%) gave a crude product (120 mg, LC / MS 19%) which was purified by preparative HPLC method H2. The resulting fraction was lyophilized to give N-((1-(4-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide (Compound No. 031) (7 mg, 11%, LC / MS 99%) as a white solid. (LC / MS; m / z 359 [M+H] + ).

[0260] Compound: Compound No. 032 was prepared in a similar manner to Compound No. 031 (using appropriate reagents and purification methods known to one of skill in the art).

[0261] Example 6: Synthesis of N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acrylamide (Compound No. 033) [ka] Step 1: 1-(2-aminophenyl)ethan-1-one (4.8 g, 35.5 mmol), Cu(OAc) in DCM (150 mL) 2 A solution of (7.74 g, 42.7 mmol), DIPEA (18.9 mL, 106.6 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (10.1 g, 53.3 mmol) was stirred at room temperature under oxygen atmosphere (balloon pressure) for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc in petroleum ether, RF: 0.49, TLC detection: UV. The reaction mixture was diluted with H 2 The organic layer was diluted with H2O (50 mL) and extracted with DCM (100 mL). 2 2×30 mL and brine (30 mL). 2 SO 4 The crude product (6.3 g, LC / MS 46%) was purified by normal phase flash column chromatography using a 40 g column (silica) and a gradient of 0-8% EtOAc in petroleum ether as eluent to give 1-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)ethan-1-one (2.8 g, 26%, LC / MS 92%) as a yellow solid. (LC / MS; m / z 280 [M+H] + ).

[0262] Step 2: 1-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)ethan-1-one (2.3 g, 8.24 mmol) and SeO in 1,4-dioxane (25 mL). 2A solution of (4.57 g, 41.2 mmol) was stirred at 80° C. for 16 h under oxygen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC. TLC mobile phase: 20% EtOAc in petroleum ether, RF: 0.15, TLC detection: UV. The reaction mixture was diluted with EtOAc (100 mL), filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product (3.2 g) was purified by normal phase flash column chromatography using a 40 g column and a gradient of 0-12% EtOAc in petroleum ether as eluent to give 1-(4-(trifluoromethyl)phenyl)indoline-2,3-dione (1.0 g, 33%, LC / MS 73%) as a red solid. (LC / MS; m / z 292 [M+H] + ).

[0263] Step 3: 1-(4-(trifluoromethyl)phenyl)indoline-2,3-dione (1.0 g, 3.43 mmol), NH in EtOH (30 mL) 2 A solution of OH.HCl (358 mg, 5.15 mmol) and NaOAc (422 mg, 5.15 mmol) was stirred at 90° C. for 4 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 30% EtOAc in petroleum ether, RF: 0.15, TLC detection: UV. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (100 mL) and H 2 The organic layer was dissolved in NaO (50 mL). 2 SO 4 After drying over 100° C. and concentrating under reduced pressure, 3-(hydroxyimino)-1-(4-(trifluoromethyl)phenyl)indolin-2-one (1.2 g, LC / MS 85%) was obtained as a yellow solid. (LC / MS; m / z 305 [MH] - ). The product was used directly without further purification.

[0264] Step 4: A solution of 3-(hydroxyimino)-1-(4-(trifluoromethyl)phenyl)indolin-2-one (200 mg, 0.65 mmol) in MeOH (5 mL) was treated with Zn dust (213 mg, 3.26 mmol) and HCl (4 M in MeOH) (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give 3-amino-1-(4-(trifluoromethyl)phenyl)indolin-2-one hydrochloride (400 mg, LC / MS 82%) as a brown gum. (LC / MS; m / z 293 [M+H] + ). The product was used directly without further purification.

[0265] Step 5: This step was carried out in a similar manner to step 5 for Compound No. 020 (using appropriate reagents and purification methods known to one skilled in the art). The starting material (200 mg, 0.68 mmol, LC / MS 82%) gave a crude product (110 mg, LC / MS 40%) which was purified by preparative HPLC method H9. The resulting fraction was lyophilized to give N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acrylamide (Compound No. 033) (44 mg, 25%, LC / MS 99%) as a white solid. (LC / MS; m / z 347 [M+H] + ).

[0266] Compound: Compound No. 034 (Ac in DCM in step 5) 2 Compound #033 (using O and DIPEA) was prepared in a similar manner to Compound #033 (using appropriate reagents and purification methods known to one of skill in the art).

[0267] Example 7: Synthesis of 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetic acid (Compound No. 035) Synthesis of methyl 2-(6-chloro-8-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl)acetate (intermediate 2) and methyl 2-(6-chloro-8-(1-(pyridin-3-ylmethyl)-1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl)acetate (intermediate 3) [ka] Step 1: A mixture of 3-bromo-5-chloropyridin-2-amine (10.0 g, 47.2 mmol) and methyl 4-chloro-3-oxobutanoate (8.5 mL, 70.9 mmol) in THF (70 mL) was heated at 66° C. for 72 h. The solid formed was filtered off, washed with THF (20 mL) and dried under reduced pressure to give methyl 2-(8-bromo-6-chloroimidazo[1,2-a]pyridin-2-yl)acetate hydrochloride (9.52 g, 58%) as a white solid. (LC / MS; m / z 303 [M+H] + ). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.09 (1H, d), 8.15 (1H, s), 8.09 (1H, s), 4.01 (2H, s), 3.68 (3H, s).

[0268] Step 2: Methyl 2-(8-bromo-6-chloroimidazo[1,2-a]pyridin-2-yl)acetate hydrochloride (1.50 g, 4.41 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (964 mg, 4.63 mmol) and 1.8 M K in 1,4-dioxane (22 mL). 2 CO 3 A solution of Pd(dppf)Cl in water (7.4 mL, 13.24 mmol) was degassed with argon for 10 min. 2 (253 mg, 0.31 mmol) was added and the mixture was stirred at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure and H 2The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The crude product was purified by normal phase flash column chromatography using a 40 g column (silica) and a gradient of 20-100% EtOAc in n-heptane as eluent to give methyl 2-(6-chloro-8-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl)acetate (Intermediate 2) (1.06 g, 79%) as a yellow solid. (LC / MS; m / z 305 [M+H] + ).

[0269] Step 3a-b: a. A solution of methyl 2-(8-bromo-6-chloroimidazo[1,2-a]pyridin-2-yl)acetate hydrochloride (156 mg, 0.52 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.52 mmol) in 1,4-dioxane (2 mL) was degassed with argon for 10 min. To this solution was added CMBP (0.284 mL, 1.03 mmol) and stirred at 150 °C for 40 min (sealed tube; microwave irradiation). b. The reaction mixture was treated with pyridin-3-ylmethanol (0.051 mL, 0.52 mmol), Pd(dppf)Cl 2 DCM (42 mg, 0.052 mmol) and 1.8 M K 2 CO 3 Aqueous solution (0.859 mL, 1.55 mmol) was added. The reaction mixture was stirred at 90° C. for 2 h (sealed tube). The mixture was diluted with H 2 The mixture was diluted with 2×O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4The crude product was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 0-10% MeOH in DCM as eluent to give methyl 2-(6-chloro-8-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl)acetate (Intermediate 3) (120 mg, 45%) as a brown solid. (LC / MS; m / z 382 [M+H] + The product contains 25% methyl 2-(6-chloro-8-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl)acetate (LC / MS; m / z 291 [M+H] + ). The product was used directly without further purification.

[0270] Synthesis of 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetic acid (Compound No. 035) [ka] Step 1: 1,4-dioxane (10 mL) and H 2 A solution of intermediate 2 (500 mg, 1.64 mmol), phenylboronic acid (240 mg, 1.97 mmol) and KF (481 mg, 8.20 mmol) in 2O (1 mL) was degassed with argon for 10 min. To this solution was added Pd(dppf)Cl 2 (135 mg, 0.16 mmol) was added and the mixture was stirred at 140° C. for 40 min (sealed tube; microwave irradiation). 2 The mixture was diluted with 2×O and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and 2 SO 4The crude product was purified by normal phase flash column chromatography using a 25 g column (silica) and a gradient of 10-100% EtOAc in n-heptane as eluent to give methyl 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetate (200 mg, 28%, LC / MS 80%) as an off-white solid. The product was used directly without further purification. (LC / MS; m / z 347 [M+H] + ).

[0271] Step 2: A solution of methyl 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetate (200 mg, 0.58 mmol) in MeOH (6 mL) and 1 M aqueous LiOH (2.3 mL, 2.31 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and H 2 The mixture was dissolved in 20 mL of HO and extracted with EtOAc (2×20 mL). To the combined organic layers was added 1 M aqueous HCl dropwise. The solid formed was filtered off and washed with H 2 O and Et 2 O and dried under reduced pressure to give 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetic acid (compound number 035) (110.0 mg, 57%) as a white solid. (LC / MS; m / z 333 [M+H] + ).

[0272] Compound: Compound No. 036 (prepared from Intermediate 3) was prepared in a similar manner to Compound No. 035 (using appropriate reagents and purification methods known to one of skill in the art).

[0273] Example 8: Synthesis of 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetic acid (Compound No. 038) [ka] Step 1: Intermediate 2 (250 mg, 0.82 mmol), K in tBuOH (7.5 mL) 2 CO 3 A solution of (227 mg, 1.64 mmol), BrettPhos (22 mg, 0.041 mmol) and BrettPhos Pd G3 (38 mg, 0.041 mmol) was degassed with argon for 10 min. To this solution was added aniline (0.091 mL, 0.98 mmol) and the mixture was stirred at 110 °C for 4 h (sealed tube). The reaction mixture was stirred at 110 °C for 4 h. 2 The mixture was diluted with 25 mL of EtOAc and extracted with 2×40 mL of EtOAc. The combined organic layers were 2 20 mL of Brine HO (20 mL) 2 Wash with O (20 mL) and add Na 2 SO 4 The crude product was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 50-85% EtOAc in DCM as eluent to give methyl 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetate (90.0 mg, 30%) as a white solid. (LC / MS; m / z 362 [M+H] + ).

[0274] Step 2: This step was carried out in a similar manner to step 2 for Compound No. 035 (using appropriate reagents and purification methods known to one skilled in the art). Starting material (90 mg, 0.25 mmol) gave 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetic acid (Compound No. 038) (74 mg, 85%) as a pale yellow solid. (LC / MS; m / z 348 [M+H] + ).

[0275] Example 9: Synthesis of N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetamide (Compound No. 037) [ka] Step 1: Compound No. 035 (50 mg, 0.15 mmol), HOAt (25 mg, 0.18 mmol), MeNH in DMF (1 mL) 2 To a solution of HCl (51 mg, 0.75 mmol) and DIPEA (0.105 mL, 0.60 mmol) was added EDC (0.040 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with H 2 The mixture was diluted with 25 mL of EtOAc (2×25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NH 4 Cl aqueous solution (25 mL), saturated NaHCO 3 Wash with aqueous solution (25 mL) and brine (15 mL) and add anhydrous Na 2 SO 4 The organic layer was concentrated under reduced pressure to give N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetamide (compound number 037) (43 mg, 82%) as a light brown solid. (LC / MS; m / z 346 [M+H] + ).

[0276] Compound: Compound No. 039 (prepared from Compound No. 038) was prepared in a similar manner to Compound No. 037 (using appropriate reagents and purification methods known to one of skill in the art).

[0277] Example 10: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)methyl)acrylamide (Compound No. 040) [ka] Step 1: A solution of 1H-pyrazolo[4,3-b]pyridine (3.5 g, 29.38 mmol) in DMF (80 mL) was treated with KOH (4.94 g, 88.14 mmol) and iodine (14.914 g, 58.76 mmol) under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ice water (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with ice water (100 mL), Na 2 S 2 O 3 Wash with aqueous solution (100 mL), brine solution (100 mL), and anhydrous Na 2 SO 4 Drying on a kettle and evaporation gave the crude compound (4.2 g) as a brown solid. The crude product was triturated with n-pentane to give 3-iodo-1H-pyrazolo[4,3-b]pyridine (4.0 g, 56%, LCMS 98%) as a brown solid. (LCMS m / z 246 [M+H]+).

[0278] Step 2: A solution of 3-iodo-1H-pyrazolo[4,3-b]pyridine (3.0 g, 12.24 mmol) in toluene (30 mL) and water (6 mL) was reacted with (4-(trifluoromethyl)phenyl)boronic acid (6.97 g, 36.73 mmol), Cu(OAC) 2 (0.667g, 3.673mmol), K 2 CO 3 (5.069 g, 36.73 mmol) and 1,10-phenanthroline (0.66 g, 3.67 mmol) at room temperature. The reaction mixture was stirred at 80° C. under oxygen for 16 h. The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (200 mL). The filtrate was washed with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine solution (100 mL) and diluted with anhydrous Na 2 SO 4Drying on a kettle and evaporation gave the crude product (4.3 g) as a brown semi-solid. The crude product was purified by normal phase chromatography (CombiFlash) using a 40 g column and a gradient of 20% EtOAc in petroleum ether as eluent to give 3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (700 mg, 15% yield) as a brown solid. (LCMS m / z 390 [M+H]+).

[0279] Step 3: A solution of 3-iodo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (600 mg, 1.54 mmol) in NMP (25 mL) was treated with CuCN (483.4 mg, 5.39 mmol) at room temperature. The reaction mixture was stirred at 150° C. for 5 h. The reaction mixture was poured into cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with cold water (2×50 mL), brine solution (50 mL) and anhydrous Na 2 SO 4 After drying over low pressure and concentrating under reduced pressure, the crude product (650 mg) was obtained as a light brown semi-solid. The crude product was purified by normal phase chromatography (CombiFlash) using a 40 g column and a gradient of 30% EtOAc in petroleum ether as eluent to give 1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine-3-carbonitrile (250 mg, 56% yield) as a light yellow semi-solid. (LCMS m / z 289 [M+H]+).

[0280] Step 4: A solution of 1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine-3-carbonitrile (200 mg, 0.694 mmol) in MeOH (5 mL) was reacted with (Boc) 2 O (0.239 mL, 1.041 mmol), NiCl 2 .6H 2 O (16.5 mg, 0.069 mmol) and NaBH 4 (128.4 mg, 3.5 mmol) at 0° C. and stirred at room temperature under argon for 30 min. The reaction mixture was concentrated and H 2The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic fractions were washed with brine (30 mL) and anhydrous Na 2 SO 4 Drying over and concentrating under reduced pressure gave the crude product (310 mg) as a brown semi-solid, which was purified by normal phase chromatography (CombiFlash) using a 40 g column with 30% EtOAc in petroleum ether as eluent to give tert-butyl ((1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)methyl)carbamate (140 mg, 52% yield) as a light brown solid. (LCMS m / z 393 [M+H]+).

[0281] Step 5: To a solution of tert-butyl ((1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)methyl)carbamate (140 mg, 0.357 mmol) in DCM (5 mL) was added TFA (1.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure to give crude (1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)methanamine (140 mg) as a TFA salt. The crude product was used in the next step without further purification. (LCMS m / z 293 [M+H]+).

[0282] Step 6: A stirred solution of (1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)methanamine TFA salt (140 mg, 0.345 mmol) in 1,4-dioxane (6.0 mL) was cooled to 0° C. and diluted with H 2 NaHCO in O (2.0 mL) 3 (144.82 mg, 1.724 mmol) and a solution of acryloyl chloride (34.3 mg, 0.379 mmol) in 1,4-dioxane (2.0 mL) under nitrogen. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled to 5° C. and cooled to 5° C. for 30 min. 2The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine solution (30 mL) and anhydrous Na 2 SO 4 Drying on a kettle and concentrating under reduced pressure gave the crude product (122 mg) as a light brown semi-solid. The crude product was purified by reverse phase preparative HPLC and lyophilized to give N-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)methyl)acrylamide (compound number 040) as a white solid. (LCMS m / z 347 [M+H]+).

[0283] Compound: Compound No. 041 (prepared from 1H-pyrazolo[4,3-c]pyridine) was prepared in a similar manner to Compound No. 040 (using appropriate reagents and purification methods known to one of skill in the art).

[0284] Example 11: Synthesis of N-[[5-(cyanomethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]methanesulfonamide (Compound No. 042 with Compound No. 056 as intermediate) [ka] Step 1: A stirred solution of 1H-indol-5-ol (25 g, 187.76 mmol) in DMF (300 mL) was treated with potassium carbonate (38.9 g, 281.64 mmol) and benzyl bromide (26.76 mL, 225.31 mmol) at room temperature. The reaction mixture was stirred at 110° C. for 16 h. The progress of the reaction was monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, Rf: 0.70, detection: UV activity). The reaction mixture was diluted with water (1 L) and extracted with EtOAc (2×900 mL). The combined organic layers were washed with cold water (2×500 mL), brine solution (500 mL) and concentrated with Na 2 SO 4The mixture was dried over 100 ml and concentrated under reduced pressure to give the crude product. The crude product (pre-absorbed on silica) was purified by normal phase flash chromatography eluting with 8% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give 5-(benzyloxy)-1H-indole (16 g, 38% yield, LCMS: 92%) as an off-white solid together with 10 g of recovered starting material (LCMS m / z 224.3 [M+H] +).

[0285] Process 2:H 2 NaNO in O+DMF (160 mL+160 mL) 2 A solution of (39.55 g, 573.29 mmol) was treated dropwise with 2N HCl (64.0 mL) and stirred at room temperature for 30 min, followed by the addition of 5-(benzyloxy)-1H-indole (16 g, 71.66 mmol) in DMF (160 mL) over 2 h at 0° C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, Rf: 0.40, detection: UV activity). The reaction mixture was diluted with cold water (1000 mL) and the solid was filtered, washed with petroleum ether and dried to give the crude product (13 g) as a yellow solid, which was used in the next step without purification. (LCMS m / z 253.2 [M+H] + ).

[0286] Step 3: A solution of 5-(benzyloxy)-1H-indazole-3-carbaldehyde (13 g, 51.53 mmol) in DCM (150 mL) is diluted with Et 3The mixture was treated with N (21.57 mL, 154.59 mmol), (4-(trifluoromethyl)phenyl)boronic acid (11.74 g, 61.83 mmol) and copper(II) acetate (18.71 g, 103.06 mmol) at room temperature. The reaction mixture was stirred at room temperature under an oxygen balloon for 16 h. The progress of the reaction was monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, Rf: 0.70, detection: UV active). The reaction mixture was diluted with cold water (400 mL), filtered through a celite pad and extracted with DCM (2 x 1000 mL). The combined organic layers were washed with brine (100 mL) and diluted with Na 2 SO 4 The crude product was purified by normal phase flash chromatography (CombiFlash, 80 g column) eluting with 8% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give 5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde (4 g, LCMS: 99%) as a white solid. (LCMS m / z 397.3 [M+H] + ).

[0287] Step 4: A solution of 5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde (4 g, 10.09 mmol) in EtOH (60 mL) is added to EtOH (60 mL). 3 The mixture was treated with N (4.22 mL, 30.27 mmol) and hydroxylamine hydrochloride (1.40 mg, 20.18 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.40, detection: UV activity). The reaction mixture was diluted with cold water (500 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (100 mL) and diluted with Na 2 SO 4Drying over and concentration under reduced pressure gave the crude product (4 g, LCMS: 96%) as a yellow solid, which was used in the next step without purification. (LCMS m / z 412.6 [M+H] + ).

[0288] Process 5:Et 2 A stirred solution of 5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde oxime (4 g, 9.72 mmol) in 2H2O (100 mL) was treated dropwise with 2M LAH in THF solution (9.72 mL, 19.44 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h and the progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.10, detection: UV activity). The reaction mixture was quenched with saturated sodium sulfate solution (2.0 mL) and EtOAc (1000 mL). The mixture was stirred for 30 min and filtered. The organic layer was extracted with Na 2 SO 4 The crude product was purified by chromatography (CombiFlash, 40 g silica column) eluting with 5% MeOH in DCM. The collected pure fractions were concentrated under reduced pressure to give 5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine (2.5 g, LCMS: 80%) as a white solid. (LCMS m / z 398.4 [M+H] + ).

[0289] Step 6: A solution of (5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine (500 mg, 1.26 mmol) in DCM (10 mL) was diluted with Et 3N (0.53 mL, 3.77 mmol) followed by MsCl (0.117 mL, 1.51 mmol) was treated at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.81, detection: UV activity). After consumption of starting material by TLC, the reaction mixture was diluted with water (100 mL) and extracted with DCM (2×75 mL). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure to give the crude product (500 mg). The crude product (pre-absorbed on silica) was purified by normal phase flash chromatography (Grace Instrument, 24 g silica column) and eluted with a gradient of 20% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give N-((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (compound no. 056, 300 mg, 50% yield) as a brown solid. (LCMS m / z 276.3 [M+H] + ).

[0290] Step 7: A solution of N-((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (300 mg, 0.63 mmol) in DCM (6 mL) was treated with 1 M BBr in DCM at 0 °C. 3 (1.89 mL, 1.89 mmol) was added and the reaction mixture was then stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.56, detection: UV activity). After consumption of starting material by TLC, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (30 mL) and diluted with Na 2 SO 4Drying over 1000° C. and concentration under reduced pressure gave crude N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (240 mg, LCMS: 85%) as a brown solid, which was used in the next step without purification. (LCMS m / z 386.3 [M+H] + ).

[0291] Step 8: A solution of N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (150 mg, 0.39 mmol) in ACN (3 mL) was reacted with K 2 CO 3 (107.6 mg, 0.78 mmol) and 2-chloroacetonitrile (45.2 mg, 0.58 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.50, detection: UV activity). After consumption of starting material by TLC, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 Drying on a kettle and concentrating under reduced pressure gave the crude product (150 mg). The crude compound was purified by preparative HPLC method H2. The collected pure fractions were concentrated and lyophilized to give N-((5-(cyanomethoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (compound number 042, 20 mg, 12% yield) as a white solid.

[0292] Compound No. 054 (prepared from ((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine) was prepared in a similar manner to that used in step 5 of the preparation of Compound No. 43 (using appropriate reagents and purification methods known to one of skill in the art).

[0293] Compound No. 055 (prepared from ((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine) was prepared in a similar manner to that used in step 2 of Example 16 (using appropriate reagents and purification methods known to one of skill in the art).

[0294] Example 12: Synthesis of N-[[5-(cyanomethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide (Compound No. 043) [ka] Step 1: A stirred solution of ((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine (2.5 g, 2.02 mmol) in THF+MeOH (37.0 mL+12.0 mL) was added to Et 3 The mixture was treated dropwise with N (1.31 mL, 9.43 mmol) and Boc-anhydride (1.73 mL, 7.54 mmol). The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.70, detection: UV activity). The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml of hexane and concentrated under reduced pressure to give the crude product (3.0 mg). The crude product was purified by normal phase flash chromatography (CombiFlash, 24 g column) eluted with 8% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give tert-butyl-((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (2.5 g, LCMS: 90%) as a white solid. (LCMS m / z 498.2 [M+H] + ).

[0295] Step 2: A solution of tert-butyl-((5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (1.8 g, 3.62 mmol) in MeOH (30 mL) was treated with 10% Pd / C (1.9 g, 18.09 mmol) and ammonium formate (2.28 g, 36.18 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.35, detection: UV active). The reaction mixture was filtered through a Celite pad and the pad was washed with MeOH (150 mL). The filtrate was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (150 mL) and diluted with Na 2 SO 4 Drying over and concentrating under reduced pressure gave the crude product (1.8 g, LCMS: 94%). The crude compound was triturated with petroleum ether (2×10 mL) and dried to give tert-butyl-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (1.2 g, LCMS: 97%) as a white solid. (LCMS m / z 384.35 [M+H] + ).

[0296] Step 3: A solution of tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (150 mg, 0.37 mmol) in DMF (10 mL) was reacted with K 2 CO 3 (254.4 mg, 1.84 mmol) and 2-bromoacetonitrile (131.3 mg, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h and monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.58, detection: UV). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was washed with brine (25 mL) and diluted with Na 2 SO 4Drying over 100° C. and concentrating under reduced pressure gave the crude product (150 mg, LCMS: 90%). The crude product (pre-absorbed on silica) was purified by normal phase flash chromatography (Grace Instrument) using a 24 g column cartridge and eluted with 70% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give tert-butyl ((5-(cyanomethoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (120 mg, 73% yield) as a white solid. (LCMS m / z 447.2 [M+H] + ).

[0297] Step 4: A solution of tert-butyl ((5-(cyanomethoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (120 mg, 0.27 mmol) in DCM (5 mL) was treated with TFA (0.21 mL, 2.68 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.15, detection: UV activity). The reaction mixture was concentrated under reduced pressure and dried to give crude 2-((3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)oxy)acetonitrile hydrochloride (120 mg, LCMS: 49%) as a brown solid. The crude product was used in the next step without purification. (LCMS m / z 347.3 [M+H] + ).

[0298] Step 5: 1,4-Dioxane + H 2A solution of 2-((3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-yl)oxy)acetonitrile hydrochloride (LCMS: 49%) (120 mg, 0.31 mmol) in 2H2O (3 mL+1 mL) was treated with sodium bicarbonate (131.68 mg, 1.57 mmol) and acryloyl chloride (31.2 mg, 0.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC (mobile phase: 70% EtOAc in petroleum ether, Rf: 0.75, detection: UV activity). After consumption of starting material by TLC, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (25 mL) and concentrated with Na 2 SO 4 Drying over and concentration under reduced pressure gave the crude product (120 mg, LCMS: 49%), which was purified by preparative HPLC method H2. The collected pure fractions were concentrated and lyophilized to give N-((5-(cyanomethoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (compound no. 043, 40 mg, 12% yield) as a white solid.

[0299] Compound No. 044, prepared from (tetrahydrofuran-3-yl)methyl) 4-methylbenzenesulfonate and tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate, was prepared in a manner similar to that used to prepare Compound Nos. 042 and 043 (using appropriate reagents and purification methods known to one of skill in the art).

[0300] Compound No. 046 (prepared from (5-((tetrahydrofuran-3-yl)methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine hydrochloride) was prepared in a similar manner to that used in step 5 of the preparation of Compound No. 043 (using appropriate reagents and purification methods known to those skilled in the art). The racemate was purified by chiral preparative SFC (Chiralcel OX-H (250 x 4.6 x 5μ), % CO 2: 85%, % Co solvent: 15% (100% MeOH), total flow: 3.0 g / min, back pressure: 100.0 bar, temperature: 30.0 °C, UV: 215 nm, stack time: 8.0 min). The collected fractions were concentrated and lyophilized to give Cpd. No. 047 (21.78 mg) as an off-white sticky solid and Cpd. No. 048 (18.97 mg) as an off-white sticky solid. The absolute structure of the isolated enantiomers was not determined.

[0301] Compounds Nos. 063, 064, 065, 066, 067, and 068 were prepared in a manner similar to that used to prepare Compound No. 043 (using appropriate reagents and purification methods known to one of skill in the art).

[0302] Example 13: Synthesis of N-[[5-phenoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]methanesulfonamide (Compound No. 45) [ka] Step 1: A solution of tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (500 mg, 1.22 mmol) in DMSO (12 mL) was reacted with iodobenzene (300.4 mg, 1.47 mmol) and K 3 PO 4 (781.5 mg, 3.68 mmol) at room temperature. The reaction mixture was treated with N 2 The reaction was degassed at 40° C. for 5 min. Picolinic acid (30.2 mg, 0.24 mmol) and copper iodide (23.37 mg, 0.24 mmol) were added and the reaction was degassed again for 5 min. The reaction mixture was stirred at 120° C. for 1 h under microwave. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.81, detection: UV activity). The reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with cold water (25 mL), brine (25 mL) and diluted with Na 2 SO 4The mixture was dried over hexane and concentrated under reduced pressure to give the crude product (500 mg, LCMS: 82%). The crude compound (pre-absorbed on silica) was purified by normal phase flash chromatography (Grace Instrument) using a 40 g column cartridge and eluted with 10% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give tert-butyl ((5-(phenoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (400 mg, 67% yield) as a white solid. (LCMS m / z 484.4 [M+H] + ).

[0303] Step 2: A solution of tert-butyl ((5-phenoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (400 mg, 0.83 mmol) in DCM (5 mL) was treated with 4 M HCl in dioxane (3.3 mL, 13.24 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.12, detection: UV activity). The reaction mixture was concentrated under reduced pressure and dried to give the crude product (350 mg, LCMS: 95.24%) as a white solid, which was used in the next step without purification. (LCMS m / z 384.4 [M+H] + ).

[0304] Step 3: A solution of (5-phenoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine hydrochloride (180 mg, 0.43 mmol) in DCM (5 mL) was treated with triethylamine (0.3 mL, 2.14 mmol) and methanesulfonyl chloride (0.04 mL, 0.51 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.73, detection: UV activity). The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (10 mL) and concentrated to dryness with Na 2 SO4 Drying over and concentration under reduced pressure gave the crude product (200 mg, LCMS: 84.75%), which was purified by preparative HPLC method H2. The collected pure fractions were concentrated and lyophilized to give N-((5-phenoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (compound no. 045, 120 mg, 60% yield) as an off-white solid.

[0305] Compound No. 049 (prepared from (5-phenoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine hydrochloride) was prepared in a similar manner to that used in step 5 of the preparation of Compound No. 043 (using appropriate reagents and purification methods known to one of skill in the art).

[0306] Compound No. 051 (prepared from tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate and 6-chloro-1-methylpyrimidine-2,4(1H,3H)-dione) was prepared in a similar manner (using appropriate reagents and purification methods known to one of skill in the art) as used in steps 1 and 2 of the preparation of Compound No. 045 and step 5 of the preparation of Compound No. 043.

[0307] Example 14: Synthesis of N-[[6-(cyclopropoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide (Compound No. 050) [ka] Step 1: NaNO in water (175 mL) and DMF (175 mL) 2A solution of (101.63 g, 1195.83 mmol) was cooled to 0° C. and treated with 3N HCl (150 mL, 448.44 mmol) at 0° C. and stirred at 0° C. for 20 min. A solution of 6-methoxy-1H-indole 1 (22 g, 149.48 mmol) in DMF (85 mL) was added to the reaction mixture over 1 h at 0° C. and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, detection: UV activity; Rf: 0.22). The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine solution (2×300 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product (30 g, LCMS 37.5%) as a black gum which was purified by normal phase chromatography (Grace) using a 120 g column and EtOAc in petroleum ether to give 6-methoxy-1H-indazole-3-carbaldehyde (6 g; LCMS purity 88.2%) as an off-white solid. (LCMS m / z 177.3 [M+H] + ).

[0308] Step 2: A solution of 6-methoxy-1H-indazole-3-carbaldehyde (10 g, 56.76 mmol) in 1,4-dioxane (250 mL) was reacted with 1-iodo-4-(trifluoromethyl)benzene (18.52 g, 68.11 mmol), K 2 CO 3(19.61 g, 141.90 mmol) at room temperature. The reaction mixture was degassed with argon for 5 min and treated with trans-N,N'-dimethylcyclohexane-1,2-diamine (1.04 g, 7.37 mmol) and CuI (1.29 g, 6.81 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.35, detection: UV active). The reaction mixture was filtered through a celite pad and washed with EtOAc (200 mL). The filtrate was washed with water (150 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product (12 g, LCMS purity 66.7%) as a brown solid, which was purified by flash column chromatography (CombiFlash) using a 40 g column and 18% EtOAc in petroleum ether to give 6-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde (4 g; LCMS purity 81.68%) as a yellow solid. (LCMS m / z 321.3 [M+H] + ).

[0309] Step 3: A solution of 6-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde (4 g, 12.48 mmol) in MeOH (100 mL) was reacted with NaBH 4 (0.70 g, 18.73 mmol) at 0° C. and allowed to slowly warm to room temperature over 2 h. Progress was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.13, detection: UV activity). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine solution (150 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product (6-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanol (3.7 g; LCMS purity 94%) as a yellow solid. The compound was used in the next step without further purification. (LCMS m / z 323.4 [M+H] + ).

[0310] Step 4: A solution of (6-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanol (3.70 g, 11.48 mmol) in THF (50 mL) was treated with isoindoline-1,3-dione (2.53 g, 17.22 mmol), diisopropyl azodicarboxylate (6.96 g, 34.44 mmol) and PPh 3 (9.03 g, 34.44 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 h and the progress of the reaction was monitored by LCMS and TLC (mobile phase: 30% EtOAc in petroleum ether, detection: UV activity, Rf: 0.30). The reaction was diluted with water (40 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product (5.0 g, LCMS purity 52%) as a brown gum, which was purified by reverse phase chromatography (Grace) using a C18 column and a gradient of CAN in water to give 2-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione (3.0 g; LCMS purity 97%) as an off-white solid. (LCMS m / z 452.4 [M+H] + ).

[0311] Step 5: A solution of 2-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione (2.8 g, 6.20 mmol) in DCM (36 mL) was treated with BBr 3 (1.0 M in DCM) (31 mL, 31.01 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, detection: UV activity, Rf: 0.25). The reaction was diluted with MeOH (40 mL) and saturated NaHCO at 0° C. 3The mixture was quenched with hexanes (40 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine (2×250 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was triturated with diethyl ether (15 mL) and dried under high vacuum to give 2-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione (1.8 g, LCMS purity 95%) as a yellow solid. (LCMS m / z 438.3 [M+H] + ).

[0312] Step 6: A solution of 2-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione (1.9 g, 4.34 mmol) in toluene (32 mL) and water (8 mL) was treated with copper(II) acetate (316 mg, 1.73 mmol), 1,10-phenanthroline (313 mg, 1.73 mmol), and potassium cyclopropyltrifluoroborate (2.57 g, 17.37 mmol) under an oxygen balloon at room temperature. The reaction mixture was stirred at 70° C. for 24 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.4, detection: UV activity). The reaction mixture was cooled to room temperature and purified with NH 4 It was diluted with aqueous Cl (200 mL) and extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (2×150 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product (LCMS: 32% of desired mass+18% of starting material) as a black gum, which was purified by normal phase column chromatography and 15% EtOAc in petroleum ether as eluent to give 2-((6-cyclopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione (320 mg; LCMS purity 81.51%) as an off-white solid. (LCMS m / z 478.3 [M+H] + ).

[0313] Step 7: A solution of 2-((6-cyclopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione (320 mg, 0.67 mmol) in EtOH (5 mL) was diluted with N 2 H 4 .H 2 The mixture was treated with 2H2O (0.16 mL, 3.35 mmol) at room temperature. The reaction mixture was stirred at 85° C. for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.19, detection: UV activity). The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (50 mL), washed with brine (2×25 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product (190 mg; LCMS purity 77.5%) as a yellow solid. (LCMS m / z 348.2 [M+H] + ).

[0314] Step 8: A solution of crude (6-cyclopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methoxamine (15 mg, 0.043 mmol) in 1,4-dioxane (5 mL) was dissolved in NaHCO in dioxane (1.0 mL). 3 (18.15 mg, 0.21 mmol) and acryloyl chloride (4.69 mg, 0.052 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and the progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.51, detection: UV activity). The reaction mixture was diluted with EtOAc (15 mL), washed with water (2×10 mL) and the combined organic layers were washed with Na 2 SO 4 Drying over and concentrating under reduced pressure gave the crude product (30 mg, LCMS 50%) as a brown gum. The crude product was purified by preparative HPLC using Method H13 and the resulting fractions were concentrated under reduced pressure to give N-((6-cyclopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (3.20 mg, LCMS 99.6%, yield: 1.7%) as an off-white solid.

[0315] Compound No. 061 (prepared from (6-cyclopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine) was prepared in a similar manner to that used in step 6 of the preparation of Compound No. 042 (using appropriate reagents and purification methods known to one of skill in the art).

[0316] Compound No. 062 (prepared from (6-cyclopropoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine and propionyl chloride) was prepared in a manner similar to that used to prepare Compound No. 050 (using appropriate reagents and purification methods known to one of skill in the art).

[0317] Example 15: Synthesis of N-[[5-(1H-pyrazol-3-ylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]methanesulfonamide (Compound No. 052) [ka] Step 1: A solution of 1H-pyrazole-5-carbaldehyde (4 g, 41.62 mmol) in DCM (80 mL) was treated with pTSA (716.00 mg, 4.16 mmol) followed by the addition of DHP (7.53 mL, 83.25 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, Rf: 0.75, detection: UV activity). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine solution (100 mL) and purified by HPLC with anhydrous NaCl. 2 SO 4Drying over low pressure and concentration under reduced pressure gave the crude product (5 g, LCMS 60%) as a brown gum. The crude product was purified by normal phase column chromatography (combi) using a 48 g column and a gradient of 0-50% EtOAc in petroleum ether as eluent to give 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carbaldehyde (3.5 g, LCMS 94.8%) as a pale yellow liquid. (LCMS m / z 181.3 [M+H] + ).

[0318] Step 2: To a stirred solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde (3.5 g, 19.44 mmol) in MeOH (40 mL) was added NaBH 4 (1.43 g, 38.88 mmol) was added portionwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, Rf: 0.15, detection: UV activity, KMnO 4 The reaction mixture was concentrated, diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine solution (100 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over hexane and concentrated under reduced pressure to give the crude product (4 g, LCMS 80%). The crude product was purified by normal phase chromatography using a 40 g column and the pure fractions were concentrated under reduced pressure to give (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (2.7 g, LCMS 92%) as a white liquid. (LCMS m / z 183.21 [M+H] + ).

[0319] Step 3: A stirred solution of (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (1 g, 5.48 mmol) in DCM (10 mL) was treated with TPP (1.43 g, 5.48 mmol) followed by CBr 4(2.18 g, 6.58 mmol) was added at 0° C. The reaction was stirred at room temperature for 16 h. The reaction mixture was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, Rf: 0.77, detection: UV activity). The reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2×70 mL). The combined organic layers were washed with Na 2 SO 4 Drying over rt and concentration under reduced pressure gave the crude product (1 g, LCMS 25%) as a brown gum. The crude product was purified by Combi Flash (normal phase) using a 40 g column and 20% EtOAc in petroleum ether as eluent to give 3-(bromomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (700 mg, LCMS 93.9%) as a white solid. (LCMS m / z 245 [M+H] + ).

[0320] Step 4: A stirred solution of N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (from Example 11, 250 mg, 0.64 mmol) in THF (3 mL) was reacted with 3-(bromomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (191.29 mg, 0.77 mmol), followed by K 2 CO 3 (134.41 mg, 0.97 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, R f The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine solution (25 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried over 100 ml and concentrated under reduced pressure to give the crude product (200 mg, LCMS 42%). The crude product was purified by normal phase flash column chromatography (Combi Flash, 48 g silica gel column) eluting with 40% EtOAc in petroleum ether to give N-((5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (180 mg, LCMS 62%) as a white solid. (LCMS m / z: 550 [M+H] + ).

[0321] Step 5: A stirred solution of N-((5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (180 mg, 0.32 mmol) in DCM (3 mL) was treated with TFA (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was monitored by TLC (mobile phase: 10% methanol in DCM, Rf: 0.29, detection: UV activity). The reaction mixture was concentrated under reduced pressure and dried. The residue was triturated with diethyl ether (2×10 mL) and dried under high vacuum to give the crude product (150 mg, LCMS 53%) as a brown gum. The crude compound was purified by preparative HPLC method H2 and the fractions were concentrated under reduced pressure to give (N-((5-((1H-pyrazol-3-yl)methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (compound no. 052) (37.9 mg, LCMS 95.0%) as a white solid.

[0322] Example 16: Synthesis of N-[[5-(3-methyl-2,6-dioxo-pyrimidin-4-yl)oxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]propenamide (Compound No. 053) [ka] Step 1: A solution of tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)carbamate (from Example 12, 200 mg, 0.49 mmol) in DCM (5 mL) was treated with 4 M HCl in dioxane (1.22 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.1, detection: UV activity). The reaction mixture was concentrated under reduced pressure to give the crude product (160 mg, LCMS: 68%), which was used in the next step without further purification. (LCMS m / z 308.37 [M+H] + ).

[0323] Step 2: 1,4-Dioxane + H 2 A solution of 3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-ol hydrochloride (160 mg, 0.46 mmol) in 2H2O (3 mL+1 mL) was treated with sodium bicarbonate (195.5 mg, 2.33 mmol) followed by propionyl chloride (172.8 mg, 1.86 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.59, detection: UV activity). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL) and diluted with Na 2 SO 4 Drying over 1000 ml and concentration under reduced pressure gave the crude (160 mg, LCMS: 61%) as a brown gum. The crude product was purified by normal phase flash chromatography (Grace Instrument) eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to give N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)propionamide (95 mg, LCMS: 90.79%) as a brown solid. (LCMS m / z 488.2 [M+H] + ).

[0324] Step 3: This step was carried out similarly to step 1 of example 13 starting with N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)propionamide (85 mg, 0.23 mmol) and 6-chloro-1-methylpyrimidine-2,4(1H,3H)-dione (45.07 mg, 0.28 mmol). The crude product was purified by preparative HPLC method H15 and the collected pure fractions were concentrated under reduced pressure to give N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)oxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)propionamide (compound no. 053, 16.3 mg, LCMS 99.8%) as a white solid.

[0325] Compound No. 060 (prepared from (N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide (see Example 11)) was prepared in a similar manner to that used in step 3 of the preparation of Compound No. 053 (using appropriate reagents and purification methods known to one of skill in the art).

[0326] Example 17: Synthesis of N-[[5-(1H-pyrazol-3-ylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide (Compound No. 058) [ka] Step 1: A solution of (5-(benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine (1 g, 2.52 mmol) in DCM (10 mL) was treated with trimethylamine (1.06 mL, 7.55 mmol) followed by trifluoroacetic anhydride (0.42 mL, 3.02 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.77, detection: UV activity). The reaction mixture was concentrated under reduced pressure, then diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure to give crude N-((5-benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)-2,2,2-trifluoroacetamide (1.2 g, LCMS: 89%) as a brown solid. The crude product was used in the next step without further purification. (LCMS m / z: 494.31 [M+H] + ).

[0327] Step 2: A solution of N-((5-benzyloxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)-2,2,2-trifluoroacetamide (1.2 g, 2.43 mmol) in methanol (15 mL) was treated with palladium on activated carbon (1.29 g, 12.16 mmol) followed by ammonium formate (1.53 g, 24.32 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 1 h. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.25, detection: UV active). The reaction mixture was filtered through a Celite pad with MeOH (100 mL). The filtrate was diluted with Na 2 SO 4The mixture was dried over hexane and concentrated under reduced pressure to give the crude product (1 g, LCMS: 75%). The crude product was purified by normal phase chromatography (Grace Instrument) using a 40 g column eluted with 30% EtOAc in petroleum ether (250 mL) to give 2,2,2-trifluoro-N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acetamide (650 mg, LCMS: 98%, 66% yield) as an off-white solid. (LCMS m / z: 404.30 [M+H] + ).

[0328] Step 3: A solution of 2,2,2-trifluoro-N-((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acetamide (650 mg, 1.61 mmol) in ACN (7 mL) was treated with 3-(bromomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (472.25 mg, 1.93 mmol) followed by K 2 CO 3 (267.09 mg, 1.93 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, R f The reaction was completed by LCMS (pH 7.0, detection: UV activity). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Drying over 1000 ml and concentration under reduced pressure gave the crude compound (700 mg, LCMS 73%) as a brown gum, which was purified by column chromatography (100-200 silica gel) eluting with 50% EtOAc in petroleum ether to give 2,2,2-trifluoro-N-((5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acetamide (500 mg, LCMS purity 91%) as a white solid. (LCMS m / z: 568.57 [M+H] +).

[0329] Step 4: A solution of 2,2,2-trifluoro-N-((5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acetamide (530 mg, 0.106 mmol) in MeOH (5 mL) was treated with 1N aqueous NaOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.42, detection: UV activity) and completion of the reaction was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After drying over 100° C. and concentrating under reduced pressure, (5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine (450 mg, LCMS: 88%) was obtained as a brown solid. The crude compound was used directly in the next step without further purification. (LCMS m / z: 472.17 [M+H] + ).

[0330] Step 5: 1,4-Dioxane + H 2 A solution of (5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methanamine (250 mg, 0.53 mmol) in 2H2O (5.0 mL + 1.8 mL) was dissolved in NaHCO 3 (111.46 mg, 1.327 mmol) and acryloyl chloride (52.84 mg, 0.58 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.56, detection: UV activity). The reaction mixture was diluted with EtOAc (30 mL), washed with brine (2×50 mL), and washed with anhydrous Na 2 SO 4Drying over 100° C. and concentration under reduced pressure afforded N-((5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (250 mg, LCMS 82%) as a brown gum. The compound was used directly in the next step without further purification. (LCMS m / z: 526.40 [M+H] + ).

[0331] Step 6: A solution of N-((5-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (250 mg, 0.47 mmol) in DCM (4.0 mL) was treated with TFA (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 70% EtOAc in petroleum ether, Rf: 0.29, detection: UV activity). The reaction mixture was concentrated under reduced pressure to give the crude compound (200 mg, LCMS 74%) as a brown gum. The crude compound was purified by preparative HPLC method H5 and the pure fractions were concentrated under reduced pressure to give N-((5-((1H-pyrazol-3-yl)methoxy-1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide (compound no. 058, 69.8 mg, 33% yield, LCMS 99.4%) as a white solid.

[0332] Example 18: Synthesis of N-[[1-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-c]pyridin-3-yl]methyl]prop-2-enamide (Compound No. 059) [ka] Step 1: Toluene (30 mL) and H 2A solution of 3-bromo-pyrazolo-1H-pyrazolo[3,4-c]pyridine (2.0 g, 10.10 mmol) in 2H2O (6 mL) was diluted with (4-(trifluoromethyl)phenyl)boronic acid (5.7 g, 30.30 mmol), KCl (1 mL), and 1H-pyrazolo[3,4-c]pyridine (1.0 g, 10.10 mmol). 2 CO 3 (4.18 g, 30.3 mmol), Cu(OAc) 2 (0.54 g, 30.03 mmol) and 1,10-phenanthroline (0.54 g, 30.03 mmol) were used. 2 The reaction mixture was stirred at 80° C. for 16 h and monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, R f (TLC detection: UV activity). The resulting solution was diluted with H 2 The mixture was diluted with 2×O (100 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were washed with brine solution (50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure to give the crude compound (2.0 g, LCMS 34%). The crude compound was purified by normal phase flash column chromatography (CombiFlash, 80 g silica gel column) eluted with 30% EtOAc in petroleum ether to give 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridine (470 mg, 13%) as a pale yellow solid. (LCMS m / z 342.08 [M+H] + ).

[0333] Step 2: t-BuOH (5 mL) and H 2 3-Bromo 1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridine (470 mg, 1.38 mmol), tert-butyl((trifluoro-14-boranyl)methyl)carbamate potassium salt (393.1 mg, 1.65 mmol) and K 3 PO 4 A solution of s-Phos (879 mg, 4.14 mmol) was degassed with argon at room temperature for 5 min. To this mixture was added s-Phos (56.6 mg, mg, 0.13 mmol) and Pd(OAc) 2(30.9 mg, 0.13 mmol) was added at room temperature. The reaction mixture was stirred in a sealed tube at 70° C. for 16 h and monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, Rf=0.4, TLC detection: UV). The resulting solution was diluted with H 2 The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R １ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ ~C ６ Alkenyl, and (8) C ２ ~C ６ Alkynyl, (b) Unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, and (6)-OZ １ 、 (c) C ２ ~C ６ Alkynyl, and (d) unsubstituted or substituted C ３ ~C ６ Heterocycles, where one or more of the substituents are halogen, cyano, C ２ ~C ８ Alkenyl, and C １ ~C ６ independently selected from the group consisting of alkyl, (iii) unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, (f) -OZ １ , and (g) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more of the substituents are halogen, C １ ~C ６ Alkyl, and C １ ~C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of: (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, (f) -OZ １ , and (g) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more of the substituents are halogen, C １ ~C ６ Alkyl, and C １ ~C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of: (v) unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (vi) unsubstituted or substituted C ３ ~C ６ heterocycle, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (vii)-S(=O) ２ Z ２ , and ()) ()) ２ 4 Y １ , = CR ２ selected from the group consisting of -, ═N-, and -C(═O)-; However, this is subject to the following conditions: (i) Y １ GA = CR ２ - or =N-, and R ４ In the absence of 【Chemistry 2】 represents a double bond, or (ii) Y １ is —C(═O)—, and R ４ is hydrogen and C １ ~C ６ When selected from the group consisting of alkyl, 【Chemistry 3】 represents a single bond; R ２ is selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii)-(CH ２ ) ｎ -NR ５ａ R ５ｂ ; n is 0 or 1; R ５ａ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ 、 (h) C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、&& (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (--)-C(=O)Z ２ 、 (iv)-C(=O)OZ ２ 、 (v)-C(=O)NZ ３ Z ４ 、 (vi)-S(=O) ２ Z ８ 、 (vii)-S(=O) ２ NZ ３ Z ４ 、 ( ) ( ) ( ) ( ) ( ) ６ )) ２ 、 (xi) -S (=Z ６ ) (=N.Z. ７ ) Z ２ , and (8)-S(=O)(=NZ ６ )NZ ３ Z ４ ; R ５ｂ is hydrogen and C １ ~C ６ selected from the group consisting of alkyl; R ３ and R ４ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii)-(CH ２ ) ｐ -NR ６ａ R ６ｂ ; p is 0 or 1; R ６ａ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ 、 (h) C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、 (w)-NZ ５ S(=O)(=NZ ６ )NZ ３ Z ４ and (x) C ２ ~C ６ Alkenyl, (--)-C(=O)Z ２ 、 (iv)-C(=O)OZ ２ 、 (v)-C(=O)NZ ３ Z ４ 、 (vi)-S(=O) ２ Z ８ 、 (vii)-S(=O) ２ NZ ３ Z ４ 、 ( ) ( ) ( ) ( ) ( ) ６ )) ２ 、 (xi) -S (=Z ６ ) (=N.Z. ７ ) Z ２ , and (8)-S(=O)(=NZ ６ )NZ ３ Z ４ ; R ６ｂ is hydrogen and C １ ~C ６ selected from the group consisting of alkyl; Each Z １ are independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ Alkyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , C ３ ~C ８ Cycloalkyl, --C(=O)OH --S(=O) ２ Z ８ , -N.Z. ３ Z ４ , 4-8 membered heterocycles, 5-9 membered heteroaryls, and unsubstituted or substituted aryls, where one or more of the substituents is halogen, C １ ~C ６ haloalkyl and cyano; (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, (vii) C １ ~C ６ Haloalkyl, (viii) unsubstituted or substituted 4- to 8-membered heterocycles, where one or more of the substituents is halogen, C １ ~C ６ Alkyl and C ２ ~C ６ alkenyl, and (ix) unsubstituted or substituted aryl, where one or more of the substituents is halogen, cyano, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is halogen, cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; Each Z ２ are independently selected from the group consisting of: (i) C １ ~C ６ Alkyl, (ii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iii) C ２ ~C ６ Alkynyl, (iv) C ３ ~C ６ Cycloalkyl, (v) C ３ ~C ６ Cycloalkenyl, and (vi) C １ ~C ６ Haloalkyl; Each Z ３ are independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more of the substituents is C ２ ~C ６ Alkenyl, cyano, -C(=O)OH, -S(=O) ２ Z ８ , halogen, -NZ ３ Z ４ and 4- to 8-membered heterocycles; (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, and (vii) C １ ~C ６ Haloalkyl; Each Z ４ , Z ５ , Z ６ , and Z ７ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii) C ３ ~C ６ Cycloalkyl; Each Z ８ are independently selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ Alkyl, where one or more of the substituents are halogen, cyano, and C １ ~C ６ independently selected from the group consisting of alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is -NZ ３ Z ４ and 4- to 8-membered heterocycles; (iv) a halogen, and (v) hydroxy; X is ═N- and ═CR ７ａ - selected from the group consisting of; X １ is =N- and =CR ７ｂ - selected from the group consisting of; X ２ is =N- and =CR ７ｃ - selected from the group consisting of; X ３ is =N- and =CR ７ｄ - selected from the group consisting of; R ７ａ , R ７ｂ , R ７ｃ , and R ７ｄ is hydrogen, halogen, hydroxy, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -OZ １ and -(CH ２ ) ｑ -NR ６ａ R ６ｂ are independently selected from the group consisting of: The compound, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein q is 0 or 1.

2. Compound of Formula II: 【Chemistry 4】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R １ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ ~C ６ Alkenyl, and (8) C ２ ~C ６ Alkynyl, (b) Unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, and (6)-OZ １ 、 (c) C ２ ~C ６ Alkynyl, (iii) unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, (f) -OZ １ , and (g) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more of the substituents are halogen, C １ ~C ６ Alkyl, and C １ ~C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of: (iv) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, (f) -OZ １ , and (g) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more of the substituents are halogen, C １ ~C ６ Alkyl, and C １ ~C ６ Haloalkyl, and -OZ １ are independently selected from the group consisting of: (v) unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (vi) unsubstituted or substituted C ３ ~C ６ Heterocycle, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (vii)-S(=O) ２ Z ２ , and ()) ()) ２ 4 Y １ , = CR ２ selected from the group consisting of -, ═N-, and -C(═O)-; However, this is subject to the following conditions: (i) Y １ GA = CR ２ - or =N-, and R ４ In the absence of 【Chemistry 5】 represents a double bond, or (ii) Y １ is —C(═O)—, and R ４ is hydrogen and C １ ~C ６ When selected from the group consisting of alkyl, 【Chemistry 6】 represents a single bond; R ２ is selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii)-(CH ２ ) ｎ -NR ５ａ R ５ｂ ; n is 0 or 1; R ５ａ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ 、 (h)-C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、&& (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (--)-C(=O)Z ２ 、 (iv)-C(=O)OZ ２ 、 (v)-C(=O)NZ ３ Z ４ 、 (vi)-S(=O) ２ Z ８ 、 (vii)-S(=O) ２ NZ ３ Z ４ 、 ( ) ( ) ( ) ( ) ６ )) ２ 、 (xi) -S (=Z ６ ) (=N.Z. ７ ) Z ２ , and (8)-S(=O)(=NZ ６ )NZ ３ Z ４ ; R ５ｂ is hydrogen and C １ ~C ６ selected from the group consisting of alkyl; R ３ and R ４ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii)-(CH ２ ) ｐ -NR ６ａ R ６ｂ ; p is 0 or 1; R ６ａ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) hydroxy, (c) cyano, (d)-OZ １ 、 (e)-SZ １ 、 (f)-NZ ３ Z ４ 、 (g)-C(=O)Z ２ 、 (h) C(=O)OH, (i)-C(=O)OZ ２ 、 (j)-C(=O)NZ ３ Z ４ 、 (k)-NZ ５ C(=O)Z ２ 、 (l)-NZ ５ C(=O)OZ ２ 、 (m)-NZ ５ C(=O)NZ ３ Z ４ 、 (n)-S(=O) ２ Z ８ 、 (o)-S(=O) ２ NZ ３ Z ４ 、 (p)-S(=O)(=NZ ６ )Z ２ 、 (ﺎ)-S(=Z) ６ )(=NZ ７ )Z ２ 、 (r)-S(=O)(=NZ ６ )NZ ３ Z ４ 、 (s)-NZ ５ S (=O) ２ Z ２ 、 (t)-NZ ５ S (=O) ２ NZ ３ Z ４ 、 (u)-NZ ５ S(=O)(=NZ) ６ )Z ２ 、 (v)-NZ ５ S(=NZ) ６ )(=NZ ７ )Z ２ 、&& (w)-NZ ５ S(=O)(=NZ) ６ )NZ ３ Z ４ 、 (--)-C(=O)Z ２ 、 (iv)-C(=O)OZ ２ 、 (v)-C(=O)NZ ３ Z ４ 、 (vi)-S(=O) ２ Z ８ 、 (vii)-S(=O) ２ NZ ３ Z ４ 、 ( ) ( ) ( ) ( ) ６ )) ２ 、 (xi) -S (=Z ６ ) (=N.Z. ７ ) Z ２ , and (8)-S(=O)(=NZ ６ )NZ ３ Z ４ ; R ６ｂ is hydrogen and C １ ~C ６ selected from the group consisting of alkyl; Each Z １ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, and (vii) C １ ~C ６ Haloalkyl; Each Z ２ are independently selected from the group consisting of: (i) C １ ~C ６ Alkyl, (ii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iii) C ２ ~C ６ Alkynyl, (iv) C ３ ~C ６ Cycloalkyl, (v) C ３ ~C ６ Cycloalkenyl, and (vi) C １ ~C ６ Haloalkyl; Each Z ３ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, and (vii) C １ ~C ６ Haloalkyl; Each Z ４ , Z ５ , Z ６ , and Z ７ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii) C ３ ~C ６ Cycloalkyl; Each Z ８ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents are halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is -NZ ３ Z ４ and 4- to 8-membered heterocycles; (iv) a halogen, and (v) hydroxy; X is ═N- and ═CR ７ａ - selected from the group consisting of; X １ is =N- and =CR ７ｂ - selected from the group consisting of; X ２ is =N- and =CR ７ｃ - selected from the group consisting of; X ３ is =N- and =CR ７ｄ - selected from the group consisting of; R ７ａ , R ７ｂ , R ７ｃ , and R ７ｄ is hydrogen, halogen, hydroxy, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -OZ １ and-N.Z. ３ Z ４ or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

3. Compound of Formula III: 【Chemistry 7】 3. The compound of claim 1 or 2, which is: or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

4. R ２ is -(CH ２ ) ｎ -NR ５ａ R ５ｂ and R ３ is hydrogen and C １ ~C ６ 4. The compound of any one of claims 1 to 3, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein the compound is selected from the group consisting of alkyl.

5. R ５ａ is -C(=O)Z ２ and R ５ｂ The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein is hydrogen.

6. R ２ is hydrogen and C １ ~C ６ is selected from the group consisting of alkyl, R ３ is -(CH ２ ) ｐ -NR ６ａ R ６ｂ 6. The compound according to any one of claims 1 to 5, wherein:

7. R ６ａ is -C(=O)Z ２ and R ６ｂ The compound of any one of claims 1 to 6, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein is hydrogen.

8. Compound of Formula IV: 【Chemistry 8】 3. The compound of claim 1 or 2, which is: or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

9. R ３ is -(CH ２ ) ｐ -NR ６ａ R ６ｂ 9. The compound of claim 1, 2, or 8, which is: or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

10. R ６ａ is -C(=O)Z ２ And -S(=O) ２ Z ８ selected from the group consisting of: R ６ｂ 10. The compound of any one of claims 1, 2, 8, or 9, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

11. Compound of Formula V: 【Chemistry 9】 3. The compound of claim 1 or 2, which is: or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

12. R ３ is -(CH ２ ) ｐ -NR ６ａ R ６ｂ 12. The compound of claim 1, 2, or 11, which is: or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

13. R ６ａ is -C(=O)Z ２ selected from the group consisting of: R ６ｂ 13. The compound of any one of claims 1, 2, 11, or 12, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein:

14. R １ is unsubstituted or substituted C ６ ~C １０ aryl, where one or more of the substituents are halogen, hydroxy, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl and -OZ １ 14. The compound of any one of claims 1, 2, or 11-13, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

15. X is -CR ７ａ = and; X １ is -CR ７ｂ = and; X ２ is -CR ７ｃ = and; X ３ is -CR ７ｄ 15. The compound of any one of claims 1, 2, or 11-14, wherein:

16. N-[[5-(cyanomethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[rac-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[(3S)-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-[[(3R)-tetrahydrofuran-3-yl]methoxy]-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-phenoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[6-(cyclopropoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(3-methyl-2,6-dioxo-pyrimidin-4-yl)oxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-benzyloxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(1H-pyrazol-3-ylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[1-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-c]pyridin-3-yl]methyl]prop-2-enamide; N-[[5-prop-2-ynoxy-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(cyclopropylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[5-(cyclopropylmethoxy)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]methanesulfonamide; 2-[[[1-[4-(trifluoromethyl)phenyl]indazol-3-yl]amino]methyl]prop-2-enoic acid; N-[[5-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; N-[[6-(trifluoromethyl)-1-[4-(trifluoromethyl)phenyl]indazol-3-yl]methyl]prop-2-enamide; and 2. The compound of claim 1, selected from the group consisting of N-[[1-(4,4-difluorocyclohexyl)indazol-3-yl]methyl]prop-2-enamide, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

17. N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acrylamide; N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)acetamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methyl)propionamide; N-(1-phenyl-1H-indol-3-yl)acrylamide; N-(1-(4-isopropylphenyl)-1H-indol-3-yl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)acrylamide; N-(1-(4-chlorophenyl)-1H-indol-3-yl)acrylamide; N-(1-(3-chlorophenyl)-1H-indol-3-yl)acrylamide; N-(1-([1,1′-biphenyl]-4-yl)-1H-indol-3-yl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)methyl)propionamide; N-((1-(3-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)benzyl)-1H-indol-2-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)acrylamide; N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)methanesulfonamide; N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acrylamide; N-(2-oxo-1-(4-(trifluoromethyl)phenyl)indolin-3-yl)acetamide; and 3. The compound of claim 2, selected from the group consisting of N-((1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl)methyl)propionamide, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

18. Compound of Formula VI: 【Chemistry 10】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein: R ８ is selected from the group consisting of: (i) Unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ ~C ６ Alkenyl, and (8) C ２ ~C ６ Alkynyl, (b) Unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, and (6)-OZ １ 、 (c) C ２ ~C ６ Alkynyl, (ii) unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (iii) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (iv) unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (v) unsubstituted or substituted C ３ ~C ６ Heterocycle, where one or more substituents are independently selected from the group consisting of: (a) a halogen, (b) cyano, (c) C １ ~C ６ Alkyl, (d) C ３ ~C ６ Cycloalkyl, (e) C １ ~C ６ Haloalkyl, and (f)-OZ １ 、 (vi)-S(=O) ２ Z ２ , and (vii)-C(=O)Z ２ ; X is -N(R １１ )-; or X is absent; R １１ is hydrogen and C １ ~C ６ selected from the group consisting of alkyl; R ９ is selected from the group consisting of: 【Chemistry 11】 R １２ is selected from the group consisting of: (i) hydrogen, (ii) unsubstituted or substituted C １ ~C ６ alkyl, where one or more substituents are independently selected from the group consisting of: (a) Unsubstituted or substituted C ６ ~C １０ aryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, (6)-OZ １ 、 (7) C ２ ~C ６ Alkenyl, and (8) C ２ ~C ６ Alkynyl, (b) Unsubstituted or substituted C ３ ~C ６ cycloalkyl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, and (6) -OZ １ , and (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more substituents are independently selected from the group consisting of: (1) halogen, (2) cyano, (3) C １ ~C ６ Alkyl, (4) C ３ ~C ６ Cycloalkyl, (5) C １ ~C ６ Haloalkyl, and (6) -OZ １ , and (iii) C １ ~C ６ Haloalkyl; R １０ is -(CH ２ ) ｑ -C(=O)R １３ and q is 0, 1, or 2; R １３ is -OH, OZ １ , and -N.Z. ３ Z ４ selected from the group consisting of: Each Z １ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, and (vii) C １ ~C ６ Haloalkyl; Each Z ２ are independently selected from the group consisting of: (i) C １ ~C ６ Alkyl, (ii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iii) C ２ ~C ６ Alkynyl, (iv) C ３ ~C ６ Cycloalkyl, (v) C ３ ~C ６ Cycloalkenyl, and (vi) C １ ~C ６ Haloalkyl; Each Z ３ are independently selected from the group consisting of: (i) hydrogen, (ii) C １ ~C ６ Alkyl, (iii) unsubstituted or substituted C ２ ~C ６ alkenyl, where one or more of the substituents is cyano, -S(=O) ２ Z ８ , halogen, and unsubstituted or substituted C １ ~C ６ Alkyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z ８ , -N.Z. ３ Z ４ and 4- to 8-membered heterocycles; (iv) C ２ ~C ６ Alkynyl, (v) C ３ ~C ６ Cycloalkyl, (vi) C ３ ~C ６ Cycloalkenyl, and (vii) C １ ~C ６ haloalkyl; and Each Z ４ are independently selected from the group consisting of (i) hydrogen, (ii) C １ ~C ６ Alkyl, and (iii) C ３ ~C ６ Cycloalkyl, the compound, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

19. 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetic acid; N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-phenylimidazo[1,2-a]pyridin-2-yl)acetamide; 2-(6-phenyl-8-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl)acetic acid; 2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetic acid; and 19. The compound of claim 18, selected from the group consisting of N-methyl-2-(8-(1-methyl-1H-pyrazol-3-yl)-6-(phenylamino)imidazo[1,2-a]pyridin-2-yl)acetamide, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

21. A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 for use as a medicament.

22. A compound according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 20, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human.

23. A compound according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 20, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder selected from the group consisting of cancer, fibrosis, and a YAP / TAZ-TEAD activation-mediated congenital disorder.

24. A compound according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 20, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer, and prostate cancer, mesothelioma, and / or sarcoma.

25. Acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and aberrant cell proliferation) plasmosis), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germinal cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphoendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's lymphoma and Non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung carcinoma, oligodendroglioma, oral cancer, osteogenic osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma 21. The compound according to any one of claims 1 to 19, or the pharmaceutical composition according to claim 20, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder selected from: myocardial infarction, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

26. A method for the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal, or human, comprising administering to said animal, mammal, or human in need of such prevention or treatment an effective amount of a compound according to any one of claims 1 to 19.

27. 27. The method of treating or preventing a YAP / TAZ-TEAD activation mediated disorder according to claim 26, in combination with one or more other medicinal agents selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor, in a patient in need thereof.

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