Tetrahydropyrazolopyrimidines and Related Analogues for Inhibiting YAP / TAZ-TEAD

Abstract

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

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 293,538, filed December 23, 2021, which is incorporated herein 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, such as the prevention or treatment of cancer or fibrosis. Methods for the prevention or treatment of diseases, including the use of novel compounds, are also disclosed herein.

[0003] The present disclosure further relates to pharmaceutical compositions or combined preparations of the novel compounds, and 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, such as the prevention or treatment of cancer or fibrosis. Processes for the preparation of the compounds are also disclosed herein. [Background technology]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0020] In some embodiments, the disclosure provides compounds of the invention for use as pharmaceuticals, uses of the compounds as pharmaceuticals, and their use for the manufacture of medicaments, more particularly their use for treating and / or preventing YAP / TAZ-TEAD activation mediated diseases, more particularly acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, and rheumatoid arthritis. Basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell carcinoma, glioma, neuro Glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma The present invention relates to their use for the treatment and / or prevention of uterine carcinoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), 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 for treating or preventing TEAD activation-mediated disorders in humans by administering one or more of the compounds, optionally in combination with one or more other pharmaceutical agents, to a patient in need thereof. The present disclosure also relates to methods for preparing the compounds disclosed herein, including steps for the synthesis of the compounds described herein. DETAILED DESCRIPTION OF THE INVENTION

[0022] definition The term "YAP / TAZ-TEAD activation-mediated disease" refers to a disease in which hippo signaling is inactivated, thereby causing, driving, sustaining, enabling, or otherwise contributing to the disease. This may be due to loss-of-function mutations or deletions of genes encoding upstream regulators of YAP / TAZ-TEAD (e.g., NF2, MST1 / 2, LATS1 / 2, FAT1, or SAV1), which cause constitutive YAP-TEAD transcriptional activity and lead to uncontrolled tumor growth and metastasis in some cancers. This may also be due to gene amplification, gene fusion, or activating mutations of YAP1 or WWTR1 (TAZ), or overexpression or hyperactivity of YAP / TAZ. 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, bile duct cancer), 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, (ii) cancers arising from neuroectodermal-derived tissues such as ependymoma, meningioma, schwannoma, peripheral nerve sheath tumor, and / or neuroblastoma, or (iii) vascular carcinomas such as epithelioid hemangioendothelioma. Fibrotic diseases or fibrosis included in YAP / TAZ-TEAD-mediated diseases include, but are not limited to, liver fibrosis, pulmonary fibrosis, and cardiac fibrosis. Congenital disorders included in YAP / TAZ-TEAD-mediated diseases include, but are not limited to, Sturge-Weber syndrome and neurofibromatosis type 2.

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

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

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

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

[0027] As used herein, the term "composition" is intended to encompass not only a product containing therapeutically effective amounts of the specified ingredients, but also any product resulting directly or indirectly from combining 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 compounds that are capable of producing functional antagonism of YAP / TAZ-TEAD activation, as the context requires.

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

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

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

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

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

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

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

[0036] As used herein, "alkyl" or "C 1-18 The term "alkyl" refers to a C-C alkyl group containing no unsaturation. 18 Examples include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl. In certain embodiments, the term alkyl refers to any of the C alkyls, as further defined hereinabove.1-12 Alkyl (C 1-12 hydrocarbons), and more particularly C 1-9 Alkyl (C 1-9 hydrocarbons), and more particularly C 1-6 Alkyl (C 1-6 refers to hydrocarbons).

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

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

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

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

[0041] As used herein, "alkenyl" or "C 2- The term "alkenyl" refers to a C2-C6 alkyl group containing at least one (usually 1-3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond. 18

[0023] Alkenyl is a normal, secondary, or tertiary, linear, branched, or straight-chain hydrocarbon. Examples include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), and 5-hexenyl (-CHCHCHCHCH=CH). The double bond can be in the cis or trans configuration. In certain embodiments, the term alkenyl refers to a C alkyl group, as further defined herein above, containing at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., a carbon-carbon sp2 double bond. 2-12 Alkenyl (C 2-12 hydrocarbons), and more particularly C 2-9 Alkenyl (C 2-9 hydrocarbons), and more particularly C 2-6 Alkenyl (C 2-6 refers to hydrocarbons).

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

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

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

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

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

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

[0048] As used herein, the term "alkenylene" refers to alkyl groups each containing 2 to 18 carbon atoms (more particularly, C 2-12 , C 2-9 or C 2-6 carbon atoms), contains at least one (usually one to three, preferably one) site of unsaturation, i.e., a carbon-carbon sp2 double bond, and has 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 alkyl groups each containing 2 to 18 carbon atoms (more particularly, C 2-12 , C 2-9 or C 2-6 carbon atoms), contains at least one (usually one to three, preferably one) site of unsaturation, i.e., a carbon-carbon sp triple bond, and has two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

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

[0051] 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, and R d is alkenyl as defined herein. In certain embodiments, the term is 2-12 Heteroalkenyl, C 2-9 heteroalkenyl, or C 2-6 In some embodiments, the heteroalkenyl is selected from the group including alkenyloxy, alkenyl-oxy-alkenyl, (mono- or di-)alkenylamino, (mono- or di-)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl.

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

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

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

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

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

[0058] As used herein, the term "arylalkyl" or "arylalkyl-" refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) has been 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; for example, the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

[0059] The term "arylalkyloxy" as a group or part of a group refers to a group of the formula -ORa -R g where R g is aryl and R a is alkylene as defined hereinabove.

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

[0061] As used herein, the term "arylalkynyl" or "arylalkynyl-" refers to an alkynyl in which one of the hydrogen atoms bonded to the carbon atom has been replaced with an aryl. An arylalkynyl group contains 6 to 20 carbon atoms; for example, the alkynyl portion of the arylalkynyl group is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

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

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

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

[0065] As used herein, the term "heterocycle" or "heterocyclyl" refers to a non-aromatic, fully saturated or partially unsaturated ring system of 3 to 18 atoms (e.g., a 3- to 7-membered monocycle, a 7- to 11-membered bicycle, or one containing a total of 3 to 10 ring atoms) containing at least one N, O, S, or P. Each ring of the heterocycle or heterocyclyl may have 1, 2, 3, or 4 heteroatoms selected from N, O, and / or S, where the N and S heteroatoms may be optionally oxidized, the N heteroatom may be optionally quaternized, and at least one carbon atom of the heterocyclyl may be oxidized to form at least one C=O. A heterocycle may be bonded at any heteroatom or carbon atom of the ring or ring system, as valence allows. The rings of a polycyclic heterocyclyl or heterocycle may be fused, bridged, and / or linked through one or more spiro atoms. A fused system of a heterocycle or heterocyclyl with an aryl ring is considered 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 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, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolinyl, and 2-isoxazolinyl. Indyl, 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-pyra nyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl. As used herein, the term "aziridinyl" includes aziridin-1-yl and aziridin-2-yl. As used herein, the term "oxiranyl" includes oxiranyl-2-yl. As used herein, the term "thiiranyl" includes thiiran-2-yl. As used herein, the term "azetidinyl" includes azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl. As used herein, the term "oxetanyl" includes oxetan-2-yl and oxetan-3-yl. As used herein, the term "thietanyl" includes thietan-2-yl and thietan-3-yl.As used herein, the term "pyrrolidinyl" includes pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. As used herein, the term "tetrahydrofuranyl" includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. As used herein, the term "tetrahydrothiophenyl" includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. As used herein, the term "succinimidyl" includes succinimide-1-yl and succinimide-3-yl. As used herein, the term "dihydropyrrolyl" includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1H-pyrrol-3-yl, and 2,5-dihydropyrrol-5-yl. As used herein, the term "2H-pyrrolyl" includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl, and 2H-pyrrol-5-yl. As used herein, the term "3H-pyrrolyl" includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl, and 3H-pyrrol-5-yl. As used herein, the term "dihydrofuranyl" includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl, and 2,5-dihydrofuran-5-yl. As used herein, the term "dihydrothiophenyl" includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl, and 2,5-dihydrothiophen-5-yl. As used herein, the term "imidazolidinyl" includes imidazolidin-1-yl, imidazolidin-2-yl, and imidazolidin-4-yl.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. As used herein, the term "dioxolanyl," also known as "1,3-dioxolanyl," includes dioxolan-2-yl, dioxolan-4-yl, and dioxolan-5-yl. As used herein, the term "dioxolyl," also known as "1,3-dioxolyl," includes dioxol-2-yl, dioxol-4-yl, and dioxol-5-yl. As used herein, the term "oxazolidinyl" includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, and oxazolidin-5-yl. As used herein, the term "isoxazolidinyl" includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl. 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 isothiazolin-2-yl, isothiazolin-3-yl, isothiazolin-4-yl, and isothiazolin-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.The term "dihydropyridinyl" as used herein includes 1,2-dihydropyridin-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, and the like. yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl, and 3,4-dihydropyridin-6-yl. The term "tetrahydropyridinyl" as used herein 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-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, 1,2,3,6-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-6-yl, 1, 2,3,4,5-tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, and 2,3,4,5-tetrahydropyridin-6-yl.As used herein, the term "tetrahydropyranyl," also known as "oxanyl" or "tetrahydro-2H-pyranyl," includes tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl. As used herein, the term "2H-pyranyl" includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, and 2H-pyran-6-yl. As used herein, the term "4H-pyranyl" includes 4H-pyran-2-yl, 4H-pyran-3-yl, and 4H-pyran-4-yl. As used herein, the term "3,4-dihydro-2H-pyranyl" includes 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl, and 3,4-dihydro-2H-pyran-6-yl. As used herein, the term "3,6-dihydro-2H-pyranyl" includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, and 3,6-dihydro-2H-pyran-6-yl. As used herein, the term "tetrahydrothiophenyl" includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl-3-yl, and tetrahydrothiophenyl-4-yl. As used herein, the term "2H-thiopyranyl" includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, and 2H-thiopyran-6-yl. As used herein, the term "4H-thiopyranyl" includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, and 4H-thiopyran-4-yl. As used herein, the term "3,4-dihydro-2H-thiopyranyl" includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl, and 3,4-dihydro-2H-thiopyran-6-yl. As used herein, the term "3,6-dihydro-2H-thiopyranyl" includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl, and 3,6-dihydro-2H-thiopyran-6-yl. As used herein, the term "piperazinyl," also known as "piperazidinyl," includes piperazin-1-yl and piperazin-2-yl. As used herein, the term "morpholinyl" includes morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl. As used herein, the term "thiomorpholinyl" includes thiomorpholin-2-yl, thiomorpholin-3-yl, and thiomorpholin-4-yl. As used herein, the term "dioxanyl" includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, and 1,4-dioxan-2-yl.As used herein, the term "dithianyl" includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl, and 1,4-dithian-2-yl. As used herein, the term "oxathianyl" includes oxathian-2-yl and oxathian-3-yl. As used herein, the term "trioxanyl" includes 1,2,3-trioxan-4-yl, 1,2,3-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl, and 1,3,4-trioxan-2-yl. 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.As used herein, the term "quinolizinyl" includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. As used herein, the term "tetrahydroquinolinyl" includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl, and tetrahydroquinolin-8-yl. As used herein, the term "tetrahydroisoquinolinyl" includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, and tetrahydroisoquinolin-8-yl. As used herein, the term "chromanyl" includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, and chroman-8-yl. As used herein, the term "1H-pyrrolidine" includes 1H-pyrrolidin-1-yl, 1H-pyrrolidin-2-yl, 1H-pyrrolidin-3-yl, 1H-pyrrolidin-5-yl, 1H-pyrrolidin-6-yl, and 1H-pyrrolidin-7-yl. 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 to 18 atoms containing at least one N, O, S, or P and containing one ring or two rings, which may be fused or covalently bonded together, each ring typically containing 5 to 6 atoms; at least one of the rings is aromatic, wherein the N and S heteroatoms are optionally oxidized, the N heteroatom is optionally quaternized, and at least one carbon atom of the heteroaryl is optionally oxidized to form at least one C=O. A fused system of a heteroaryl ring with a cycloalkyl ring, cycloalkenyl ring, or cycloalkynyl ring is considered heteroaryl regardless of the ring attached to the core structure. A fused system of a heteroaryl ring with a heterocyclic ring is considered heteroaryl regardless of the ring attached to the core structure. A fused system of a heteroaryl ring with an aryl ring is considered heteroaryl regardless of the ring attached to the core structure.Non-limiting examples of such heteroaryls include triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl ... thieno[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, sily In some embodiments, the heteroaryl group is selected from the group including pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl, and thiazolyl; in some embodiments, the heteroaryl group is selected from the group including pyridyl, pyrazinyl, pyrimidinyl, indolyl, and benzimidazolyl.

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

[0069] Heteroaryl and heterocycle or heterocyclyl as used herein include, by way of example and not limitation, 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, C.W. 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 where 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 where R i is heterocyclyl and R a is alkyl as defined hereinabove.

[0072] The term "heteroaryloxy" as a group or part of a group refers to a heteroaryl group of the formula -OR k where 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 -ORa -R i where R i is heteroaryl, and R a is alkyl as defined hereinabove.

[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) has been 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 has been replaced with a heterocyclyl. The heterocyclyl-alkenyl or heterocycle-alkenyl group can contain 6 to 20 atoms, e.g., the alkenyl portion is 2 to 6 carbon atoms and the heterocyclyl portion is 3 to 14 atoms.

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

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

[0078] The 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; for example, the heteroalkenyl portion can contain 2 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms. In some embodiments, the heterocyclyl-heteroalkenyl or heterocycle-heteroalkenyl is selected from the group including heterocyclyl-O-alkenyl, heterocyclylalkyl-O-alkenyl, heterocyclyl-NH-alkenyl, heterocyclyl-N(alkenyl), heterocyclylalkyl-NH-alkenyl, heterocyclylalkyl-N-(alkenyl), 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 has been replaced with a heterocyclyl. The heterocyclyl-heteroalkynyl or heterocycle-heteroalkynyl group can contain 6 to 20 atoms; for example, the heteroalkynyl portion can contain 2 to 6 carbon atoms and the heterocyclyl portion can contain 3 to 14 atoms. In some embodiments, the heterocyclyl-heteroalkynyl is selected from the group including heterocyclyl-O-alkynyl, heterocyclylalkynyl-O-alkynyl, heterocyclyl-NH-alkynyl, heterocyclyl-N(alkynyl), heterocyclylalkynyl-NH-alkynyl, heterocyclylalkynyl-N-(alkynyl), heterocyclyl-S-alkynyl, and heterocyclylalkynyl-S-alkynyl.

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

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

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

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

[0084] The term "heteroaryl-heteroalkenyl," as used herein, 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 heteroaryl. The heteroaryl-heteroalkenyl group contains 8 to 20 atoms; for example, the heteroalkenyl portion of the heteroaryl-heteroalkenyl group is 3 to 6 carbon atoms and the heteroaryl portion is 5 to 14 atoms. In some embodiments, the heteroaryl-heteroalkenyl is selected from the group including heteroaryl-O-alkenyl, heteroarylalkenyl-O-alkenyl, heteroaryl-NH-alkenyl, heteroaryl-N(alkenyl), heteroarylalkenyl-NH-alkenyl, heteroarylalkenyl-N-(alkenyl), heteroaryl-S-alkenyl, and heteroarylalkenyl-S-alkenyl.

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

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

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

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

[0089] The term "alkenylthio" as a group or part of a group refers to a group of the formula -SR d where 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 where 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 where Rg 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 where R a is alkylene and R g is aryl as defined hereinabove.

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

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

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

[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, and Rb is alkyl. Thus, alkylamino includes mono-alkylamino groups (e.g., mono-alkylamino groups such as methylamino and ethylamino) and di-alkylamino groups (e.g., di-alkylamino groups such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, i-butylamino, sec-butylamino, t-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-i-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-i-propylamino, n-butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n-propylamino, ethyl-i-propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di-n-butylamino, di-i-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

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

[0099] The term “mono- or di-heteroarylamino” as a group or part of a group refers to a group of the formula —N(R u )(R v ) group, wherein R u and R v are each independently selected from hydrogen, heteroaryl, or alkyl; R u or R 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 specified, the term halogen means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

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

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

[0104] The combination of a group "optionally containing one or more heteroatoms selected from the group consisting of O, S, and N" with a group "optionally, two or more hydrogen atoms on the carbon atoms or heteroatoms of the group may together form =O or =S" combines the two aspects described hereinabove, and when the group being referred to is alkyl, examples include, among others, CH3-C(O)O-, CH3-C(O)O-CH2-, CH3-NH-C(O)-, CH3-C(O)-NH-CH3-NH-C(O)-CH2-, CH3-NH-C(S)-CH2-, CH3-NH-C(S)-NH-CH2-, CH3-NH-S(O)2-, and CH3-NH-S(O)2-NH-CH2-.

[0105] The term "single bond," as used herein in reference to a linking group, i.e., in formulae herein where a particular linking group is selected from a single bond, refers to a molecule in which the linking group is absent, and thus refers to a compound with a direct single bond connection between the two moieties that are joined by the linking group.

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

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

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

[0109] As used herein, and unless otherwise specified, the term "solvate" includes any combination that may be formed 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] As used herein, the term "heteroatom(s)" means an atom selected from nitrogen, which may be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.

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

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

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

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

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

[0116] In one embodiment, the compounds of the present disclosure have Formula I: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: Y is N and Y 1 is N and Y 2 is CR 3a and Y 3 is CR 2 or Y is N and Y 1 is N and Y 2 is CR 3a and Y 3 is N; or Y is N and Y 1 is N and Y 2 is CH and Y 3 is N; or Y is N and Y 1 is N and Y 2 is CH and Y 3 is CR 2 or Y is N and Y 1is CR 3a and Y 2 is N and Y 3 is CR 2 or Y is N and Y 1 is CR 3a and Y 2 is N and Y 3 is N; or Y is N and Y 1 is CR 3a and Y 2 is CH and Y 3 is CR 2 or Y is N and Y 1 is CR 3a and Y 2 is CH and Y 3 is N; or Y is C and Y 1 is NR 3b and Y 2 is N and Y 3 is CR 2 or Y is C and Y 1 is NR 3b and Y 2 is N and Y 3 is N; or Y is C and Y 1 is NR 3b and Y 2 is CH and Y 3 is CR 2 or Y is C and Y 1 is NR 3b and Y 2 is CH and Y 3 is N; or Y is C and Y 1 is N and Y 2 is NR 3c and Y 3 is CR 2 or Y is C and Y 1 is N and Y 2 is NR 3c and Y3 is N; or Y is C and Y 1 is N and Y 2 is CH and Y 3 is CR 2 or Y is C and Y 1 is N and Y 2 is CH and Y 3 is N; R 1 teeth, (i) hydrogen, (ii) -C(=O)Z 2 (iii) -S(=O)Z 2 , (iv) Unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of (c) C2-C6 alkynyl Independently selected from the group consisting of: (v) Unsubstituted or substituted C6-C 10Aryl, wherein one or more of the substituents are (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of (e) C1-C6 haloalkyl, (f) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of halogen and alcohol; (g)-OZ 1 , (h)-SZ 1 , (i)-SF 5 , and (j) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (vi) Unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , (g) oxo, and (h) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (vii) Unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 Independently selected from the group consisting of: (viii) Unsubstituted or substituted C3-C6 heterocycles, wherein one or more of the substituents is (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) oxo Independently selected from the group consisting of: (ix)-S(=O)Z 2 , and (x)-C(=O)Z 2 selected from the group consisting of: R 2 teeth, (i) hydrogen, (ii) unsubstituted or substituted C-C alkyl (wherein one or more substituents are independently unsubstituted or substituted C-C 10 aryl, where one or more substituents are C1-C6 haloalkyl; (iii) halogens, and (iv) Unsubstituted or substituted C1-C6 alkynyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ1 (independently selected from the group consisting of: (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (v) Unsubstituted or substituted C6-C 10 aryl, wherein one or more substituents are independently selected from the group consisting of halogen, C-C alkyl, and C-C haloalkyl; selected from the group consisting of: R 3a , R 3b , and R 3c teeth, (i) hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl, where one or more of the substituents are cyano, C3-C6 cycloalkyl, and unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 independently selected from the group consisting of (iii) C3-C6 cycloalkyl are independently selected from the group consisting of: R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R 6 teeth, (i)-(CH2) m -NR 10a R 10b , (ii) -C(=O)NZ 3 Z 4, and (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more of the substituents is (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2 , (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 2 , (f)-S(=O)2NZ 3 Z 4 , and (g) halogens), (iv) -CH2-C(=O)OH is selected from the group consisting of R 7 teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; or R 6 and R 7 together with the carbon to which they are attached form an unsubstituted or substituted 4-8 membered heterocycle (wherein one or more of the substituents is C1-C6 alkyl, -C(=O)Z 2 , -S(=O)2Z 2 and oxo); m is 0 or 1; R 10a teeth, (i)-C(=O)Z 2 (ii) -C(=O)OZ 2 , (iii) -C(=O)NZ 3 Z 4 , (iv) -S(=O)Z 2 , (v)-S(=O)2NZ 3 Z 4 , (vi)-S(=O)(=NZ 5 )Z 2 , (vii)-S(=NZ 5 )(=NZ 6 )Z 2 , (viii)-S(=O)(=NZ 5 )NZ 3 Z 4 (ix) -CH2-C(=O)OH (x) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; and (xi) Unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , and -C(=O)OZ 2 (independently selected from the group consisting of selected from the group consisting of: R 10a and R 10b together with the nitrogen to which they are attached form an unsubstituted or substituted 4- to 8-membered heterocyclic ring; R 10b teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl (wherein one or more of the substituents is cyano, OZ 1 and C2-C6 alkynyl) selected from the group consisting of: each Z 1 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z4 , 4- to 8-membered heterocycles), (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 2 teeth, (i) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl); (ii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycle, -OZ 1 , -C(=O)OZ 3 (independently selected from the group consisting of (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, (vi) C1-C6 haloalkyl, (vii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of: (viii) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of are independently selected from the group consisting of: each Z 3 and Z 4 teeth, (i) hydrogen, (ii) -S(=O)Z 2 , (iii) unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of (c) unsubstituted or substituted 5- to 9-membered heteroaryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl Independently selected from the group consisting of: (iii) C2-C6 alkenyl, (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 5 and Z 6 teeth, (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl are independently selected from the group consisting of:

[0117] In another embodiment, the compounds of the present disclosure have Formula II: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: Y is N and Y 1 is N and Y 2 is CR 3a or Y is N and Y 1 is CR 3a and Y 2 is N; or Y is C and Y 1 is NR 3b and Y 2 is N; or Y is C and Y 1 is N and Y 2 is NR 3c and; R 1 teeth, (i) hydrogen, (ii) -C(=O)Z 2 (iii) -S(=O)Z 2 , (iv) Unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of (c) C2-C6 alkynyl Independently selected from the group consisting of: (v) Unsubstituted or substituted C6-C 10 Aryl, wherein one or more of the substituents are (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , (g)-SZ 1 , (h)-SF 5 , and (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (vi) Unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , (g) oxo, and (h) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (vii) Unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 Independently selected from the group consisting of: (viii) Unsubstituted or substituted C3-C6 heterocycles, wherein one or more of the substituents is (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) oxo Independently selected from the group consisting of: (ix)-S(=O)Z 2 , and (x)-C(=O)Z 2 selected from the group consisting of: R 2 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) halogens, and (iv) Unsubstituted or substituted C1-C6 alkynyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of: (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of is selected from the group consisting of R 3a , R 3b , and R 3c teeth, (i) hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl, where one or more of the substituents are cyano, C3-C6 cycloalkyl, and unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 independently selected from the group consisting of (iii) C3-C6 cycloalkyl are independently selected from the group consisting of: R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R 6 teeth, (i)-(CH2) m -NR 10a R 10b , (ii) -C(=O)NZ 3 Z 4 , and (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more of the substituents is (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2 , (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 2 , (f)-S(=O)2NZ 3 Z 4 , and (g) halogens) is selected from the group consisting of R 7 teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; or R 6 and R 7 together with the carbon to which they are attached form an unsubstituted or substituted 4-8 membered heterocycle (wherein one or more of the substituents is C1-C6 alkyl, -C(=O)Z 2 , -S(=O)2Z 2 and oxo); m is 0 or 1; R 10a teeth, (i)-C(=O)Z 2 (ii) -C(=O)OZ 2 , (iii) -C(=O)NZ 3Z 4 , (iv) -S(=O)Z 2 , (v)-S(=O)2NZ 3 Z 4 , (vi)-S(=O)(=NZ 5 )Z 2 , (vii)-S(=NZ 5 )(=NZ 6 )Z 2 , (viii)-S(=O)(=NZ 5 )NZ 3 Z 4 , and (ix) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl. selected from the group consisting of: R 10b teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; selected from the group consisting of: each Z 1 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycles), (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 2 teeth, (i) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl); (ii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycles), (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, (vi) C1-C6 haloalkyl, (vii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of: (viii) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of are independently selected from the group consisting of: each Z 3 and Z 4 teeth, (i) hydrogen, (ii) -S(=O)Z 2 , (iii) unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of (c) unsubstituted or substituted 5- to 9-membered heteroaryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl Independently selected from the group consisting of: (iv) C2-C6 alkenyl, (v) C2-C6 alkynyl, (vi) C3-C6 cycloalkyl, (vii) C3-C6 cycloalkenyl, and (viii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 5 and Z 6 teeth, (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl are independently selected from the group consisting of:

[0118] In another embodiment, the compounds of the present disclosure have formula III: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3a is as defined in relation to Formula I or Formula II.

[0119] In another embodiment, the compound of the disclosure is a compound of Formula I, Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 3a is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0120] In another embodiment, the compounds of the present disclosure have formula IV: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0121] In another embodiment, the compound of the disclosure is a compound of Formula I, Formula II, or Formula IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 3b is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0122] In another embodiment, the compounds of the present disclosure have formula V: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0123] In another embodiment, the compound of the disclosure is a compound of Formula I, Formula II, or Formula V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 3c is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0124] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: R 6 is -(CH2) m -NR 10a R 10b and; m is 1; R 7 is hydrogen, R 10b is hydrogen.

[0125] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 10a is -C(=O)Z 2 is.

[0126] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 2 is an unsubstituted or substituted C2-C6 alkenyl, wherein one or more of the substituents are halogen, -NZ 3 Z 4 , and 4- to 6-membered heterocycles.

[0127] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z 2 is unsubstituted C2-C6 alkenyl.

[0128] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is unsubstituted or substituted C6-C 10 It is aryl.

[0129] In another embodiment, the compound of the present disclosure is a compound of any one of Formulas I-V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 is unsubstituted or substituted phenyl, wherein one or more of the substituents are halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -OZ 1 are independently selected from the group consisting of:

[0130] In another embodiment, the compound of the disclosure is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Y 3 is nitrogen.

[0131] In another embodiment, the compound of the disclosure is a compound of Table 1, or any one or more of its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0132] In another embodiment, the compound of the present disclosure is N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (S)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (S)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; and (S)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide, or a tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0133] Preferred or specific descriptions (features) and embodiments of the compounds of the present disclosure are defined herein below. Each description, aspect, and embodiment of the present disclosure defined in this manner may be combined with any other description, aspect, and / or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as preferred, specific, or advantageous may be combined with any other feature or description indicated as preferred, specific, or advantageous. The present disclosure is now specifically captured by any one or any combination of one or more of the following numbered descriptions and embodiments with any other description, aspect, and / or embodiment (not numbered).

[0134] Embodiment 1. Formula II: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Y is N and Y 1 is N and Y 2 is CR 3a or Y is N and Y 1 is CR 3a and Y 2 is N; or Y is C and Y 1 is NR 3b and Y 2 is N; or Y is C and Y 1 is N and Y 2 is NR 3c and; R 1 teeth, (i) hydrogen, (ii) -C(=O)Z 2 , (iii) -S(=O)Z 2 , (iv) Unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of (c) C2-C6 alkynyl Independently selected from the group consisting of: (iii) Unsubstituted or substituted C6-C 10 Aryl, wherein one or more of the substituents are (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , (g)-SZ 1 , (h)-SF 5 , and (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (iv) Unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (v) Unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 Independently selected from the group consisting of: (vi) Unsubstituted or substituted C3-C6 heterocycles, wherein one or more of the substituents is (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 Independently selected from the group consisting of: (vii)-S(=O)Z 2 , and (viii)-C(=O)Z 2 selected from the group consisting of: R 2 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) halogens, and (iv) Unsubstituted or substituted C1-C6 alkynyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of: (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of is selected from the group consisting of R 3a , R 3b , and R 3c teeth, (i) hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl, where one or more of the substituents are cyano, C3-C6 cycloalkyl, and unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 independently selected from the group consisting of (iii) C3-C6 cycloalkyl are independently selected from the group consisting of: R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R 6 teeth, (i)-(CH2) m -NR 10a R 10b , (ii) -C(=O)NZ 3 Z 4 , and (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more of the substituents is (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2, (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 2 , (f)-S(=O)2NZ 3 Z 4 , and (g) halogens) is selected from the group consisting of R 7 teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; or R 6 and R 7 together with the carbon to which they are attached form an unsubstituted or substituted 4-8 membered heterocycle (wherein one or more of the substituents is C1-C6 alkyl, -C(=O)Z 2 , -S(=O)2Z 2 and oxo); m is 0 or 1; R 10a teeth, (i)-C(=O)Z 2 (ii) -C(=O)OZ 2 , (iii) -C(=O)NZ 3 Z 4 , (iv) -S(=O)Z 2 , (v)-S(=O)2NZ 3 Z 4 , (vi)-S(=O)(=NZ 5 )Z 2 , (vii)-S(=NZ 5 )(=NZ 6 )Z 2 , (viii)-S(=O)(=NZ 5 )NZ 3 Z4 , and (ix) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl. selected from the group consisting of: R 10b teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; selected from the group consisting of: each Z 1 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycles), (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 2 teeth, (i) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl); (ii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycles), (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, (vi) C1-C6 haloalkyl, (vii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of: (viii) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of are independently selected from the group consisting of: each Z 3 and Z 4 teeth, (i) hydrogen, (ii) -S(=O)Z 2 , (iii) unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1(independently selected from the group consisting of (c) unsubstituted or substituted 5- to 9-membered heteroaryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl Independently selected from the group consisting of: (iii) C2-C6 alkenyl, (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 5 and Z 6 teeth, (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl independently selected from the group consisting of:

[0135] Embodiment 2. Formula III: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3a is as defined in relation to embodiment 1).

[0136] Embodiment 3. R 3ais selected from the group consisting of hydrogen and C1-C6 alkyl.

[0137] Embodiment 4. Formula IV: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3a is as defined in relation to embodiment 1).

[0138] Embodiment 5. R 3b is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0139] Embodiment 6. Formula V: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3c is as defined in relation to embodiment 1).

[0140] Embodiment 7. R 3c is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0141] Embodiment 8. R 6 is -(CH2) m -NR 10a R 10b and; m is 1; R 7 is hydrogen, R10b is hydrogen, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0142] Embodiment 9. R 10a is -C(=O)Z 2 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0143] Embodiment 10. Z 2 is an unsubstituted or substituted C2-C6 alkenyl, wherein one or more of the substituents are halogen, -NZ 3 Z 4 , 4-6 membered heterocycles, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, of any one of Formulas I-V, wherein the compound is independently selected from the group consisting of:

[0144] Embodiment 11. Z 2 is unsubstituted C2-C6 alkenyl, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0145] Embodiment 12. R 1 is unsubstituted or substituted C6-C 10 A compound of any one of Formulas IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0146] Embodiment 13. R 1 is unsubstituted or substituted phenyl, wherein one or more of the substituents are halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -OZ 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, of any one of Formulas I-V, independently selected from the group consisting of:

[0147] Embodiment 14. Formula II: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Y is N and Y 1 is N and Y 2 is CR 3a or Y is N and Y 1 is CR 3a and Y 2 is N; or Y is C and Y 1 is NR 3b and Y 2 is N; or Y is C and Y 1 is N and Y 2 is NR 3c and; R 1 teeth, (i) hydrogen, (ii) -C(=O)Z 2 , (iii) -S(=O)Z 2 , (iv) Unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of (c) C2-C6 alkynyl Independently selected from the group consisting of: (v) Unsubstituted or substituted C6-C 10 Aryl, wherein one or more of the substituents are (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , (g)-SZ 1 , (h)-SF 5 , and (i) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (vi) Unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, (f)-OZ 1 , and (g) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of: (vii) Unsubstituted or substituted C3-C6 cycloalkyl, wherein one or more of the substituents is: (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 Independently selected from the group consisting of: (viii) Unsubstituted or substituted C3-C6 heterocycles, wherein one or more of the substituents is (a) halogens, (b) cyano, (c) C1-C6 alkyl, (d) C3-C6 cycloalkyl, (e) C1-C6 haloalkyl, and (f)-OZ 1 Independently selected from the group consisting of: (ix)-S(=O)Z 2 , and (x)-C(=O)Z 2 selected from the group consisting of: R 2 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) halogens, and (iv) Unsubstituted or substituted C1-C6 alkynyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of: (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1 (independently selected from the group consisting of Independently selected from the group consisting of is selected from the group consisting of R 3a , R 3b , and R 3c teeth, (i) hydrogen, (ii) Unsubstituted or substituted C1-C6 alkyl, where one or more of the substituents are cyano, C3-C6 cycloalkyl, and unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 independently selected from the group consisting of (iii) C3-C6 cycloalkyl are independently selected from the group consisting of: R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; R 6 teeth, (i)-(CH2) m -NR 10a R 10b , (ii) -C(=O)NZ 3 Z 4 , and (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more of the substituents is (a) C1-C6 alkyl, (b)-C(=O)Z 2 (c)-C(=O)OZ 2, (d)-C(=O)NZ 3 Z 4 , (e)-S(=O)2Z 2 , (f)-S(=O)2NZ 3 Z 4 , and (g) halogens) is selected from the group consisting of R 7 teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; or R 6 and R 7 together with the carbon to which they are attached form an unsubstituted or substituted 4-8 membered heterocycle (wherein one or more of the substituents is C1-C6 alkyl, -C(=O)Z 2 , -S(=O)2Z 2 and oxo); m is 0 or 1; R 10a teeth, (i)-C(=O)Z 2 , (ii) -C(=O)OZ 2 , (iii) -C(=O)NZ 3 Z 4 , (iv) -S(=O)Z 2 , (v)-S(=O)2NZ 3 Z 4 , (vi)-S(=O)(=NZ 5 )Z 2 , (vii)-S(=NZ 5 )(=NZ 6 )Z 2 , (viii)-S(=O)(=NZ 5 )NZ 3Z 4 , and (ix) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl. selected from the group consisting of: R 10b teeth, (i) hydrogen, and (ii) unsubstituted or substituted C1-C6 alkyl, wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl; selected from the group consisting of: each Z 1 teeth, (i) hydrogen, (ii) C1-C6 alkyl, (iii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycles), (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 2 teeth, (i) unsubstituted or substituted C1-C6 alkyl (wherein one or more substituents are independently selected from the group consisting of cyano and C2-C6 alkynyl); (ii) unsubstituted or substituted C2-C6 alkenyl (wherein one or more of the substituents is cyano, -S(=O)2Z 1 , -S(=O)2NZ 3 Z 4 , halogen, -NZ 3 Z 4 , 4- to 8-membered heterocycles), (iii) C2-C6 alkynyl, (iv) C3-C6 cycloalkyl, (v) C3-C6 cycloalkenyl, (vi) C1-C6 haloalkyl, (vii) Unsubstituted or substituted C6-C 10 Aryl (wherein one or more of the substituents are halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of: (viii) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is halogen, C1-C6 alkyl, and C1-C6 haloalkyl, and -OZ 1 (independently selected from the group consisting of are independently selected from the group consisting of: each Z 3 and Z 4 teeth, (i) hydrogen, (ii) -S(=O)Z 2 , (iii) unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents is: (a) Unsubstituted or substituted C6-C 10 aryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl, (b) unsubstituted or substituted C3-C6 cycloalkyl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, and (6)-OZ 1(independently selected from the group consisting of (c) unsubstituted or substituted 5- to 9-membered heteroaryl (wherein one or more of the substituents is (1) halogen, (2) Cyano, (3) C1-C6 alkyl, (4) C3-C6 cycloalkyl, (5) C1-C6 haloalkyl, (6)-OZ 1 , (7) C2-C6 alkenyl, and (8) independently selected from the group consisting of C2-C6 alkynyl Independently selected from the group consisting of: (iii) C2-C6 alkenyl, (iv) C2-C6 alkynyl, (v) C3-C6 cycloalkyl, (vi) C3-C6 cycloalkenyl, and (vii) C1-C6 haloalkyl are independently selected from the group consisting of: each Z 5 and Z 6 teeth, (i) hydrogen, (ii) C1-C6 alkyl, and (iii) C3-C6 cycloalkyl independently selected from the group consisting of:

[0148] Embodiment 15. Formula V: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3a is as defined in relation to embodiment 14).

[0149] Embodiment 16. R 3aThe compound of embodiment 14 or 15, wherein is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0150] Embodiment 17. Formula IV: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3b is as defined in relation to embodiment 14).

[0151] Embodiment 18. R 3b The compound of embodiment 14 or 17, wherein is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0152] Embodiment 19. Formula V: [ka] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R 1 , R 6 , R 7 , and R 3a is as defined in relation to embodiment 14).

[0153] Embodiment 20. R 3c is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0154] Embodiment 21. R 6 is -(CH2) m -NR 10a R 10b and; m is 1; R 7 is hydrogen, R 10b is hydrogen, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0155] Embodiment 22. R 10a is -C(=O)Z 2 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0156] Embodiment 23. Z 2 is an unsubstituted or substituted C2-C6 alkenyl, wherein one or more of the substituents are halogen, -NZ 3 Z 4 , 4- to 6-membered heterocycles, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, of any one of Formulas II-V, wherein the compound is independently selected from the group consisting of:

[0157] Embodiment 24. Z 2 is unsubstituted C2-C6 alkenyl, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0158] Embodiment 25. R 1 is unsubstituted or substituted C6-C 10 A compound of any one of Formulas IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0159] Embodiment 26. R 1 is unsubstituted or substituted phenyl, wherein one or more of the substituents are halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -OZ 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, of any one of Formulas I-V, independently selected from the group consisting of:

[0160] Embodiment 27. A compound selected from one or more of the compounds in Table 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0161] Embodiment 28. N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (S)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (S)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; and (S)-N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide 28. The compound of embodiment 27, selected from the group consisting of:

[0162] Embodiment 29. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.

[0163] Embodiment 30. A compound according to any one of embodiments 1 to 28 or a pharmaceutical composition according to embodiment 29 for use as a medicament.

[0164] Embodiment 31. A compound according to any one of embodiments 1 to 28, or a pharmaceutical composition according to embodiment 29, for use in the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder in an animal, mammal or human.

[0165] Embodiment 32. The use described in embodiment 31, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from the group comprising cancer, fibrosis, and YAP / TAZ-TEAD activation-mediated congenital disorder.

[0166] Embodiment 33. The use of embodiment 31, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma.

[0167] Embodiment 34. A method for the prevention or treatment of a YAP / TAZ-TEAD activation-mediated disorder in an animal, mammal or human, comprising administering to said animal, mammal or human in need of such prevention or treatment an effective dose of a compound according to any one of embodiments 1 to 28.

[0168] Embodiment 35. 35. A method for treating or preventing a YAP / TAZ-TEAD activation-mediated disorder according to embodiment 34 in a patient in need thereof, in combination with one or more other pharmaceutical agents selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor.

[0169] More broadly, 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 uses referred to in the present disclosure may be limited to non-medical, non-therapeutic, non-diagnostic, or in vitro only, or to uses involving cells separate from an animal.

[0170] The compounds of the present disclosure are small molecule YAP / TAZ-TEAD inhibitors. Small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers including, but not limited to, lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer, and prostate cancer, mesothelioma, and / or sarcoma. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers characterized by squamous cell carcinoma of the lung, cervix, ovary, head and neck, esophagus, and / or skin. In other embodiments, small molecule YAP / TAZ-TEAD inhibitors are useful for treating cancers arising from neuroectodermal-derived tissues, such as ependymoma, meningioma, schwannoma, peripheral nerve sheath tumor, and / or neuroblastoma. 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 porocarcinoma. In some embodiments, the solid tumor has a gain-of-function gene amplification, gene fusion, or activating mutation in the YAP1 or WWTR1 (TAZ) gene. In some embodiments, the solid tumor has a loss-of-function mutation or deletion in the NF2, LATS1 / 2, BAP1, FAT1, SAV1, and / or MST1 / 2 genes. In some embodiments, the solid tumor has a gain-of-function mutation in the GNAQ and / or GNA11 genes, e.g., in uveal melanoma. In some embodiments, the solid tumor is characterized by constitutive nuclear presence of YAP and / or TAZ. In some embodiments, the solid tumor is characterized by overexpression of YAP / TAZ-TEAD signature genes, including, but not limited to, CTGF, CYR61, AMOTL2, and / or ANKRD1.

[0171] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating cancers that have developed resistance to previous treatments. This may include, for example, treating cancers that have developed resistance to chemotherapy or targeted therapy. In some embodiments, this includes treatment of cancers that have developed resistance to receptor tyrosine kinase inhibitors, such as those against EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or those against AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), or to RAS itself. This may include treatment of cancers that have developed resistance to components of the RAS-MAPK signaling cascade, including inhibitors of RAS-MAPK (e.g., AMG510, MRTX849, BI1701963, ARS1620), inhibitors of B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib), or inhibitors of MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0172] Small molecule YAP / TAZ-TEAD inhibitors may also be useful when administered simultaneously or sequentially in combination with other agents used to treat cancer, including, for example, inhibitors or monoclonal antibodies targeting receptor tyrosine kinases, such as those against EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib), and RA. Combination treatment with inhibitors of S itself (e.g., AMG510, MRTX849, BI1701963, ARS1620), inhibitors of B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib), or those against components of the RAS-MAPK signaling cascade, including inhibitors of MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib), may be included.

[0173] Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating metastatic cancers, optionally 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.

[0174] In some embodiments, the cancer being treated may be malignant pleural mesothelioma or lung cancer.

[0175] In some embodiments, compounds of the present disclosure are useful in treating acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myeloid leukemia, ... Intestinal cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia Disease, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendrocyte colony leukemia, leukemia, leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, ovariectomy, thyroid cancer ... It may be used for the treatment of adenoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0176] Malignant pleural mesothelioma Small molecule YAP / TAZ-TEAD inhibitors may also be useful for treating malignant pleural mesothelioma, either as single agents or in combination with inhibitors such as pemetrexed disodium, raltitrexed, carboplatin, oxaliplatin, gemcitabine, and doxorubicin, or monoclonal antibodies such as bevacizumab. Combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. Combination with cell therapy, such as chimeric antigen receptor (CAR) T therapy or CAR NK therapy (which may use mesothelin (MSLN) as an antigen), for example, in combination with monoclonal antibodies that recognize mesothelin as an antigen, such as BMS-986148, BAY 94-9343, amatuximab, and / or LMB-100.

[0177] lung cancer Small molecule YAP / TAZ-TEAD inhibitors may also be useful in treating lung cancer as single agents or in combination with inhibitors such as afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, and / or onartuzumab, or in combination with checkpoint inhibitors such as pembrolizumab, atezolizumab, and / or nivolumab. In combination with cisplatin, carboplatin, paclitaxel, protein-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, pemetrexed, afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, necitumumab, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, onartuzumab, pembrolizumab, atezolizumab, and / or nivolumab.

[0178] 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 a transcriptional coactivator with a PDZ-binding motif / Yes-associating protein transcriptional coactivator (TAZ / YAP). In some embodiments, the congenital disease is characterized by a mutant Ga protein. In some embodiments, the mutant Ga protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the congenital disease is characterized by a loss-of-function mutation or deletion in the NF2 gene. Exemplary congenital diseases include, but are not limited to, Sturge-Weber syndrome, port-wine staining, and neurofibromatosis. In some embodiments, the congenital disease is neurofibromatosis, including, but not limited to, neurofibromatosis type 2.

[0179] 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 nonalcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, chronic kidney disease, and / or myocardial infarction injury.

[0180] 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 on cancer growth in xenograft cancer models.

[0181] The compounds of the present disclosure can optionally be covalently attached to an insoluble matrix and used in affinity chromatography (separation according to the nature of the compound's groups; for example, compounds with pendant aryl groups are useful for hydrophobic affinity separation).

[0182] When using one or more derivatives of the formula as defined herein: - The active ingredients of the compound(s) may be administered to the animal or mammal (including human) to be treated by any means known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intraarterially, parenterally or by catheterization. - A therapeutically effective amount of a preparation of compound(s), particularly for the treatment of diseases mediated by the activity of YAP / TAZ-TEAD transcription (such as cancer, fibrosis, and certain congenital disorders) in humans and other mammals, is preferably a YAP / TAZ-TEAD transcription-inhibiting amount of a compound of the formulas, descriptions, aspects and embodiments as defined herein, corresponding to an amount ensuring plasma levels capable of inhibiting YAP / TAZ-TEAD activation, between 1 μg / ml and 100 mg / ml.

[0183] A suitable dosage of the compound or composition of the present disclosure should be used to treat or prevent the target disease in a subject. Depending on the condition to be treated and the condition of the patient, the effective amount may be divided into several subunits per day or may be administered at intervals of more than one day.

[0184] According to certain embodiments of the present disclosure, the compounds of the present disclosure may be used in combination with other therapeutic agents for the treatment or prevention of diseases mediated by the activity of YAP / TAZ-TEAD transcription in humans and other mammals, such as cancer, fibrosis, and certain congenital disorders. (a) one or more compounds of the formulae and aspects, descriptions, and embodiments herein; (b) with one or more additional therapeutic or prophylactic agents used for the prevention or treatment of cancer or fibrosis as biologically active agents in the form of a combined preparation for simultaneous, separate, or sequential use. The present invention relates to the use of a composition comprising:

[0185] The compound or composition may be administered simultaneously with, before, or after one or more additional therapeutic agents (different from the compounds described herein and which may be useful, e.g., as a combination therapy).

[0186] Such additional therapeutic agents for use in combination include: EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab, etc.), AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, duvelmatinib, etc.), Components of the RAS-MAPK signaling cascade, such as inhibitors of RAS itself (AMG510, MRTX849, BI1701963, ARS1620, etc.), B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib, etc.), or MEK1 / 2 (trametinib, selumetinib, cobimetinib, mirdametinib).

[0187] The pharmaceutical compositions or combined preparations according to the present disclosure may contain the compounds of the present disclosure in a wide range of content depending on the intended use and expected effect of the preparation. Generally, the content of the derivatives of the present disclosure in the combined preparations is within the range of 0.1 to 99.9% by weight, preferably 1 to 99% by weight, and more preferably 5 to 95% by weight.

[0188] Those skilled in the art will also recognize that the compounds of the present disclosure can exist in many different protonation states, depending on the pH of their environment, etc. While the structural formulas provided herein represent the compounds in only one of several possible protonation states, it will be understood that these structures are exemplary only, and that the present disclosure is not limited to any particular protonation state, and that compounds in any and all protonation forms are intended to be within the scope of the present disclosure.

[0189] As used herein, the term "pharmaceutically acceptable salts" refers to the therapeutically active, non-toxic salt forms that the compounds of the formulae herein are able to form. Thus, the compounds of the present disclosure may optionally be used in the form of salts of the compounds herein, particularly salts of, for example, Na + , Li + , K. + , Ca 2+ and Mg 2+ These salts include pharmaceutically acceptable, non-toxic salts containing the compounds of formula (I). Such salts may include those derived from the combination of suitable cations, such as alkali metal and alkaline earth metal ions, or ammonium and quaternary amino ions, with an acidic anion moiety, typically a carboxylic acid. The compounds of the present disclosure may bear multiple positive or negative charges. The net charge of the compounds of the present disclosure may be either positive or negative. Any associated counterion is typically determined by the synthesis and / or isolation method used to obtain the compound. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counterion is not a critical feature of the present disclosure, and that the present disclosure encompasses compounds associated with any type of counterion. Furthermore, because the compounds may exist in a variety of different forms, the present disclosure encompasses compounds in forms associated with counterions (e.g., dry salts) as well as forms not associated with counterions (e.g., aqueous or organic solutions). Metal salts are typically prepared by reacting a metal hydroxide with a compound of the present disclosure. Examples of metal salts prepared in this manner include Li + , Na + , and K +(Illegible) . Less soluble metal salts can be precipitated from the solution of a more soluble salt by the addition of a suitable metal compound. Furthermore, salts can be formed from the acid addition of certain organic and inorganic acids to a basic center, typically an amine, or to an acidic group. Examples of suitable acids include inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, and the like. Furthermore, this term also includes solvates, such as, for example, hydrates, alcoholates, etc., that the compounds of the formulae herein and their salts can form. Finally, it should be understood that the compositions herein include compounds of the present disclosure in non-ionized and zwitterionic form, as well as in combination with a stoichiometric amount of water as hydrates.

[0190] 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, typically those with side chains containing basic or acidic groups, such as lysine, arginine, or glutamic acid, or those with side chains containing neutral groups, such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0191] The compounds of the present disclosure also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the present disclosure include alkali metal (e.g., sodium), alkaline earth (e.g., magnesium), ammonium, and NX4 salts. +(wherein X is C1-C4 alkyl). Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of compounds containing a hydroxy group include salts of Na + and NX4 + (wherein X is typically independently selected from H or a C1-C4 alkyl group), and the like. However, salts of acids or bases that are not physiologically acceptable may also be used, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether derived from a physiologically acceptable acid or base, are within the scope of the present disclosure.

[0192] As used herein, and unless otherwise specified, the term "enantiomer" means each individual optically active form of a compound of the present disclosure having an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (e.g., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0193] As used herein, the term "isomer" refers to all possible isomeric forms, including tautomeric and stereochemical forms, but not positional isomers, that a compound of the formula herein may possess. Typically, a structure depicted herein exemplifies only one tautomeric or resonance form of a compound, although corresponding alternative configurations are also contemplated. Unless otherwise specified, the chemical name of a compound represents a mixture of all possible stereochemically isomeric forms, including not only stereochemically pure or enriched compounds, but also all diastereomers and enantiomers of the basic molecular structure (since compounds of the formula herein may have at least one chiral center). More specifically, stereocenters may have either the R or S configuration, and multiple bonds may have either the cis- or trans-configuration.

[0194] A pure isomeric form of the compound is defined as an isomer that is substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. Specifically, the term "stereoisomerically pure" or "chirally pure" refers to a compound having a stereoisomeric excess of at least about 80% (e.g., at least 90% of one isomer and at most 10% of the other possible isomer), preferably at least 90%, more preferably at least 94%, and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in the same way, taking into account the enantiomeric excess and diastereomeric excess, respectively, of the mixture in question.

[0195] Separation of stereoisomers can be achieved by standard methods known to those skilled in the art. One enantiomer of a compound of the present disclosure can be separated substantially free of its opposite enantiomer by methods such as the formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E.L. Liel, McGraw Hill; Lochmuller, C.H., (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in a mixture can be achieved by any suitable method, including: (1) formation of ionic diastereomeric salts using chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds using chiral derivatizing agents, separation of diastereomers, and conversion to pure enantiomers; or (3) direct separation of enantiomers under chiral conditions. In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like, with asymmetric compounds containing acidic functional groups, such as carboxylic and sulfonic acids. Diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. In the case of the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in the formation of diastereomeric salts. Alternatively, in method (2), the substrate to be resolved can be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reaction of asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation and hydrolysis of the diastereomers to give the free enantiomerically enriched compounds.A method for determining optical purity involves preparing chiral esters, such as menthyl or Mosher esters, of the racemic mixture, i.e., α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal-phase and reverse-phase chromatography according to methods for the separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96 / 15111). In method (3), a racemic mixture of the two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, particularly cellulose or amylose derivatives. Commercially available polysaccharide-based chiral stationary phases include ChiralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ, and OK, and Chiralpak™ AD, AS, OP(+), and OT(+). Suitable eluents or mobile phases for use in combination with these polysaccharide chiral stationary phases include hexane modified with alcohols such as ethanol and isopropanol. ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513:375-378).

[0196] The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of substituents on a ring moiety. The absolute stereochemical configuration of compounds of the formulae described herein can be readily determined by one skilled in the art using well-known methods such as, for example, X-ray diffraction.

[0197] The present disclosure also includes isotopically labeled compounds that are identical to those recited in the formulas recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 CI. Compounds of the present disclosure and pharmaceutically acceptable salts of such compounds, or those that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those incorporating radioactive isotopes such as 1C are useful for drug and / or substrate tissue distribution assays. Tritium-labeled (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium, i.e., 2Substitution with H may be preferred in some circumstances because it may confer certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the disclosed formulae may generally be prepared by following the procedures disclosed in the examples and preparations described herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0198] The present disclosure also encompasses modified forms of compounds of Formula (I) or other formulae, embodiments, aspects, or portions thereof, or metabolites thereof using PROTAC technology (Schapira M. et al., Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, PROTAC technology designs bifunctional small molecules with one end being a compound of general formula (I) or other formulae, embodiments, aspects, or portions thereof, or metabolites thereof, and the other end being connected via a connecting chain to a ligand of an E3 ubiquitin ligase to form a targeted protein degradation complex. Because this degradation is catalytic, efficient degradation can be achieved at lower dosages. A compound of general formula (I) or other formulae, an embodiment, aspect or portion thereof, or a metabolite thereof can be connected to a ligand of an E3 ubiquitin ligase, such as a thalidomide analog, via a linker arm (e.g., long-chain ethylene glycols of 2-10 in length, long-chain propylene glycols of 2-10 in length, and long-chain fatty alkanes of 2-10 in length).

[0199] The compounds of the present disclosure can be formulated using conventional carriers and excipients selected according to ordinary practice. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic if intended for delivery by other than oral administration. Formulations optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986), including ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0200] Continuing, as used herein, the term "pharmaceutically acceptable carrier" refers to any material or substance with which an active ingredient is formulated to facilitate its application or penetration to a treatment site, for example, by dissolving, dispersing, or diffusing the composition, and / or to facilitate its storage, transportation, or handling without impairing its effectiveness. A pharmaceutically acceptable carrier can be a solid, or a liquid, or a gas compressed to form a liquid; for example, the compositions of the present disclosure may be suitably used as a concentrate, emulsion, solution, granule, dust, spray, aerosol, suspension, ointment, cream, tablet, pellet, or powder.

[0201] Suitable pharmaceutical carriers for use in the pharmaceutical compositions and their formulations are well known to those skilled in the art, and the present disclosure does not place any particular restrictions on their selection. They may contain additives such as wetting agents, dispersing agents, adhesives, adhesives, emulsifiers, solvents, coatings, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (e.g., sugars or sodium chloride), etc., provided that they are consistent with pharmaceutical practice, e.g., carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present disclosure can be prepared in any known manner, e.g., by homogeneously mixing, coating, and / or grinding the active ingredient with the selected carrier material and, if appropriate, other additives, such as surfactants, in a single-step or multi-step procedure. They can also be prepared by micronization, e.g., to obtain them in the form of microspheres, typically having a diameter of about 1 to 10 gm, i.e., for the production of microcapsules for controlled or sustained release of the active ingredient.

[0202] Suitable surfactants, also known as emulsifiers 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 metal or alkaline earth metal salts, higher fatty acids (C 10 -C 22Examples of suitable surfactants include unsubstituted or substituted ammonium salts of oleic acid or stearic acid, or natural fatty acid mixtures obtainable from coconut oil or tallow, such as the sodium or potassium salts of oleic acid or stearic acid. Synthetic surfactants include sodium or calcium salts of polyacrylic acid; fatty acid sulfonates and sulfates; sulfonated benzimidazole derivatives and alkylarylsulfonates. The fatty acid sulfonates or sulfates are usually in the form of alkali metal or alkaline earth metal salts, unsubstituted ammonium salts, or ammonium salts substituted with alkyl or acyl groups having 8 to 22 carbon atoms, such as the sodium or calcium salts of lignosulfonic acid or dodecylsulfonic acid, or mixtures of fatty alcohol sulfates obtained from natural fatty acids, alkali metal or alkaline earth metal salts of sulfates or sulfonate esters (e.g., sodium lauryl sulfate), and fatty alcohol / ethylene oxide adducts of sulfonic acids. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium, or alcoholamine salts of dodecylbenzenesulfonic acid, dibutyl-naphthalenesulfonic acid, or naphthalenesulfonic acid / formaldehyde condensation products. Corresponding phosphates, such as salts of phosphoric acid esters and ethylene and / or propylene oxide adducts of p-nonylphenol, or phospholipids are also suitable. Suitable phospholipids for this purpose are natural (animal or plant cell-derived) or synthetic phospholipids of the cephalin or lecithin type, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerin, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphosphatidylcholine, and mixtures thereof.

[0203] Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, aliphatic alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkyl arenesulfonates and dialkyl sulfosuccinates, such as polyglycol ether derivatives of aliphatic and alicyclic 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 moiety, and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable nonionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol and ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain; these adducts contain 20 to 250 ethylene glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds typically contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic acid ether, polypropylene / polyethylene oxide adduct, tributylphenoxypolyethoxyethanol, polyethylene glycol, and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose, and pentaerythritol are also suitable nonionic surfactants.

[0204] Suitable cationic surfactants include quaternary ammonium salts, especially halides having four hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl, or hydroxy; e.g., at least one C as an N-substituent. 8-22Quaternary ammonium salts containing alkyl (e.g., cetyl, lauryl, palmityl, myristyl, oleyl, etc.) and containing as further substituents unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy-lower alkyl.

[0205] A more detailed description of suitable surfactants for this purpose can be found, for example, in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Company, Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw", 2nd ed. (Hanser Verlag, Vienna, 1981), and "Encyclopaedia of Surfactants" (Chemical Publishing Co., New York, 1981).

[0206] The compounds of the present disclosure and their pharmaceutically acceptable salts (hereinafter collectively referred to as the active ingredients) can be administered by any route appropriate to the condition to be treated, with suitable routes including oral, rectal, nasal, topical (including ophthalmic, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). The preferred route of administration can vary, for example, depending on the condition of the recipient.

[0207] While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The formulations of the present disclosure, for both veterinary and human use, comprise at least one active ingredient, as described above, together with one or more pharmaceutically 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. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, 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.

[0208] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0209] 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, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant.Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.Tablets can be optionally coated or stamped, and can be formulated to cause slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues, e.g., mouth and skin, formulations are optionally applied as a topical ointment or cream containing, for example, 0.075 to 20 w / w% active ingredient(s) (including active ingredient(s) within the range of 0.1% to 20% in 0.1 w / w% increments, e.g., 0.6 w / w% increments, 0.7 w / w% increments, etc.), preferably 0.2 to 15 w / w%, and most preferably 0.5 to 10 w / w%. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, e.g., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include 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.

[0210] The oily phase of the emulsion of the present disclosure can be composed of known ingredients in a known manner. This phase may contain only an emulsifier (also known as an emulgent), but preferably contains a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Optionally, a hydrophilic emulsifier is included, along with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. In summary, the emulsifier(s), with or without stabilizer(s), constitute the so-called emulsifying wax, and the wax, together with the oil and fat, constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of a cream formulation.

[0211] Because the solubility of active compounds in most oils that can be used in pharmaceutical emulsion formulations is very low, the selection of an oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. Therefore, creams must be non-greasy, non-staining, and washable products, optionally with a consistency suitable for avoiding leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, the latter three being preferred esters. These can be used alone or in combination depending on the desired properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0212] Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5 w / w%. Formulations suitable for topical administration to the mouth include lozenges, which comprise the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which comprise the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes, which comprise the active ingredient in a suitable liquid carrier.

[0213] Formulations for rectal administration may be provided as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for nasal administration, where the carrier is a solid, include a coarse powder, for example, having a particle size in the range of 20 to 500 microns (including 5 micron increments within the range of 20 to 500 microns, e.g., 30 microns, 35 microns, etc.), administered in a nasal insufflation manner, for example, by rapid inhalation through the nasal passages from a container of the powder held close to the nose. Suitable formulations where the carrier is a liquid, for administration as, for example, 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.

[0214] 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.

[0215] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0216] Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0217] It will be understood that the formulations of the present disclosure may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0218] The compounds of the present disclosure can be used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds of the present disclosure as active ingredients, the release of which can be controlled and regulated to allow for reduced dosing frequency or improved pharmacokinetic or toxicity profile of a given compound of the present disclosure. Controlled-release formulations adapted for oral administration, in which discrete units contain one or more compounds of the present disclosure, can be prepared according to conventional methods.

[0219] Additional components may be included to control the duration of action of the active ingredient in the composition. Controlled-release compositions can be achieved by selecting appropriate polymeric carriers, such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, and protamine sulfate. 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, and nanocapsules. Depending on the route of administration, pharmaceutical compositions may require protective coatings. Suitable pharmaceutical forms for injection include sterile aqueous solutions or suspensions and sterile powders for their extemporaneous preparation. Typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, and the like, and mixtures thereof.

[0220] Considering that when several active ingredients are used in combination, they do not necessarily directly produce a combined 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 ingredients in separate but adjacent containers or compartments. In the latter context, each active ingredient may therefore be formulated in a form suitable for an administration route different from that of the other ingredients, for example, one of them may be in the form of an oral or parenteral preparation, while the other may be in the form of an ampoule or aerosol for intravenous injection.

[0221] 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 have no significant biological activity themselves, but that, when delivered to an animal, mammal, or human, undergo a chemical reaction catalyzed by enzymes present in the normal functioning of the animal, mammal, or human body, particularly in the stomach or serum, which has the effect of releasing a compound as defined herein. Thus, the term "prodrug" relates to these species that are converted into the active pharmaceutical ingredient in vivo.

[0222] Prodrugs of the compounds of the present disclosure can have any form suitable for the formulator, for example, esters are non-limiting common prodrug forms. However, in the present 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, a CC covalent bond may be selectively cleaved by one or more enzymes at the target site, and therefore prodrugs in forms other than readily hydrolyzable precursors, particularly esters, amides, etc., may be used. The counterpart of the active pharmaceutical ingredient in the prodrug may have a different structure, such as an amino acid or peptide structure, an alkyl chain, a sugar moiety, and others known in the art.

[0223] For purposes of this disclosure, the term "therapeutically suitable prodrug" is defined herein as "a compound that, upon contact with the tissues of an animal, mammal, or human to which the prodrug has been administered, is modified so as to be converted in vivo, whether by a single biological transformation or by multiple biological transformations, into a therapeutically active form that achieves an intended therapeutic result without undue toxicity, irritation, or allergic response."

[0224] More specifically, the term "prodrug" as used herein refers to an inactive or less active derivative of a compound such as that represented by the structural formulas described herein, which undergoes spontaneous or enzymatic conversion in the body to release a pharmacologically active form of the compound. For a comprehensive review, see Rautio J. et al. ("Prodrugs: design and clinical applications" Nature Reviews Drug Discovery, 2008, doi:10.1038 / nrd2468).

[0225] The compounds of the present disclosure can be prepared using a series of chemical reactions well known to those skilled in the art, which together constitute a process for preparing the compounds and are exemplified hereinafter. The processes described hereinafter are intended as examples only and are not intended to limit the scope of the present disclosure in any way. [Example]

[0226] general synthesis Compounds of the present invention can be prepared according to the general procedures outlined in Scheme 1. [ka] Scheme 1: R 1 , R 3a , R 10a , R 10b , and Z 2 are all as described for the compounds of the invention and their embodiments and formulas; X = halogen, nitrogen, or carbon depending on the compound; FGT = functional group transformation; PG = protecting group.

[0227] 3-Substituted-1H-pyrazol-5-amines 1, which are commercially available or synthesized by procedures known to those skilled in the art, can be reacted with ethyl 2-formyl-3-oxopropanoate in a suitable solvent (e.g., MeOH, EtOH, etc.) at room temperature, followed by a reduction step using an appropriate reducing agent (e.g., NaBH4, etc.) and the introduction of an N-protecting group to provide intermediates of general formula Int-A. Further information can be found in T.W. Greene and P.G.M.Wuts in Protective Groups in Organic Chemistry, 3 rded., John Wiley and Sons, 1999. Intermediates of general formula 2 can be obtained from intermediate Int-A by reduction using a suitable reducing agent (e.g., NaBH4, etc.) in the presence of a metal catalyst (e.g., CoCl2, NiCl2, etc.). Further information can be found in Journal of the American Chemical Society 1986, 67. Intermediates of general formula 3 can be obtained from intermediate 2 by functional group transformation followed by removal of the N-protecting group using procedures known to those skilled in the art. Reaction of the intermediate of general formula 3 with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, boronic acid, and boronic acid ester in combination with the corresponding Pd or Cu catalyst can provide intermediates of general formula Int-B. Furthermore, N-alkylation, N-acylation, and N-sulfonylation of the intermediate of general formula 3 using procedures known to those skilled in the art can provide intermediates of general formula Int-B. Intermediates of general formula 4 can be obtained from intermediate Int-B after removal of the protecting groups by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.) or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Furthermore, intermediates of general formula 4 can be obtained from intermediate Int-B after removal of the protecting groups by N-alkylation and N-sulfonylation using procedures known to those skilled in the art.

[0228] In another embodiment, compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 2. [ka] Scheme 2: R 1 , R 2 , R 3a , R 10a , and R 10bare all as described for the compounds of the invention and their embodiments and formulas; PG = protecting group.

[0229] The intermediate of general formula Int-B can be reacted with a halogenating agent (e.g., NCS, NBS, etc.) in a suitable solvent (e.g., DCM, CHCl, etc.), and then with a suitable coupling agent selected from, but not limited to, boronic acids and boronic acid esters in combination with a Pd catalyst to provide the intermediate of general formula 5. Furthermore, the intermediate of general formula Int-B can be reacted with an aldehyde in the presence of a reducing agent (e.g., NaBH, NaCNBH, etc.) in a suitable solvent (e.g., MeOH, EtOH, etc.) to provide the intermediate of general formula 5. Further information can be found in Journal of Organic Chemistry 1985, 1927. Intermediates of general formula 6 can be obtained from intermediate 5 after removal of the protecting groups by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.) or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Furthermore, intermediates of general formula 6 can be obtained from intermediate 5 after removal of the protecting groups by N-alkylation and N-sulfonylation using procedures known to those skilled in the art.

[0230] Alternatively, compounds of the present invention can be synthesized according to the general procedures outlined in Scheme 3. [ka] Scheme 3: R 1 , R 3a , R 10a , R 10b , and Z 2 are all as described for the compounds of the invention and their embodiments and formulas; X=halogen.

[0231] Reaction of the intermediate of general formula 7 with tert-butyl carbamate in combination with a suitable Pd catalyst, followed by a reduction step using a suitable reducing agent (such as NaBH4), can provide an intermediate of general formula 8. Further information can be found in Journal of Organic Chemistry 2009, 4634. Reaction of the intermediate of general formula 8 with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, boronic acid, and boronic acid ester in combination with the corresponding Pd or Cu catalyst can provide an intermediate of general formula 9. Furthermore, N-alkylation, N-acylation, and N-sulfonylation of the intermediate of general formula 8 using procedures known to those skilled in the art can provide an intermediate of general formula 9. Intermediates of general formula 10 can be obtained from intermediate 9 after removal of the protecting groups by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.) or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Furthermore, intermediates of general formula 10 can be obtained from intermediate 9 after removal of the protecting groups by N-alkylation and N-sulfonylation using procedures known to those skilled in the art.

[0232] Compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 4. [ka] Scheme 4: R 1 , R 3b , R 3c , R 10a , R 10b , and Z 2 are all as described for the compounds of the invention and their embodiments and formulas; PG = protecting group.

[0233] Intermediates of general formulas 12 and 13 can be obtained from 6-bromo-1H-pyrazolo[4,3-b]pyridine 11 by N-alkylation using procedures known to those skilled in the art. Intermediates of general formulas 12 and 13 can be coupled with potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate in combination with a Pd catalyst. Further information can be found in Organic Letters 2011, 3956. Reduction of the bicyclic core by hydrogenation using an appropriate catalyst (e.g., PtO, Pd(OH), etc.) in a suitable solvent (e.g., EtOH, AcOH, etc.) followed by reaction with a suitable coupling agent selected from, but not limited to, halo(hetero)aryls, boronic acids, and boronic acid esters in combination with the corresponding Pd or Cu catalyst can provide intermediates of general formulas 14 and 15. Further, intermediates of general formulas 14 and 15 can be obtained by N-alkylation, N-acylation, and N-sulfonylation using procedures known to those skilled in the art (Protocol A). Intermediates of general formulas 16 and 17 can be obtained from intermediates 14 and 15 after removal of the protecting groups by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Further, intermediates of general formulas 16 and 17 can be obtained from intermediates 14 and 15 after removal of the protecting groups by N-alkylation and N-sulfonylation using procedures known to those skilled in the art (Protocol B). Alternatively, 6-bromo-1H-pyrazolo[4,3-b]pyridine 11 can be converted to intermediates of general formula 18 by the introduction of an N-protecting group. Further information can be found in T.W. Greene and P.G.M. Butts in Protective Groups in Organic Chemistry, 3 rded., John Wiley and Sons, 1999. Intermediates of general formula 19 can be obtained by using the steps and conditions of Protocol A. Intermediates of general formula 19 can be selectively deprotected (PG removal) followed by N-alkylation using procedures known to those skilled in the art. Intermediates of general formulas 16 and 17 can be obtained by using the steps and conditions of Protocol B.

[0234] In another embodiment, compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 5. [ka] Scheme 5: R 1 , R 3a , R 10a , R 10b , and Z 2 are all as described for the compounds of the invention and their embodiments and formulas.

[0235] Intermediates of general formula Int-A can be reduced with a suitable reductant (e.g., NH4HCO2 / Pd / C, etc.) in a suitable solvent (e.g., EtOH, HO, etc.) at temperatures increasing from 80°C to 100°C. After removal of the protecting groups, the bicyclic core can be reacted with a suitable coupling agent selected from, but not limited to, halo(hetero)aryls, boronic acids, and boronic esters in combination with the corresponding Pd or Cu catalyst to provide intermediates of general formula Int-C. Further N-alkylation, N-acylation, and N-sulfonylation can be performed using procedures known to those skilled in the art to provide intermediates of general formula Int-C. Reaction of intermediates of general formula Int-C with alkyl halides in the presence of a suitable base (e.g., LDA, LHDMS, etc.) and in a suitable solvent (e.g., THF, 1,4-dioxane, etc.) can provide intermediates of general formula Int-D. Intermediates of general formula 20 and 22 can be obtained from intermediates of general formula Int-D by reduction using a suitable reducing agent (e.g., NaBH) in the presence of a metal catalyst (e.g., CoCl, BF, OEt, etc.). Intermediates of general formula 21 and 23 can be obtained from intermediates 20 and 23 by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Furthermore, intermediates of general formula 21 and 23 can be obtained from intermediates 20 and 23 by N-alkylation and N-sulfonylation using procedures known to those skilled in the art. Using procedures known to those skilled in the art, the ester moiety of intermediates of general formula Int-C can be reduced to give the corresponding aldehyde, which can then be reacted with a Wittig reagent in the presence of a suitable base (e.g., LDA, K2CO3, etc.) to give intermediates of general formula 24.Intermediates of general formula 25 can be obtained from intermediates of general formula 24 by cycloaddition with 1,1-dibromoformaldoxime in the presence of a suitable base (e.g., NaHCO3, K2CO3, etc.) and a suitable solvent (e.g., HO, EtOAc, etc.). Further information can be found in Organic Letters 2009, 1159. Intermediates of general formula 26 can be obtained from intermediates of general formula Int-C by saponification followed by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.).

[0236] Compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 6. [ka] Scheme 6: R 1 , R 10a , R 10b , and Z 2 are all as described for compounds of the invention and their embodiments and formulas; FGT = functional group transformation.

[0237] The intermediate of general formula 28 can be obtained from ethyl 2-methylpyrimidine-5-carboxylate 27 by bromination followed by nucleophilic substitution using procedures known to those skilled in the art. The intermediate of general formula 28 can be reacted with an acid anhydride in the presence of a base (e.g., TEA, Pyr, etc.) and a suitable solvent (e.g., THF, DCM, etc.). Further information can be found in Organic Letters 2017, 6578. The intermediate of general formula 29 can be partially reduced with a suitable reducing agent (e.g., H2 / Pd / C, etc.) and then reacted with a suitable coupling agent selected from, but not limited to, halo(hetero)aryl, boronic acid, and boronic acid ester in combination with the corresponding Pd or Cu catalyst to obtain the intermediate of general formula 30. Further, the intermediate of general formula 30 can be obtained by N-alkylation, N-acylation, and N-sulfonylation using procedures known to those skilled in the art. Intermediates of general formula 30 can be converted to intermediates of general formula 31 by ester reduction followed by functional group transformation using procedures known to those skilled in the art. Intermediates of general formula 32 can be obtained from intermediate 31 by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.). Furthermore, intermediates of general formula 32 can be obtained from intermediate 31 by N-alkylation and N-sulfonylation using procedures known to those skilled in the art.

[0238] Compounds of the present invention can also be synthesized according to the general procedures outlined in Scheme 7. [ka] Scheme 7: R 1 , R 2 , R 3a , R 10a , and R 10bare all as described for the compounds of the invention and their embodiments and formulas.

[0239] Intermediates of general formula Int-A can be reduced with a suitable reductant (e.g., NH4HCO2 / Pd / C, etc.) in a suitable solvent (e.g., EtOH, HO, etc.) at temperatures increasing from 80 to 100°C. After halogenation with a halogenating agent (e.g., NCS, NBS, etc.), the bicyclic core can be reacted with a suitable coupling agent selected from, but not limited to, boronic acids and boronic esters in combination with a Pd catalyst to give intermediates of general formula Int-E. Intermediates of general formula 33 can be obtained from intermediates of general formula Int-E by saponification followed by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.) followed by deprotection. Alternatively, intermediates of general formula Int-E can be obtained by rearrangement with diphenylphosphoryl azide in the presence of BnOH followed by hydrogenolysis using H and a Pd catalyst to give intermediates of general formula 34. Intermediates of general formula 35 can be obtained from intermediates of general formula 34 by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.) followed by deprotection.

[0240] Compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 8. [ka] Scheme 8: R 1 , R 2 , R 3a , R 10a , and R 10bare all as described for the compounds of the invention and their embodiments and formulae. FGT = functional group transformation.

[0241] Intermediates of general formula Int-A can be reduced with a suitable reductant (e.g., NH4HCO2 / Pd / C, etc.) in a suitable solvent (e.g., EtOH, HO, etc.) at temperatures increasing from 80°C to 100°C. Formylation with a suitable reagent (e.g., POCl3, DMF) can provide intermediates of general formula 36. Intermediates of general formula 36 can be reacted with tosylhydrazine followed by treatment with a suitable coupling agent, such as a boronic acid or boronic ester, to provide intermediates of general formula 37. Functional group transformations of intermediates of general formula 37 can be carried out by methods known to those skilled in the art to provide intermediates of general formula 38. Intermediates of general formula 39 can be obtained from intermediates of general formula 38 by standard peptide coupling conditions in the presence of a coupling agent (e.g., T3P, HATU, EDC.HCl, etc.) and a base (e.g., TEA, DIPEA, etc.) in a polar aprotic solvent (e.g., CHCl, DMF, etc.), or by reaction with an acyl chloride in the presence of a base (e.g., NaHCO3, TEA, DIPEA, etc.) in a suitable solvent (e.g., THF, 1,4-dioxane, etc.), followed by deprotection. Intermediates of general formula 40 can be obtained by reacting intermediates of general formula 39 with formaldehyde in the presence of a suitable reducing agent (e.g., NaCNBH3, NaBH4).

[0242] Compounds of the present invention may also be synthesized according to the general procedures outlined in Scheme 9. [ka] Scheme 9: R 1 , R 2 , R 3a , R 10a , and R 10b are all as described for the compounds of the invention and their embodiments and formulas.

[0243] The ester moiety of intermediates of general formula Int-C can be homologated using procedures known to those skilled in the art to provide compounds of general formula 41. Additionally, Int-C can be alkylated at the alpha position of the ester moiety using an alkylating agent (e.g., alkyl halide or sulfonate) and a suitable base (e.g., LiHMDS, LDA, NaHMDS) and then converted to intermediates of general formula 42 by functional group transformations using procedures known to those skilled in the art. Additionally, the ester moiety of intermediates of general formula Int-C can be reacted with an organometallic reagent such as an alkyl Grignard, followed by reaction with acrylonitrile in sulfuric acid to provide compounds of general formula 43.

[0244] The above general schemes should be considered as non-limiting examples, and it will be appreciated that the compounds of the present invention may be obtained by other methods known to those skilled in the art.

[0245] Abbreviations used herein, particularly in the schemes and examples, are as follows: aq: aqueous solution, ACN: acetonitrile, AcOH: acetic acid, Ac2O: acetic anhydride, BF3.OEt2: boron trifluoride diethyl etherate, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, Boc: tert-butyloxycarbonyl, Boc2O: di-tert-butyl dicarbonate, BzCl: benzoyl chloride, CDI: carbonyldiimidazole, CDCl3: deuterated chloroform, Conc.: concentrated, CoCl2: cobalt(II) chloride, CuI: copper iodide, Cs 2CO3: cesium carbonate, DCM: dichloromethane, DHP: 3,4-dihydropyran, DIPA: diisopropylamine, DIBAL-H: diisobutylaluminum hydride, DIPEA: diisopropylethylamine, DMAP: 4-dimethylaminopyridine, DME: 1,2-dimethoxyethane, DMF: N,N-dimethylformamide, DMF-DMA: N,N-dimethylformamide dimethyl acetal, DMSO: dimethyl sulfoxide, DMSO-d6: deuterated dimethyl sulfoxide, EDC.HCl: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride, EtOH: ethanol, EtOAc: ethyl acetate, Et2O: diethyl ether, Eq: equivalent, FA: formic acid, h: hour, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HCl: hydrogen chloride, HPLC: high performance liquid chromatography, H2SO4: sulfuric acid, IPA: 2-propanol, K2CO3: potassium carbonate, K3PO4: potassium phosphate, LAH: lithium aluminum hydride, LDA: lithium diisopropylamide, LG: leaving group , LHDMS: lithium bis(trimethylsilyl)amide, Ms: mesyl, MsCl: methanesulfonyl chloride, MeOH: methanol, min: minute, MIPA: mono-isopropylamine, NaI: sodium iodide, NaN3: sodium azide, NaCNBH3: sodium cyanoborohydride, NaBH4: sodium borohydride, NaH: sodium hydride, NaHCO3: sodium bicarbonate, Na2SO4: sodium sulfate, n-BuLi: n-butyllithium, NBS: N-bromosuccinimide, NCS: N-chlorosuccinimide, NH2Boc: tert-butylcarbamate, NH2NH2.H2O: hydrazine monohydrate, NH4Cl: ammonium chloride, NiCl2: nickel(II) chloride, Pd / C: palladium on carbon, Pd(OAc)2: palladium(II) acetate, Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, Pet ether: petroleum ether, POCl3: phosphoryl trichloride, PtO2: platinum(IV) oxide, pTSA: p-toluenesulfonic acid, Pyr: pyridine, RF: retention factor, RT: room temperature, sat: saturated, Su: succinimidyl, TBAF: tetra-n-butylammonium fluoride, TEA: triethylamine, t-BuOH: tert-butanol, THF: tetrahydrofuran, THP: tetrahydropyridine nyl, TFA: trifluoroacetic acid, TFAA: trifluoroacetic anhydride, TFE: 2,2,2-trifluoroethan-1-ol, TLC: thin layer chromatography, TMEDA: N,N,N',N'-tetramethylethane-1,2-diamine, TMS: trimethylsilyl, TMSCl: trimethylsilyl chloride, T3P: propanephosphonic anhydride, SPhos: dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, ZnCl2: zinc chloride. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

[0246] These examples are provided for the purpose of illustrating the disclosure and should not be construed in any way as limiting the scope of the disclosure.

[0247] 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 is already well 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.

[0248] Reactions were carried out under an inert atmosphere (mostly argon and N2) if necessary. The number of equivalents of reagents and the amount of solvent used, as well as the reaction temperature and time, may vary slightly between different reactions carried out by similar methods. Workup and purification methods are adapted according to the unique properties of each compound and may vary slightly for similar methods. The yields of the prepared compounds have not been optimized.

[0249] The designation "equivalent" ("eq." or "eq" or "equiv.") means molar equivalent, "RT" or "rt" means room temperature T (23±7°C), "M" is the designation of concentration in mol / l, "sol." means solution, and "conc." means concentrated. Solvent mixture ratios are usually written as volume / volume ratios.

[0250] To carry out reactions under microwave irradiation, a CEM microwave (Discover SP) was used (heating rate: 2-6 °C / s; temperature: 30-300 °C volume-independent infrared (IR) and 80-300 °C fiber optic (FO) temperature measurement; pressure: 0-435 psi, ActiVent™ technology; power: 0-300 W; magnetron frequency: 2450 MHz; reaction stirring: electromagnetic stirring; air cooling: ≥ 25 psi (flow rate 20 L / min); system control: Synergy™ software).

[0251] Key analytical characterizations were performed for all exemplary compounds and selected intermediate products. 1 H-NMR spectroscopy and / or mass spectrometry (MS, [M+H] + and / or [MH] - In certain cases, e.g., when regioisomers and / or diastereomers were or could be formed during the reaction, the chromatograms were optionally determined by, e.g., 13 Additional analyses such as C NMR and NOE (nuclear Overhauser effect) NMR experiments were performed.

[0252] The analytical instruments used were, for example, a BRUKER AVANCE 400 MHz (Topspin software) or a VARIAN MR 400 MHz (VNMRJ software) for NMR analysis. For LC / MS analysis, for example, an Acquity UPLC H-Class, mass: Acquity SQD2 Detector (ESI), Acquity UPLC, mass: Quatro premier XE Detector (ESI), Acquity UPLC, mass: Waters Xevo TQ-S Detector (ESI / ESCI), or Alliance Waters 2695, mass: Quattromicro™ (ESCI) multimode ionization was used. Analytical HPLC was measured, for example, with an Alliance Waters 2695. Analytical SFC was performed, for example, with PIC solution (SFC PIC Lab Online software), WATERS-X5 (MASSLYNX software), or WATERS-UPC2 (Empower).

[0253] 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).

[0254] The structures of exemplary compounds containing stereocenters are depicted and named with absolute stereochemistry, if known. When the absolute stereochemistry is unknown, the compound may be either a racemate, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia 1 and Dia 2 mean that the diastereoisomers have been separated but the stereochemistry is unknown. En 1 and En 2 mean that both enantiomers have been separated 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.

[0255] The LC / MS analyses mentioned in the experimental part were also carried out on an Alliance Waters 2695 HPLC (equipped with a PDA detector) connected to a mass spectrometer Waters Quattromicro (ESCI, multimode ionization) (Method L in the table below).

[0256] Conditions used for HPLC analysis in the experimental part. LC / MS analyses mentioned in the experimental part were performed on an Alliance Waters 2695 HPLC (equipped with a PDA detector) connected to a Waters Quattromicro mass spectrometer (ESCI, multimode ionization). Separation was performed using an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) column, an Acquity BEH C18 (1.7 μm, 2.1 × 100 mm) column, or an X-Bridge C18 (3.5 μm, 4.6 × 75 mm) column, thermostated at 30–35 °C, with the PDA acquisition wavelength set in the range of 210–400 nm (acquisition software: MassLynx) (Method L in the table below). Elution was performed as described in the table below. For Method L1, Solvent A: milliQ water containing 0.05% TFA LC-MS grade. Solvent B: ACN LC-MS grade with 0.05% TFA LC-MS grade. For methods L2, L3, and L4, Solvent A: milliQ water with 0.05% TFA LC-MS grade. Solvent B: ACN LC-MS grade with 0.05% TFA LC-MS grade. For method L5, Solvent A: milliQ water with 5 mM (NH4)HCO3. Solvent B: ACN LC-MS grade. For method L6, Solvent A: milliQ water with 0.05% TFA LC-MS grade. Solvent B: TFA ACN LC-MS grade. Column temperature = 50 °C. For method L7, Solvent A: water with 0.05% TFA LC-MS grade. Solvent B: methanol. Column temperature = 50 °C. For method L8, Solvent A: water with 0.05% FA LC-MS grade. Solvent B: ACN containing 0.05% FA LC-MS grade. Column temperature = 35°C. [Table 2-1] [Table 2-2]

[0257] Conditions used for SFC analysis in the experimental part. The SFC analysis mentioned in the experimental part was performed on a WATERS Acquity UPC2 QDa (Empower-3 software) equipped with an Acquity PDA and an Acquity QDa Detector. Separations were performed using Chiralpak AD-3 (3 μm, 4.6 × 150 mm), Chiralpak IG (5 μm, 4.6 × 150 mm), Chiralpak IG-3 (3 μm, 4.6 × 150 mm), Chiralpak AD-H (5 μm, 4.6 × 250 mm), Chiralcel OJ-3 (3 μm, 4.6 × 150 mm), Chiralpak IA-3 (3 μm, 4.6 × 150 mm), Chiralpak IC-3 (3 μm, 4.6 × 150 mm), (R,R)Whelk-O1 (3.5 μm, 4.6 × 150 mm), or Lux Cellulose-2 (3 μm, 4.6 × 150 mm) columns, CO as the mobile phase, and MeOH as the cosolvent. The columns were thermostated at 30 °C. The elution was carried out as described in the table below. [Table 3-1] [Table 3-2] [Table 3-3]

[0258] Preparative HPLC purifications mentioned in this experimental part were performed using the following systems: Waters 2545 (Empower software, 2996 PDA detector, 2707 autosampler), Gilson (software Trilution, 171 DAD detector, GX-271 autosampler), or Shimadzu (software LC Solution, CMB-20A detector, SIL-10AP autosampler). Separation was performed on a Luna C18 (5 μm, 25 × 150 mm; 5 μm, 19 × 250 mm; 5 μm, 21 × 250 mm; or 10 μm, 25 × 150 mm) column, an X-Bridge C18 (5 μm, 19 × 150 mm; 5 μm, 19 × 250 mm; or 5 μm, 25 × 150 mm) column, an X-Select CSH Phenyl-Hexyl (5 μm, 19 × 250 mm; 5 μm, 21 × 250 mm; or 5 μm, 25 × 150 mm) column, or a YMC-Triart C18 (10 μm, 25 × 150 mm) column. Elution was performed using the columns and solvents listed in the table below. A gradient system for each compound was used with the solvents listed in the table. The detection wavelengths were fixed at 210 and 254 nm. [Table 4-1] [Table 4-2]

[0259] The preparative SFC purifications mentioned in this experimental section were performed using the following system: a Thar SCF-200 (software Chromscope) equipped with a UV / PDA detector and modifier flow injection mode. Separations were performed using Chiralpak AD-H (5 μm, 30 × 250 mm), Chiralpak IG (5 μm, 30 × 250 mm), Chiralpak IA (5 μm, 30 × 250 mm), (R,R)Whelk-O1 (5 μm, 30 × 250 mm), Lux Cellulose-2 (5 μm, 30 × 250 mm), or Lux Cellulose-5 (5 μm, 30 × 250 mm) columns, CO2 as the mobile phase, and MeOH as the cosolvent. The columns were thermostated at 30 °C. The detection wavelength was fixed at 214 nm. Elution was performed as described in the table below. [Table 5-1] [Table 5-2]

[0260] Synthesis of 5-(cyclopropylmethyl)-1H-pyrazol-3-amine (BB-01) [ka] Step 1: To a solution of 2-cyclopropylacetic acid (10 g, 100 mmol) in MeOH (20 mL) was added H2SO4 (0.75 mL) at RT, and the reaction mixture was stirred at 65 °C for 12 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% EtOAc / pet ether, RF: 0.52, TLC detection: UV. The reaction mixture was poured into ice water (100 mL) and extracted with Et2O (2 x 150 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure (10 °C) to give methyl 2-cyclopropylacetate as a colorless liquid (9.0 g, 79%). 1H NMR (400 MHz, CDCl3) δ ppm: 3.69 (s, 3H), 2.23-3.47 (d, 2H), 1.05-1.06 (m, 1H), 0.52-0.57 (m, 2H), 0.13-0.17 (m, 2H).

[0261] Step 2: A solution of ACN (8.29 mL, 158 mmol) in THF (250 mL) was cooled to -78 °C and treated with n-BuLi (2.5 M in hexanes; 60.1 mL, 158 mmol) and stirred for 1 h. Methyl 2-cyclopropylacetate (9.0 g, 79 mmol) was added to the reaction mixture at -40 °C and stirred for 2 h. The pH of the mixture was adjusted to 5 with 1 M HCl and extracted with EtO (2 × 350 mL). The organic layer was concentrated under reduced pressure (10 °C) to give a brown liquid (9 g). This crude product was used in the next step without further purification.

[0262] Step 3: A solution of the crude product (9 g) in EtOH (90 mL) was treated with NH2NH2.H2O (5.75 mL, 118 mmol) and heated at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product (9.0 g), which was purified by normal-phase flash chromatography using an 84 g column (silica) and a gradient of 0-8% MeOH / DCM as eluent to give 5-(cyclopropylmethyl)-1H-pyrazol-3-amine (BB-01) as a brown liquid (7.0 g, 58%, LC / MS 90%). (LC / MS; m / z 138.3 [M+H] + ). This product was used for the preparation of Int-06 without further purification.

[0263] Synthesis of 5-amino-1H-pyrazole-3-carbonitrile (BB-02) [ka] Step 1: To a stirred solution of 5-nitro-1H-pyrazole-3-carboxylic acid (25 g, 159 mmol) in DMF (250 mL) was added CDI (51.6 g, 318 mmol) at RT. After 30 min, 7M NH3 / MeOH (675 mL) was added and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.23, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, washed with EtO2 (400 mL), and dried under reduced pressure to give 5-nitro-1H-pyrazole-3-carboxamide as an off-white solid (25 g, 95%, LC / MS 95%). (LC / MS; m / z 155.2 [M H] - ).

[0264] Step 2: A solution of 5-nitro-1H-pyrazole-3-carboxamide (25 g, 160 mmol) in pyridine (250 mL) was treated with POCl (29.9 mL, 320 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.11, TLC detection: UV. The reaction mixture was diluted with ice water (200 mL), extracted with DCM (2 × 250 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 5-nitro-1H-pyrazole-3-carbonitrile as a brown solid (20 g, LC / MS 78%). (LC / MS; m / z 137.1 [M H] - ). This crude product was used in the next step without further purification.

[0265] Step 3: A solution of 5-nitro-1H-pyrazole-3-carbonitrile (20 g, 145 mmol) in AcOH (200 mL) and HO (40 mL) was treated with zinc powder (47 g, 723 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.27, TLC detection: UV. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 using aqueous NHOH and extracted with EtOAc (2 × 600 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give 5-amino-1H-pyrazole-3-carbonitrile (BB-02) as a yellow solid (7.0 g, LC / MS 55%). (LC / MS; m / z 107.1 [MH] - ). This crude product was used for the preparation of Int-07 without further purification.

[0266] Synthesis of 4-(tert-butyl) 6-ethylpyrazolo[1,5-a]pyrimidine-4,6(7H)-dicarboxylate (Int-01), tert-butyl 6-(((methylsulfonyl)oxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (Int-02), and tert-butyl ((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (Int-03) [ka] Step 1: A solution of 1H-pyrazol-5-amine (40 g, 481 mmol), ethyl 2-formyl-3-oxopropanoate (69.4 g, 482 mmol), and AcOH (57.8 g, 964 mmol) in MeOH (2.4 L) was stirred at RT for 1 h. The reaction mixture was cooled to 10 °C and treated portionwise with NaBH (109.9 g, 2.892 mol) and stirred at RT for 30 min. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.5, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, diluted with HO (800 mL), and extracted with EtOAc (1.5 L). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give 4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (100 g, LC / MS 98%). (LC / MS; m / z 194.1 [M+H] + ). This product was carried on to the next step.

[0267] Step 2: A solution of ethyl 4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (100 g, 518 mmol) in THF (2.5 L) was treated with DMAP (12.6 g, 104 mmol) and BocO (135.5 g, 622 mmol). The reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.5, TLC detection: UV. The reaction mixture was diluted with H2O (1.0 L) and extracted with EtOAc (2.0 L). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (150 g, LC / MS 83%). The crude product was purified by normal-phase flash chromatography using silica gel (60-120 mesh) and a gradient of 0-20% EtOAc / pet ether as eluent to give 4-(tert-butyl) 6-ethylpyrazolo[1,5-a]pyrimidine-4,6(7H)-dicarboxylate (Int-01) as a pale yellow solid (105 g, 68%, LC / MS 96%). (LC / MS; m / z 294.2 [M+H] + ).

[0268] Step 3: A solution of Int-01 (60 g, 205 mmol), DIPA (6.2 g, 61.4 mmol), and CoCl (7.9 g, 61.4 mmol) in EtOH (1.75 L) was treated portionwise with NaBH (93.7 g, 1.229 mol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.12, TLC detection: UV. The reaction mixture was cooled to 0 °C, quenched with H O (1.0 L), diluted with EtOAc (200 mL), and filtered through a pad of Celite. The aqueous layer was separated and extracted with EtOAc (1.3 L). The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure to give the crude product (60 g, LC / MS 70%). The crude product was purified by normal phase flash column chromatography on silica gel (100-200 mesh) using a gradient of 0-70% EtOAc / pet ether as eluent to give tert-butyl 6-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate as a pale yellow gum (40 g, 75%, LC / MS 94%). (LC / MS; m / z 254.3 [M+H] + ).

[0269] Step 4: A solution of tert-butyl 6-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (45 g, 178 mmol) and TEA (27 g, 268 mmol) in DCM (800 mL) was treated with MsCl (24.4 g, 214 mmol). The reaction mixture was stirred at RT for 30 min. The progress of the reaction was monitored by TLC. TLC mobile phase: EtOAc / pet ether, RF: 0.3, TLC detection: UV. The reaction mixture was diluted with aqueous NaHCO3 (500 mL) and extracted with DCM (1.0 L). The organic layer was washed with HO (500 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give tert-butyl 6-(((methylsulfonyl)oxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (Int-02) (45 g, 77%, LC / MS 95%). (LC / MS; m / z 332.2 [M+H] + ). This product was used in the next step without further purification.

[0270] Step 5: A solution of Int-02 (45 g, 136 mmol) and NaN3 (26.5 g, 408 mmol) in DMF (234 mL) and HO (118 mL) was stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.3. TLC detection: UV. The reaction mixture was diluted with HO (300 mL) and extracted with EtOAc (1.0 L). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (45 g, LC / MS 78%). The crude product was purified by normal-phase flash chromatography using silica gel (60-120 mesh) and a gradient of 0-40% EtOAc / pet ether as eluent to give tert-butyl 6-(azidomethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate as a light brown gum (30 g, 80%, LC / MS 96%). (LC / MS; m / z 279.3 [M+H] + ).

[0271] Step 6: A suspension of tert-butyl 6-(azidomethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (30 g, 108 mmol) and Pd / C (10 wt %; 15 g) in MeOH (500 mL) was stirred in a steel bomb under a hydrogen gas atmosphere (50 psi) at room temperature for 1 h. The reaction progress was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.1, TLC detection: UV. The reaction mixture was filtered through a pad of Celite and washed with MeOH (250 mL). The filtrate was concentrated under reduced pressure to give crude tert-butyl 6-(aminomethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (27 g, 95%, LC / MS 92%). (LC / MS; m / z 253.3 [M+H] + ). This product was used in the next step without further purification.

[0272] Step 7: A solution of tert-butyl 6-(aminomethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (11 g, 43.6 mmol) in DCM (100 mL) was treated with HCl (4 M in 1,4-dioxane; 44 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 15% MeOH / DCM, RF: 0.06, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give crude (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine hydrochloride (8.1 g, 100%, LC / MS 95%). (LC / MS; m / z 153.2 [M+H] + ). This product was used in the next step without further purification.

[0273] Step 8: A solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine hydrochloride (8.1 g, 43.1 mmol), TEA (8.9 mL, 64.6 mmol), and BocO (8.9 mL, 38.8 mmol) in THF (170 mL) and MeOH (58 mL) was stirred at RT for 2 h. The reaction progress was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.1, TLC detection: UV. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (80 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (12 g, LC / MS 87%). The crude product was purified by normal-phase flash column chromatography using silica gel (60-120 mesh) and 0-10% MeOH / DCM as the eluent to give tert-butyl ((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (Int-03) as an orange solid (8.0 g, 69%, LC / MS 90%). (LC / MS; m / z 253.2 [M+H] + ). This product was used directly in the next step.

[0274] The following intermediates were prepared in a similar manner to Int-03 (using appropriate reagents and purification methods known to those skilled in the art): Int-06 and Int-07 were prepared from BB-01 and BB-02, respectively. [Table 6]

[0275] Synthesis of 2-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)isoindoline-1,3-dione (Int-09) [ka] Step 1: A solution of tert-butyl 6-(((methylsulfonyl)oxy)methyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (Int-02) (12 g, 36.2 mmol, LC / MS 95%) and potassium phthalimide (8.0 g, 43.5 mmol) in DMF (100 mL) was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.4, TLC detection: UV. The reaction mixture was poured into ice water (250 mL) and the precipitate was collected by filtration. The solid was washed with pet ether and dried under reduced pressure to give crude tert-butyl 6-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (8.0 g, LC / MS 90%). (LC / MS; m / z 383.4 [M+H] + ). This product was used in the next step without further purification.

[0276] Step 2: A solution of tert-butyl 6-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (8.0 g, 20.9 mmol) in DCM (80 mL) was treated with HCl (4 M in 1,4-dioxane; 25 mL) at 0° C. The reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.2, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, and the residue was washed with n-pentane to give crude 2-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)isoindoline-1,3-dione (Int-09) (5.0 g, LC / MS 82%). (LC / MS; m / z 283.3 [M+H] + ). This product was used in the next step without further purification.

[0277] Examples 1-2: Synthesis of (4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine hydrochloride (Compound No. 001) and N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 002) [ka] Step 1: A solution of (Int-03) (500 mg, 1.98 mmol, LC / MS 90%), 1-bromo-4-(trifluoromethyl)benzene (446 mg, 1.98 mmol), and CsCO (1.61 g, 4.95 mmol) in 1,4-dioxane (10 mL) was degassed with argon for 20 minutes. To this mixture was added Pd(dba) (109 mg, 0.11 mmol) and BINAP (148 mg, 0.23 mmol). The reaction mixture was stirred at 100 °C for 19 hours (sealed tube). The progress of the reaction was monitored by TLC. TLC mobile phase: 5% MeOH / DCM, RF: 0.5, TLC detection: UV. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (850 mg). The crude product was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-2% MeOH / DCM as eluent to give tert-butyl ((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (Int-10) as a yellow solid (600 mg, 68%, LC / MS 80%). (LC / MS; m / z 397.2 [M+H] + ).

[0278] Step 2: A solution of Int-10 (600 mg, 1.51 mmol) in DCM (9 mL) was cooled to 0 °C and treated with HCl (4 M in 1,4-dioxane; 18 mL). The reaction mixture was stirred at RT for 20 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.1, TLC detection: UV. The reaction mixture was concentrated under reduced pressure to give crude (4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine hydrochloride (Int-11) as a yellow solid (500 mg, 94%, LC / MS 76%). (LC / MS; m / z 297.2 [M+H] + ). This product was used in the next step without further purification.

[0279] Step 3: A solution of Int-11 (580 mg, 1.74 mmol) and NaHCO3 (439 mg, 5.22 mmol) in 1,4-dioxane (8 mL) and HO (1 mL) was cooled to 0 °C and treated with acryloyl chloride (158 mg, 1.74 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.4, TLC detection: UV. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow gum (640 mg, LC / MS 31%), which was purified by preparative HPLC method H1. The collected fractions were lyophilized to give N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 002) as a white solid (73 mg, 16%, LC / MS 98%). (LC / MS; m / z 351.3 [M+H] +). Chiral SFC purification: 54 mg of Compound No. 002 was purified by preparative SFC method K1 to give Compound No. 002-En1 (14 mg) and Compound No. 002-En2 (9 mg), both as off-white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S1: Compound No. 002-En1, 99.9% ee; Compound No. 002-En2, 99.7% ee.

[0280] The following compounds were prepared in a similar manner to Compound No. 002 (using appropriate reagents and purification methods known to those of skill in the art): Compound No. 003, Compound No. 004, Compound No. 005, Compound No. 006, Compound No. 007, Compound No. 008, Compound No. 009, Compound No. 010, Compound No. 011, Compound No. 012, Compound No. 013, Compound No. 014, Compound No. 015, Compound No. 016, Compound No. 017, Compound No. 018 (XPhos was used instead of BINAP in Step 1), Compound No. Compound No. 019, Compound No. 020, Compound No. 021, Compound No. 022, Compound No. 023 (Xantphos was used instead of BINAP in step 1), Compound No. 024, Compound No. 025 (XPhos was used instead of BINAP in step 1), Compound No. 026 (XPhos was used instead of BINAP in step 1), Compound No. 027 (MsCl and TEA in DCM were used in step 3), and Compound No. 028 (propionic anhydride and TEA in DCM were used in step 3).

[0281] The following single enantiomers were isolated in a similar manner (using appropriate purification methods known to those of skill in the art) as Compound No. 002-En1 and Compound No. 002-En2: Compound No. 003-En1 (97.6% ee), Compound No. 003-En2 (93.9% ee), Compound No. 004-En1 (99.9% ee), Compound No. 004-En2 (99.9% ee), Compound No. 005-En1 (99.9% ee), Compound No. 005-En2 (99.9% ee), Compound No. 006-En1 (99.9% ee), Compound No. 006-En2 (99.3% ee), Compound No. 006-En3 (99.9% ee), Compound No. 006-En4 (99.3% ee). Compound No. 008-En1 (99.9% ee), Compound No. 008-En2 (98.9% ee), Compound No. 009-En1 (99.9% ee), Compound No. 009-En2 (99.9% ee), Compound No. 010-En1 (99.8% ee), Compound No. 010-En2 (99.8% ee), Compound No. 011-En1 (99.9% ee), Compound No. 011-En2 (99.9% ee), Compound No. 012-En1 (99.6% ee), Compound No. 012-En2 (99.8% ee), Compound No. 013-En1 (99.9% ee), Compound No. 0 13-En2 (99.5% ee), Compound No. 014-En1 (99.8% ee), Compound No. 014-En2 (95.6% ee), Compound No. 015-En1 (99.4% ee), Compound No. 015-En2 (99.8% ee), Compound No. 016-En1 (99.9% ee), Compound No. 016-En2 (99.7% ee), Compound No. 017-En1 (99.3% ee), Compound No. 017-En2 (98.1% ee), Compound No. 018-En1 (94.7% ee), Compound No. 018-En2 (99.2% ee), Compound No. 019-En 1 (99.9% ee), Compound No. 019-En2 (99.3% ee), Compound No. 020-En1 (99.9% ee), Compound No. 020-En2 (99.9% ee), Compound No. 021-En1 (99.8% ee), Compound No. 021-En2 (96.6% ee), Compound No. 022-En1 (99.8% ee), Compound No. 022-En2 (99.7% ee), Compound No. 023-En1 (99.9% ee), Compound No. 023-En2 (99.8% ee), Compound No. 024-En1 (97.8% ee), Compound No. 024-En2 (98.3% ee), Compound No. 026-En1 (94.4% ee), Compound No. 026-En2 (91.9% ee), Compound No. 028-En1 (99.9% ee), Compound No. 028-En2 (99.9% ee).

[0282] The following compounds were prepared in a similar manner to Compound No. 002 (using appropriate reagents and purification methods known to those of skill in the art): Compound No. 029 (from Int-04), Compound No. 030 (from Int-04; XPhos was used instead of BINAP in step 1), Compound No. 031 (from Int-05), Compound No. 032 (from Int-06), Compound No. 033 (from Int-07), Compound No. 034 (from Int-08), Compound No. 035 (from Int-08), Compound No. 098, Compound No. 099, Compound No. 133, Compound No. 131, Compound No. 135, and Compound No. 146.

[0283] The following single enantiomers were isolated in a similar manner (using appropriate purification methods known to those of skill in the art) as Compound No. 002-En1 and Compound No. 002-En2: Compound No. 029-En1 (99.9% ee), Compound No. 029-En2 (99.9% ee), Compound No. 030-En1 (99.9% ee), Compound No. 030-En2 (99.8% ee), Compound No. 031-En1 (97.4% ee), Compound No. 031-En2 (92.6% ee), Compound No. 032-En1 (96.8% ee), Compound No. 032-En2 (94.5% ee), Compound No. 033-En1 (99.9% ee), Compound No. 033-En2 (96.7% ee), Compound No. 034-En1 (99.6% ee). , Compound No. 034-En2 (99.3% ee), Compound No. 035-En1 (99.9% ee), Compound No. 035-En2 (99.1% ee), Compound No. 107-EN1 (98.6% ee), Compound No. 107-EN2 (99.4% ee), Compound No. 108-EN1 (99.9% ee), Compound No. 108-EN2 (99.9% ee), Compound No. 143-EN1 (99.9% ee), Compound No. 143-EN2 (99.4% ee), Compound No. 142-EN1 (99.6% ee), Compound No. 142-EN3 (99.9% ee), Compound No. 142-EN4 (99.4% ee), Compound No. 144-EN1 (99.8% ee), and Compound No. 144-EN2 (99.6% ee).

[0284] Example 3: Synthesis of N-((4-(4-ethynylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 036) [ka] Step 1: This step was carried out in a similar manner to Step 1 towards Compound No. 002 (using appropriate reagents and purification methods known to one of skill in the art). Int-03 (1.0 g, 3.96 mmol, LC / MS 90%) gave a crude product (1.5 g, LC / MS 11%) which was purified by normal phase flash column chromatography using a 24 g column (silica) and a gradient of 0-50% EtOAc / pet ether as eluent to give tert-butyl ((4-(4-((trimethylsilyl)ethynyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a yellow gum (550 mg, 19%, LC / MS 52%). (LC / MS; m / z 425.4 [M+H] + ).

[0285] Step 2: A solution of tert-butyl ((4-(4-((trimethylsilyl)ethynyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (550 mg, 1.29 mmol) in THF (10 mL) was treated with TBAF (1 M in THF; 2.59 mL) and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.3, TLC detection: UV. The reaction mixture was diluted with EtOAc (25 mL) and washed with HO (10 mL) and brine (10 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give a crude brown gum (600 mg, LC / MS 49%). The crude product was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-50% EtOAc / pet ether as eluent to give tert-butyl ((4-(4-ethynylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a brown gum (200 mg, 68%, LC / MS 81%). (LC / MS; m / z 353.3 [M+H] + ).

[0286] Step 3: A solution of tert-butyl ((4-(4-ethynylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (150 mg, 0.42 mmol) in TFE (4 mL) was cooled to 0 °C, treated with TMSCl (139 mg, 1.22 mmol), and stirred at RT for 1 h. The reaction progress was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.01, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, washed with EtO (2 × 20 mL), and dried under reduced pressure to give (4-(4-ethynylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine hydrochloride as a pale yellow solid (100 mg, 29%, LC / MS 29%). (LC / MS; m / z 253.2 [M+H] + ). This product was used in the next step without further purification.

[0287] Step 4: This step was carried out in a similar manner to Step 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). (4-(4-ethynylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine hydrochloride (100 mg, 0.34 mmol) gave a crude product (110 mg, LC / MS 27%), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-(4-ethynylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 036) as a white solid (9 mg, 29%, LC / MS 99%). (LC / MS; m / z 307.4 [M+H] + ).

[0288] Example 4: Synthesis of N-((4-cyclohexyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 037) [ka] Step 1: A solution of Int-03 (1.0 g, 3.96 mmol) in DMF (20 mL) was cooled to 0 °C and treated in small portions with NaH (60% dispersion in mineral oil; 190 mg, 7.92 mmol). After stirring at 0 °C for 10 min, the solution was treated with 3-bromocyclohex-1-ene (702 mg, 4.36 mmol). The reaction mixture was stirred at RT for 16 h. The progress of the reaction mixture was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.47, TLC detection: UV. The reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown oil (1.2 g, LC / MS 27%). The crude product was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-30% EtOAc / pet ether as eluent to give tert-butyl ((4-(cyclohex-2-en-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a brown gum (200 mg, 11%, LC / MS 67%). (LC / MS; m / z 333.3 [M+H] + ).

[0289] Step 2: A suspension of tert-butyl ((4-(cyclohex-1-en-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (170 mg, 0.51 mmol) and Pd / C (10 wt%; 60 mg) in MeOH (10 mL) was stirred under a hydrogen atmosphere (balloon pressure) at RT for 4 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.44, TLC detection: UV. The reaction mixture was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give tert-butyl ((4-cyclohexyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a light brown gum (120 mg, 76%, LC / MS 73%). (LC / MS; m / z 335.4 [M+H] +).

[0290] Steps 3-4: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((4-cyclohexyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (120 mg, 0.36 mmol) gave a crude product (75 mg, LC / MS 58%), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-cyclohexyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 037) as an off-white solid (16 mg, 21%, LC / MS 98%). (LC / MS; m / z 289.4 [M+H] + ).

[0291] Example 5: Synthesis of N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)propiolamid (Compound No. 038) [ka] Step 1: A solution of Int-11 (250 mg, 0.75 mmol, LC / MS 76%), DIPEA (0.52 mL, 3.01 mmol), and propiolic acid (0.056 mL, 0.90 mmol) in DCM (5 mL) and THF (5 mL) was treated with T3P (50 wt % in EtOAc) (0.33 mL, 1.13 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.65, TLC detection: UV. The reaction mixture was diluted with HO (40 mL) and extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a brown gum (250 mg, LC / MS 62%). The crude product was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)propiolamide (Compound No. 038) as a white solid (68 mg, 34%, LC / MS 99%). (LC / MS; m / z 349.1 [M+H] + ).

[0292] The following compounds were prepared in a similar manner to Compound No. 038 (using appropriate reagents and purification methods known to those of skill in the art): Compound No. 039, Compound No. 040, Compound No. 041, Compound No. 121, Compound No. 122, Compound No. 123, and Compound No. 149.

[0293] Chiral SFC purification of Compound No. 039: 250 mg of the racemic product was purified by preparative SFC method K3 to give Compound No. 137 (50 mg) and Compound No. 132 (65 mg), both as white solids. The chiral purity of both enantiomers was assessed by analytical SFC method K3: Compound No. 137, 97.0% ee; Compound No. 132, 94.6% ee.

[0294] The following single enantiomers were isolated in a similar manner (using appropriate purification methods known to those skilled in the art) to Compound No. 137 and Compound No. 132: Compound No. 138-EN1 (99.8% ee), Compound No. 138-EN2 (99.8% ee).

[0295] Example 6: Synthesis of 2-cyano-N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acetamide (Compound No. 042) [ka] Step 1: A solution of Int-11 (200 mg, 0.60 mmol, LC / MS 76%) and DIPEA (0.42 mL, 2.41 mmol) in DCM (5 mL) was treated with succinimidyl cyanoacetate (132 mg, 0.72 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.63, TLC detection: UV. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (270 mg, LC / MS 74%). The crude product was purified by preparative HPLC method H3. The collected fractions were lyophilized to give 2-cyano-N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acetamide (Compound No. 042) as a white solid (101 mg, 60%, LC / MS 99%). (LC / MS; m / z 364.1 [M+H] + ).

[0296] Examples 7-8: Synthesis of N-(cyanomethyl)-N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acetamide (Compound No. 043) and N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)prop-2-yn-1-amine (Compound No. 044) [ka] Step 1: A solution of Int-11 (400 mg, 1.20 mmol, LC / MS 76%) and DIPEA (0.42 mL, 2.41 mmol) in ACN (16 mL) was cooled to 0 °C and treated with 2-bromoacetonitrile (0.08 mL, 1.20 mmol). The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.58, TLC detection: UV. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (300 mg, LC / MS 61%). The crude product was purified by normal-phase flash column chromatography using a 40 g column (silica) and a gradient of 0-8% MeOH / DCM as eluent to afford 2-(((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)amino)acetonitrile as a pale yellow gum (170 mg, 54%, LC / MS 98%). (LC / MS; m / z 336.2 [M+H] + ).

[0297] Step 2: A solution of 2-(((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)amino)acetonitrile (170 mg, 0.50 mmol) and TEA (0.21 mL, 1.52 mmol) in DCM (6 mL) was cooled to 0 °C and treated with AcO (0.073 mL, 0.76 mmol). The reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.64, TLC detection: UV. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (200 mg, LC / MS 82%). The crude product was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-(cyanomethyl)-N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acetamide (compound number 043) as a white solid (31 mg, 16%, LC / MS 99%). (LC / MS; m / z 378.3 [M+H] + ).

[0298] Step 3: A solution of Int-11 (200 mg, 0.60 mmol, LC / MS 76%) and DIPEA (0.21 mL, 1.20 mmol) in ACN (8 mL) was cooled to 0 °C and treated with 3-bromoprop-1-yne (0.05 mL, 0.60 mmol). The reaction mixture was stirred at RT for 5 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.76, TLC detection: UV. The reaction mixture was diluted with HO (40 mL) and extracted with DCM (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (90 mg, LC / MS 54%). The crude product was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)prop-2-yn-1-amine (Compound No. 044) as an off-white solid (115 mg, 75%, LC / MS 99%). (LC / MS; m / z 335.2 [M+H] + ).

[0299] Example 9: Synthesis of N-((4-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 045) [ka] Step 1: A solution of Int-03 (500 mg, 1.98 mmol, LC / MS 90%), TEA (601 mg, 5.95 mmol), and DMAP (24 mg, 0.19 mmol) in DCM (10 mL) was treated with 4-(trifluoromethyl)benzenesulfonyl chloride (728 mg, 2.97 mmol). The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.25, TLC detection: UV. The reaction mixture was diluted with HO (60 mL) and extracted with DCM (100 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give a brown gum (1.1 g, LC / MS 77%). The crude product was purified by normal phase flash column chromatography using a 12 g column (silica) and a gradient of 0-50% EtOAc / pet ether as eluent to give tert-butyl ((4-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a pale yellow solid (600 mg, 69%, LC / MS 94%). (LC / MS; m / z 461.1 [M+H] + ).

[0300] Steps 2-3: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((4-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (600 mg, 1.30 mmol) gave a crude product (626 mg, LC / MS 87%), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 045) as a white solid (220 mg, 44%, LC / MS 99%). (LC / MS; m / z 415.2 [M+H] +). Chiral SFC purification: 200 mg of Compound No. 045 was purified by preparative SFC method K2 to give Compound No. 045-En1 (48 mg) and Compound No. 045-En2 (58 mg), both as white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S16: Compound No. 045-En1, 99.9% ee; Compound No. 045-En2, 97.5% ee.

[0301] Example 10: Synthesis of N-((4-(cyclohexanecarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 046) [ka] Step 1: A solution of Int-03 (1.0 g, 3.96 mmol, LC / MS 90%) and DIPEA (1.5 g, 11.90 mmol) in DCM (15 mL) was treated with cyclohexanecarbonyl chloride (0.87 g, 5.95 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.18, TLC detection: UV. The reaction mixture was diluted with H2O (70 mL) and extracted with DCM (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown gum (1.4 g, LC / MS 94%). The crude product was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-50% EtOAc / pet ether as eluent to give tert-butyl ((4-(cyclohexanecarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a light brown gum (1.2 g, 89%, LC / MS 96%). (LC / MS; m / z 363.2 [M+H] + ).

[0302] Steps 2-3: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((4-(cyclohexanecarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (400 mg, 1.10 mmol) gave a crude product (360 mg, LC / MS 78%), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-(cyclohexanecarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 046) as a white solid (165 mg, 49%, LC / MS 99%). (LC / MS; m / z 317.3 [M+H] + ). Chiral SFC purification: 145 mg of Compound No. 046 was purified by preparative SFC method K3 to give Compound No. 046-En1 (33 mg) and Compound No. 046-En2 (40 mg), both as white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S17: Compound No. 046-En1, 97.7% ee; Compound No. 046-En2, 82.6% ee.

[0303] The following compound was prepared in a similar manner to Compound No. 046 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 047 (using DCM with BzCl and TEA in Step 1).

[0304] Example 11: Synthesis of N-((4-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 048) [ka] Step 1: A solution of Int-09 (2.5 g, 8.86 mmol, LC / MS 82%), DIPEA (5.7 g, 44.32 mmol), and 1-(bromomethyl)-4-(trifluoromethyl)benzene (2.1 g, 8.86 mmol) in ACN (25 mL) was stirred at 90 °C for 16 h. The reaction progress was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.3, TLC detection: UV. The reaction mixture was diluted with HO (100 mL) and extracted with DCM (200 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give a brown solid (2.5 g, LC / MS 33%). The crude product was purified by normal-phase flash column chromatography using a 40 g column (silica) and a gradient of 0-40% EtOAc / pet ether as eluent to give 2-((4-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)isoindoline-1,3-dione as a colorless gum (450 mg, 13%, LC / MS 93%). (LC / MS; m / z 441.3 [M+H] + ).

[0305] Step 2: A solution of 2-((4-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)isoindoline-1,3-dione (450 mg, 1.02 mmol) in EtOH (5 mL) was treated with hydrazine monohydrate (256 mg, 5.10 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The progress of the reaction was monitored by TLC. TLC mobile phase: 10% MeOH / DCM, RF: 0.16, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ACN (10 mL). The precipitated solid was isolated by filtration, washed with ACN (5 mL), and the filtrate was concentrated under reduced pressure to give (4-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine (280 mg, 82%, LC / MS 87%). (LC / MS; m / z 311.4 [M+H] +). This crude product was used in the next step without further purification.

[0306] Step 3: This step was carried out in a similar manner to Step 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). 4-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methanamine (150 mg, 0.48 mmol) gave a crude product (160 mg, LC / MS 67%), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give N-((4-(4-(trifluoromethyl)benzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 048) as an off-white solid (19 mg, 12%, LC / MS 99%). (LC / MS; m / z 365.4 [M+H] + ).

[0307] The following compounds were prepared in a similar manner to Compound No. 048 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 049, Compound No. 050 (using propionyl chloride and TEA in DCM in step 3), Compound No. 051 (using MsCl and TEA in DCM in step 3), Compound No. 052, Compound No. 053 (using propionyl chloride and TEA in DCM in step 3), Compound No. 054 (using MsCl and TEA in DCM in step 3), Compound No. 126 (using 1-(chloromethyl)-4-fluorobenzene and DIPEA in ACN in step 1), and Compound No. 127 (using 1-chloro-4-(chloromethyl)benzene and DIPEA in ACN in step 1).

[0308] Chiral SFC purification of Compound No. 049: 50 mg of the racemic product was purified by preparative SFC method K4 to give Compound No. 049-En1 (15 mg) and Compound No. 049-En2 (13 mg), both as light brown solids. The chiral purity of both enantiomers was assessed by analytical SFC method S1: Compound No. 049-En1, 99.8% ee; Compound No. 049-En2, 99.8% ee.

[0309] Example 12: Synthesis of N-((4-(cyclohexylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl)methyl)acrylamide (Compound No. 055) [ka] Step 1: A solution of Int-03 (500 mg, 1.98 mmol, LC / MS 90%), cyclohexanecarbaldehyde (333 mg, 2.97 mmol), and AcOH (238 mg, 3.96 mmol) in MeOH (10 mL) was stirred at RT for 16 h. The reaction mixture was treated with NaCNBH (375 mg, 5.95 mmol) at 0 °C and stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.3, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, diluted with H2O (80 mL), and extracted with EtOAc (120 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a black gum (700 mg, LC / MS 79%). The crude product was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-40% EtOAc / pet ether as eluent to give tert-butyl ((4-(cyclohexylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a light brown gum (600 mg, 81%, LC / MS 84%). (LC / MS; m / z 349.3 [M+H] + ).

[0310] Steps 2-3: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((4-(cyclohexylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (500 mg, 1.43 mmol) gave a crude product (270 mg, LC / MS 86%), which was purified by preparative HPLC method H2. The collected fractions were lyophilized to give N-((4-(cyclohexylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl)methyl)acrylamide (Compound No. 055) as a colorless gum (90 mg, 24%, LC / MS 99%). (LC / MS; m / z 303.3 [M+H] + ). Chiral SFC purification: 60 mg of Compound No. 055 was purified by preparative SFC method K5 to give Compound No. 055-En1 (29 mg) and Compound No. 055-En2 (29 mg), both as white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S18: Compound No. 055-En1, 99.8% ee; Compound No. 055-En2, 99.6% ee.

[0311] Example 13: Synthesis of N-((4-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 056) [ka] Step 1: A DMF solution (20 mL) of Int-03 (300 mg, 1.19 mmol, LC / MS 90%), K2CO3 (493 mg, 3.56 mmol), (3-chloroprop-1-yn-1-yl)benzene (269 mg, 1.78 mmol), and NaI (534 mg, 3.56 mmol) was stirred at 50 °C for 16 h. The reaction progress was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.15, TLC detection: UV. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a pale yellow solid (250 mg, LC / MS 12%). The crude product was purified by normal-phase flash column chromatography using a 40 g column (neutral alumina) and a gradient of 0-60% EtOAc / pet ether as eluent to give tert-butyl ((4-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a pale yellow gum (100 mg, 20%, LC / MS 79%). (LC / MS; m / z 367.3 [M+H] + ).

[0312] Steps 2-3: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((4-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (100 mg, 0.27 mmol) gave a crude product (80 mg, LC / MS 39%), which was purified by preparative HPLC method H3. The collected fractions were lyophilized to give N-((4-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 056) as a white solid (9 mg, 13%, LC / MS 99%). (LC / MS; m / z 321.4 [M+H] + ).

[0313] The following compound was prepared in a similar manner to Compound No. 056 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 057 (using propargyl bromide in Step 1).

[0314] Example 14: Synthesis of N-((3-bromo-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 058) [ka] Step 1: A solution of Int-10 (250 mg, 0.63 mmol, LC / MS 80%) in DCM (5.0 mL) was cooled to 0 °C and treated with NBS (135 mg, 0.75 mmol). The reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.63, TLC detection: UV. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (300 mg, LC / MS 80%), which was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-60% EtOAc / pet ether as eluent to give tert-butyl ((3-bromo-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a yellow gum (200 mg, 73%, LC / MS 88%). (LC / MS; m / z 475.3 [M+H] + ).

[0315] Steps 2-3: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((3-bromo-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (200 mg, 0.421 mmol) gave a crude product (160 mg, LC / MS 70%), which was purified by preparative HPLC method H4. The collected fractions were lyophilized to give N-((3-bromo-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 058) as a white solid (21 mg, 13%, LC / MS 99%). (LC / MS; m / z 429.2 [M+H] + ).

[0316] The following compounds were prepared in a similar manner to Compound No. 058 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 141 (using Selectfluor and aqueous NaHCO3 in DMF in Step 1) and Compound No. 152 (using NCS in DCM in Step 1).

[0317] Chiral SFC purification of Compound No. 141: 156 mg of the racemic product was purified by preparative SFC method xx to give Compound No. 145-EN1 (36 mg) and Compound No. 145-EN2 (44 mg), both as pale yellow semi-solids. The chiral purity of both enantiomers was assessed by analytical SFC method K14: 145-EN1, 99.9% ee; 145-EN2, 97.9% ee.

[0318] Example 15: Synthesis of N-((3-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 059) [ka] Step 1: A solution of Int-03 (1.0 g, 3.96 mmol, LC / MS 90%), 3-phenylpropioaldehyde (1.03 g, 7.93 mmol), and ZnCl (1 M in THF; 11.9 mL, 11.89 mmol) in MeOH (15 mL) was treated portionwise with NaCNBH (747 mg, 11.89 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.4, TLC detection: UV. The reaction mixture was diluted with H O (20 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous Na SO and concentrated under reduced pressure to a brown gum (1.5 g, LC / MS 16%). The crude product was purified by normal phase flash column chromatography using a 24 g column (silica) and a gradient of 0-35% EtOAc / pet ether as eluent to give tert-butyl ((3-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate as a brown gum (320 mg, 19%, LC / MS 76%). (LC / MS; m / z 367.3 [M+H] + ).

[0319] Steps 2-3: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl ((3-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (300 mg, 0.819 mmol) gave a crude product (250 mg, LC / MS 62%), which was purified by preparative HPLC method H5. The collected fractions were lyophilized to give N-((3-(3-phenylprop-2-yn-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide (Compound No. 059) as an off-white solid (54 mg, 27%, LC / MS 99%). (LC / MS; m / z 321.4 [M+H] + ).

[0320] Examples 16-17: Synthesis of 4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-amine hydrochloride (Compound No. 060) and N-(4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)acrylamide (Compound No. 061) [ka] Step 1: A mixture of 6-bromopyrazolo[1,5-a]pyrimidine (2.0 g, 10.1 mmol), Cs2CO3 (18.4 g, 56.6 mmol), and tert-butyl carbamate (5.67 g, 48.5 mmol) in 1,4-dioxane (80 mL) was degassed with argon for 20 minutes. To this mixture was added Pd2(dba)3 (1.85 g, 2.02 mmol) and XPhos (2.65 g, 5.55 mmol). The reaction mixture was stirred at 120 °C for 16 hours (sealed tube). The reaction progress was monitored by TLC. TLC mobile phase: 30% EtOAc / pet ether, RF: 0.4, TLC detection: UV. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a black gum (2.5 g). The crude product was purified by normal-phase flash column chromatography using a 48 g column (silica) and a gradient of 0-10% EtOAc / pet ether as eluent to give tert-butyl pyrazolo[1,5-a]pyrimidin-6-ylcarbamate as a yellow solid (900 mg, 28%, LC / MS 75%). (LC / MS; m / z 235.3 [M+H] + ).

[0321] Step 2: A solution of tert-butyl pyrazolo[1,5-a]pyrimidin-6-ylcarbamate (900 mg, 3.84 mmol) in EtOH (200 ml) was treated with NaBH (1.31 g, 34.6 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.2, TLC detection: UV. The reaction mixture was diluted with H O (200 mL) and extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na SO and concentrated under reduced pressure to give a black gum (700 mg). The crude product was purified by normal-phase flash column chromatography using a 48 g column (silica) and a gradient of 0-60% EtOAc / pet ether as eluent to give tert-butyl (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)carbamate as a yellow solid (350 mg, 49%, LC / MS 95%). (LC / MS; m / z 239.3 [M+H] + ).

[0322] Step 3: This step was carried out in a similar manner to Step 1 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)carbamate (100 mg, 0.42 mmol) gave a crude product (150 mg, LC / MS 48%), which was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-60% EtOAc / pet ether as the eluent to give tert-butyl (4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)carbamate as an off-white solid (70 mg, 40%, LC / MS 89%). (LC / MS; m / z 383.3 [M+H] + ).

[0323] Steps 4-5: These steps were carried out in a similar manner to Steps 2 and 3 towards Compound No. 002 (using appropriate reagents and purification methods known to those skilled in the art). tert-Butyl (4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)carbamate (68 mg, 0.18 mmol) gave a crude product (32 mg, LC / MS 75%), which was purified by preparative HPLC method H5. The collected fractions were lyophilized to give N-(4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)acrylamide (Compound No. 061) as an off-white solid (18 mg, 34%, LC / MS 99%). (LC / MS; m / z 337.3 [M+H] + ). Chiral SFC purification: 50 mg of Compound No. 061 was purified by preparative SFC method K6 to give Compound No. 061-En1 (24 mg) and Compound No. 061-En2 (24 mg), both as off-white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S22: Compound No. 061-En1, 99.8% ee; Compound No. 061-En2, 99.6% ee.

[0324] The following compounds were prepared in a similar manner to Compound No. 061 (using appropriate reagents and purification methods known to one of skill in the art): Compound No. 062 (using propionic anhydride and TEA in DCM in step 5), Compound No. 063, Compound No. 064, Compound No. 065, Compound No. 066, and Compound No. 067 (using MsCl and TEA in DCM in step 5).

[0325] The following single enantiomers were isolated in a similar manner (using appropriate purification methods known to those skilled in the art) to Compound No. 061-En1 and Compound No. 061-En2: Compound No. 064-En1 (99.9% ee), Compound No. 064-En2 (99.8% ee), Compound No. 065-En1 (99.9% ee), Compound No. 065-En2 (99.9% ee).

[0326] Synthesis of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (Int-13) and 6-bromo-2-methyl-2H-pyrazolo[4,3-b]pyridine (Int-14) [ka] Step 1: To a solution of DMF-DMA (2.7 mL, 20.2 mmol) in anhydrous DMF (10 mL) was added 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 5.05 mmol). The reaction mixture was stirred at 90 °C for 2 h (sealed tube). The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 40 g column (silica) and a gradient of 10-80% EtOAc / pet ether as eluent to afford 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (Int-13) (642 mg, 60%) and 6-bromo-2-methyl-2H-pyrazolo[4,3-b]pyridine (Int-14) (312 mg, 29%), both as off-white solids. (LC / MS; m / z 212.2 [M+H] + ). Int-13: 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.58 (s, 2H), 8.31 (s, 1H), 4.07 (s, 3H);Int-14: 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.72 (s, 1H), 8.54 (d, 1H), 8.43 (dd, 1H), 4.22 (s, 3H).

[0327] Example 18: Synthesis of N-((1-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)acrylamide (Compound No. 068) [ka] Step 1: A reaction tube was charged with Int-13 (1.1 g, 5.19 mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (1.6 g, 6.75 mmol), KPO (7.9 g, 36.1 mmol), Pd(OAc) (60 mg, 0.27 mmol), and SPhos (220 mg, 0.53 mmol). The tube was purged with argon, and a mixture of argon-sparged t-BuOH (9 mL) and water (9 mL) was added. The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was filtered, diluted with water, and extracted with DCM (2 × 30 mL). The organic layer was washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 40 g column (silica) and a gradient of 0-7% MeOH / DCM as eluent to give tert-butyl ((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (1.3 g, 95%). (LC / MS; m / z 263.2 [M+H] + ).

[0328] Step 2: To a mixture of tert-butyl ((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (1.35 g, 5.15 mmol) in EtOH (48 mL) was added PtO (117 mg, 0.51 mmol) and HSO (0.72 mL, 12.9 mmol). The reaction mixture was stirred under a hydrogen atmosphere (4 bar) at RT for 16 h. The reaction mixture was filtered through a pad of Celite and partially concentrated. Saturated NaHCO solution (50 mL) was added and the mixture was extracted with DCM (3 × 50 mL). The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 25 g column (silica) and a gradient of 0-15% MeOH / DCM as eluent to give tert-butyl ((1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (220 mg, 16%). (LC / MS; m / z 211.3 [M-tBu+H] + ).

[0329] Step 3: A reaction tube was charged with tert-butyl ((1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (74 mg, 0.28 mmol), Cs2CO3 (136 mg, 0.42 mmol), 1-bromo-4-(trifluoromethyl)benzene (40 μL, 0.28 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), and SPhos (21 mg, 0.05 mmol). The flask was purged with argon, and argon-sparged 1,4-dioxane (2.6 mL) was added to the flask. The reaction mixture was stirred at 95 °C for 20 h. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 20-100% EtOAc / pet ether as eluent to give tert-butyl ((1-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (59 mg, 52%). (LC / MS; m / z 411.4 [M+H] + ).

[0330] Step 4-5: To a mixture of tert-butyl ((1-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (263 mg, 0.64 mmol) in 1,4-dioxane (2.5 mL) was added a solution of 4 M HCl (2.5 mL, 10 mmol) in 1,4-dioxane. This mixture was stirred at RT for 16 h. The mixture was concentrated and dissolved in DCM (6.5 mL). To this solution was added TEA (0.269 mL, 1.92 mmol) followed by acryloyl chloride (0.071 mL, 0.83 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM (20 mL) and washed with 0.1 M HCl solution (15 mL), saturated NaHCO solution (15 mL), and brine (10 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-7% MeOH / DCM as eluent to afford N-((1-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)acrylamide (Compound No. 068) as an off-white solid (155 mg, 65%). (LC / MS; m / z 365.3 [M+H] + ).

[0331] The following compounds were prepared from Int-13 in a similar manner to Compound No. 068 by using appropriate reagents and purification methods known to one of skill in the art: Compound No. 070, Compound No. 072 (using propionyl chloride and TEA in DCM in step 5), Compound No. 074 (using propionyl chloride and TEA in DCM in step 5), Compound No. 076 (using MsCl and TEA in DCM in step 5), Compound No. 078 (using MsCl and TEA in DCM in step 5).

[0332] The following compounds were prepared from Int-14 in a similar manner to Compound No. 068 by using appropriate reagents and purification methods known to one of skill in the art: Compound No. 069, Compound No. 071, Compound No. 073 (using propionyl chloride and TEA in DCM in step 5), Compound No. 075 (using propionyl chloride and TEA in DCM in step 5), Compound No. 077 (using MsCl and TEA in DCM in step 5), Compound No. 079 (using MsCl and TEA in DCM in step 5).

[0333] Synthesis of tert-butyl ((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (Int-15) [ka] Step 1: A stirred solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (5.0 g, 25.3 mmol) and 3,4-dihydro-2H-pyran (4.61 mL, 50.5 mmol) in THF (120 mL) was treated with pTSA (0.434 g, 2.53 mmol). The reaction mixture was stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 20% EtOAc / pet ether, RF: 0.6, TLC detection: UV. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown solid (6.5 g, LC / MS 76%). The crude product was purified by normal-phase flash column chromatography using an 80 g column (silica) and a gradient of 10-13% EtOAc / pet ether as eluent to give 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.6 g, 74%, LC / MS 94%). (LC / MS; m / z 282.0 [M+H] + ).

[0334] Step 2: A mixture of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (5.6 g, 19.9 mmol), KPO (12.6 g, 59.5 mmol), and Sphos (0.815 g, 1.99 mmol) in t-BuOH (75 mL) and HO (75 mL) was degassed with argon for 10 minutes. To this mixture was added Pd(OAc) (0.446 g, 1.99 mmol) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (6.115 g, 25.8 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The progress of the reaction was monitored by TLC. TLC mobile phase: 30% EtOAc / pet ether, RF: 0.35, TLC detection: UV. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (200 mL). The filtrate was washed with HO (100 mL), and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a brown solid (6.5 g, LC / MS 56%). The crude product was purified by normal-phase flash column chromatography using an 80 g column (silica) and a gradient of 0-15% EtOAc / pet ether as eluent to give tert-butyl ((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate as a brown solid (3.5 g, 45%, LC / MS 81%). (LC / MS; m / z 333.5 [M+H] + ).

[0335] Step 3: A stirred mixture of tert-butyl ((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (3 g, 9.03 mmol) and NiCl2.6H2O (2.14 g, 9.03 mmol) in MeOH (50 mL) was treated with NaBH4 (2.39 g, 63.3 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h. After 1 h, NiCl2.6H2O (0.5 eq) and NaBH4 (5 eq) were added at 0 °C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with HO (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a 55:45 mixture of product and starting material. The crude mixture was dissolved in MeOH (50 mL) and treated with NiCl.6H0 (0.5 eq) and NaBH (5 eq), and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.4, TLC detection: UV. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with H0 (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give crude tert-butyl ((1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate as a brown solid (2.9 g, LC / MS 52%). (LC / MS; m / z 337.4 [M+H] + ). This crude product was used in the next step without further purification.

[0336] Step 4: A solution of tert-butyl ((1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (2.9 g, 8.62 mmol), Cs2CO3 (7.0 g, 21.55 mmol), 1-bromo-4-(trifluoromethyl)benzene (1.455 mL, 10.34 mmol), and XPhos (0.411 g, 0.862 mmol) in 1,4-dioxane (80 mL) was degassed with argon for 10 minutes. To this mixture was added Pd2(dba)3 (0.474 g, 0.517 mmol). The reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.51, TLC detection: UV. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with HO (100 mL), and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a brown solid (3.5 g, LC / MS 56%). The crude product was purified by normal-phase flash column chromatography using a 40 g column (silica) and a gradient of 0 to 30% EtOAc / pet ether as the eluent to give tert-butyl ((1-(tetrahydro-2H-pyran-2-yl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6yl)methyl)carbamate as a brown solid (1.9 g, 82%, LC / MS 93%). (LC / MS; m / z 481.3 [M+H] + ).

[0337] Step 5: A solution of tert-butyl ((1-(tetrahydro-2H-pyran-2-yl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (1.9 g, 3.95 mmol) in MeOH (70 mL) was treated with pTSA (0.376 g, 1.98 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 50% EtOAc / pet ether, RF: 0.36, TLC detection: UV. The reaction mixture was concentrated, diluted with H2O (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown solid (1.85 g, LC / MS 80%). The crude product was triturated with n-pentane to give tert-butyl ((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (Int-15) as a brown solid (1.70 g, 99%, LC / MS 85%). (LC / MS; m / z 397.5 [M+H] + ).

[0338] Synthesis of tert-butyl ((2-(3-carbamoylbenzyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (Int-16) and tert-butyl ((1-(3-carbamoylbenzyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (Int-17) [ka] Step 1: To a mixture of Int-15 (130 mg, 0.33 mmol, LC / MS 85%) and K2CO3 (114 mg, 0.82 mmol) in DMF (3.5 mL) was added 3-(bromomethyl)benzamide (80 mg, 0.36 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with HO (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, 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 0-7% MeOH / DCM as eluent to give tert-butyl ((2-(3-carbamoylbenzyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (Int-16) (55 mg, 37%, LC / MS 99%) and tert-butyl ((1-(3-carbamoylbenzyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate (Int-17) (43 mg, 29%, LC / MS 99%). (LC / MS; m / z 530.2 [M+H] + ).

[0339] Example 19: Synthesis of 3-((6-(acrylamidomethyl)-4-(4-(trifluoromethyl)-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-2-yl)methyl)benzamide (Compound No. 081) [ka] Steps 1-2: These steps were carried out in a similar manner to Steps 4 and 5 towards Compound No. 068 (using appropriate reagents and purification methods known to one of ordinary skill in the art). Int-16 (55 mg, 0.10 mmol) gave a crude product (53 mg, LC / MS 94%) which was purified by normal-phase flash column chromatography using a 12 g column (silica) and a gradient of 0-10% MeOH / DCM as eluent to give 3-((6-(acrylamidomethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-2-yl)methyl)benzamide (Compound No. 081) as a white solid (22 mg, 43%, LC / MS 99%). (LC / MS; m / z 484.3 [M+H] + ).

[0340] The following compound was prepared from Int-16 in a similar manner to Compound No. 081 by using appropriate reagents and purification methods known to one of skill in the art: Compound No. 083 (using propionyl chloride and DIPEA in DCM in Step 2).

[0341] The following compounds were prepared from Int-17 in a similar manner to Compound No. 081 by using appropriate reagents and purification methods known to one of skill in the art: Compound No. 080 and Compound No. 082 (using propionyl chloride and DIPEA in DCM in Step 2).

[0342] Examples 20 to 21: Synthesis of N-((1-(difluoromethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)acrylamide (Compound No. 084) and N-((2-(difluoromethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-6-yl)methyl)acrylamide (Compound No. 085) [ka] Step 1: A solution of Int-15 (1.75 g, 4.42 mmol) in DMF (50 mL), CsCO (5.75 g, 17.66 mmol), and sodium 2-chloro-2,2-difluoroacetate (2.69 g, 17.66 mmol) was stirred at 120 °C for 16 h. The reaction progress was monitored by TLC. TLC mobile phase: 40% EtOAc / pet ether, RF: 0.45 and 0.39, TLC detection: UV. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give a brown solid (1.8 g, LC / MS 40% and 36%). The crude product was purified by normal phase flash column chromatography using a 40 g column (silica) and a gradient of 0-25% EtOAc / pet ether as eluent to give a mixture of tert-butyl ((1-(difluoromethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate and tert-butyl ((1-(difluoromethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)carbamate as a brown solid (1.5 g, LC / MS 34% and 62%). (LC / MS; m / z 447.4 [M+H] + ). This mixture of regioisomers was used in the next step without further purification.

[0343] Steps 2-3: These steps were carried out in a similar manner to Steps 4 and 5 towards Compound No. 068 (using appropriate reagents and purification methods known to those skilled in the art). The regioisomeric mixture (1.5 g, 3.36 mmol) gave crude product (1.3 g, LC / MS 81%), which was purified by preparative HPLC method H6. The collected fractions were lyophilized to give N-((1-(difluoromethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl)acrylamide (Compound No. 084) (224 mg, 17%, LC / MS 99%) and N-((2-(difluoromethyl)-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-6-yl)methyl)acrylamide (Compound No. 085) (235 mg, 18%, LC / MS 99%), both as white solids. (LC / MS; m / z 401.2 [M+H] + ).

[0344] Chiral SFC purification: 254 mg of Compound No. 084 was purified by preparative SFC method K7 to give Compound No. 084-En1 (91 mg) and Compound No. 084-En2 (91 mg), both as off-white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S25: Compound No. 084-En1, 99.7% ee; Compound No. 084-En2, 99.4% ee.

[0345] Chiral SFC purification: 265 mg of Compound No. 085 was purified by preparative SFC method K8 to give Compound No. 085-En1 (96 mg) and Compound No. 085-En2 (94 mg), both as white solids. The chiral purity of both enantiomers was assessed by analytical SFC method S24: Compound No. 085-En1, 99.6% ee; Compound No. 085-En2, 87.4% ee.

[0346] Examples 22-23: Synthesis of 3-bromo-5-(4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)-4,5-dihydroisoxazole (Compound No. 086-Dia1 and Compound No. 086-Dia2) [ka] Step 1: A mixture of Int-01 (20 g, 68.2 mmol), Pd / C (10 wt%; 21.8 g), and ammonium formate (43 g, 681.8 mmol) in EtOH (1.6 L) was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.3, TLC detection: UV. The reaction mixture was filtered through a pad of Celite and washed with EtOH (100 mL). The filtrate was concentrated under reduced pressure, diluted with HO (300 mL), and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 4-(tert-butyl) 6-ethyl 6,7-dihydropyrazolo[1,5-a]pyrimidine-4,6(5H)-dicarboxylate as an off-white solid (18 g, 90%, LC / MS 97%). (LC / MS; m / z 296.2 [M+H] + ). This product was used in the next step without further purification.

[0347] Step 2: A solution of 4-(tert-butyl)6-ethyl 6,7-dihydropyrazolo[1,5-a]pyrimidine-4,6(5H)-dicarboxylate (18 g, 61.0 mmol) in DCM (250 mL) was treated with HCl (4 M in 1,4-dioxane; 21.2 mL) at 0 °C. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: EtOAc, RF: 0.09, TLC detection: UV. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with n-pentane (2 × 5 mL). The solid was isolated by filtration and dried under reduced pressure to give ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxylate hydrochloride (10.8 g, 79%) as an off-white solid. 1 H NMR (400 MHz, CDCl) δ ppm: 7.05-7.06 (d, 1H), 6.09 (s, 1H), 5.17 (s, 1H), 4.25-4.31 (m, 1H), 4.08-4.15 (q, 4H), 3.56-3.90 (s, 1H), 3.30-3.37 (m, 1H), 1.49 (s, 3H). This product was used in the next step without further purification.

[0348] Step 3: A solution of ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 21.6 mmol), 1-bromo-4-(trifluoromethyl)benzene (5.8 g, 25.9 mmol), CsCO (14.0 g, 43.2 mmol), and XPhos (1.23 g, 2.59 mmol) in 1,4-dioxane (45 mL) was degassed with argon for 10 minutes. To this mixture was added Pd(dba) (1.19 g, 1.30 mmol), and the reaction mixture was stirred at 100 °C for 16 hours (sealed tube). The reaction progress was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.52, TLC detection: UV. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a brown gum (5.5 g). The crude product was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-50% EtOAc / pet ether as eluent to give ethyl 4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxylate (Int-18) as an off-white solid (3.9 g, 51%, LC / MS 97%). (LC / MS; m / z 340.1 [M+H] + ).

[0349] Step 4: A DCM solution (10 mL) of Int-18 (500 mg, 1.47 mmol, LC / MS 97%) was treated with DIBAL-H (1 M in heptane; 2.06 mL, 2.06 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.29, TLC detection: UV. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with DCM (80 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbaldehyde as an off-white solid (325 mg, LC / MS 51%). (LC / MS; m / z 296.3 [M+H] + ). This crude product was used in the next step without further purification.

[0350] Step 5: A solution of methyltriphenylphosphonium bromide (472 mg, 1.32 mmol) and K2CO3 (228 mg, 1.65 mmol) in DME (8 mL) was stirred at RT for 1 h. To this solution was added 4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carbaldehyde (325 mg, 1.10 mmol) dissolved in DME (2 mL). The reaction mixture was stirred at 80 °C for 3 h. The progress of the reaction was monitored by TLC. TLC mobile phase: 70% EtOAc / pet ether, RF: 0.82, TLC detection: UV. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a brown solid (350 mg, LC / MS 45%). The crude product was purified by normal-phase flash column chromatography using silica gel (100-200 mesh) and a gradient of 0-50% EtOAc / pet ether as eluent to give 4-(4-(trifluoromethyl)phenyl)-6-vinyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine as a pale yellow solid (130 mg, 72%, LC / MS 91%). (LC / M...

Claims

1. Formula I: 【Chemistry 1】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Y is N, and Y １ is N and Y ２ is CR ３ａ And Y ３ is CR ２ Is it; or Y is N, and Y １ is N and Y ２ is CR ３ａ And Y ３ is N; or Y is N, and Y １ is N and Y ２ is CH, and Y ３ is N; or Y is N, and Y １ is N and Y ２ is CH, and Y ３ is CR ２ Is it; or Y is N, and Y １ is CR ３ａ And Y ２ is N and Y ３ is CR ２ Is it; or Y is N, and Y １ is CR ３ａ And Y ２ is N and Y ３ is N; or Y is N, and Y １ is CR ３ａ And Y ２ is CH, and Y ３ is CR ２ Is it; or Y is N, and Y １ is CR ３ａ And Y ２ is CH, and Y ３ is N; or Y is C, and Y １ is NR ３ｂ And Y ２ is N and Y ３ is CR ２ Is it; or Y is C, and Y １ is NR ３ｂ And Y ２ is N and Y ３ is N; or Y is C, and Y １ is NR ３ｂ And Y ２ is CH, and Y ３ is CR ２ Is it; or Y is C, and Y １ is NR ３ｂ And Y ２ is CH, and Y ３ is N; or Y is C, and Y １ is N and Y ２ is NR ３ｃ And Y ３ is CR ２ Is it; or Y is C, and Y １ is N and Y ２ is NR ３ｃ And Y ３ is N; or Y is C, and Y １ is N and Y ２ is CH, and Y ３ is CR ２ Is it; or Y is C, and Y １ is N and Y ２ is CH, and Y ３ is N; R １ teeth, (i) hydrogen, (ii)-C(=O)Z ２ (iii)S(O) ２ ﺺ ２ 、 (iv) unsubstituted or substituted C １ -C ６ Alkyl, where one or more of the substituents are (a) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents is (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 (wherein one or more of the substituents is (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 (Independently selected from the group consisting of: (c) C ２ -C ６ Alkynyl Independently selected from the group consisting of: (v) unsubstituted or substituted C ６ -C １０ Aryl, wherein one or more of the substituents are (a) a halogen, (b) cyano, (c) C １ -C ６ Alkyl, (d) unsubstituted or substituted C ３ -C ６ Cycloalkyl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (Independently selected from the group consisting of: (e) C １ -C ６ Haloalkyl, (f) unsubstituted or substituted C １ -C ６ alkyl, where one or more substituents are independently selected from the group consisting of halogen and alcohol; (g)-OZ １ 、 (h)-SZ １ 、 (i)-SF ５ , and (j) unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of Independently selected from the group consisting of: (vi) Unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more of the substituents is (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 、 (g) oxo, and (h) unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of Independently selected from the group consisting of: (vii) unsubstituted or substituted C ３ -C ６ Cycloalkyl, where one or more of the substituents are (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 Independently selected from the group consisting of: (viii) unsubstituted or substituted C ３ -C ６ A heterocycle, wherein one or more of the substituents are (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) oxo Independently selected from the group consisting of: (ix)-S(=O) ２ Z ２ , and (x)-C(=O)Z ２ selected from the group consisting of: R ２ teeth, (i) hydrogen, (ii) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are independently unsubstituted or substituted C ６ -C １０ aryl, where one or more of the substituents are C １ -C ６ haloalkyl); (iii) a halogen, and (iv) unsubstituted or substituted C １ -C ６ Alkynyl, wherein one or more of the substituents are (a) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents is (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 (independently selected from the group consisting of: (b) Unsubstituted or substituted C ３ -C ６ Cycloalkyl (wherein one or more of the substituents is (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 (independently selected from the group consisting of Independently selected from the group consisting of: (v) unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ haloalkyl) selected from the group consisting of: R ３ａ , R ３ｂ , and R ３ｃ teeth, (i) hydrogen, (ii) unsubstituted or substituted C １ -C ６ Alkyl, where one or more of the substituents are cyano, C ３ -C ６ Cycloalkyl, and unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ Independently selected from the group consisting of (iii) C ３ -C ６ Cycloalkyl are independently selected from the group consisting of: R ４ , R ５ , R ８ , and R ９ is hydrogen and C １ -C ６ independently selected from the group consisting of alkyl; R ６ teeth, (i)-(CH ２ ) ｍ -NR １０ａ R １０ｂ 、 (ii) -C(=O)NZ ３ Z ４ , and (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more of the substituents is (a) C １ -C ６ Alkyl, (b)-C(=O)Z ２ (c)-C(=O)OZ ２ 、 (d)-C(=O)NZ ３ Z ４ 、 (e)-S(=O) ２ Z ２ 、 (f) -S(=O) ２ New Zealand ３ Z ４ , and (g) selected from the group consisting of halogens; (iv)-CH ２ -C(=O)OH is selected from the group consisting of R ７ teeth, (i) hydrogen, and (ii) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl) or R ６ and R ７ together with the carbons to which they are attached form an unsubstituted or substituted 4-8 membered heterocycle, where one or more of the substituents is １ -C ６ Alkyl, -C(=O)Z ２ , -S(=O) ２ Z ２ and oxo); m is 0 or 1; R １０ａ teeth, (i)-C(=O)Z ２ (ii)-C(=O)OZ ２ 、 (iii)-C(=O)NZ ３ Z ４ 、 (iv)-S(=O) ２ Z ２ 、 (v)-S(=O) ２ NZ ３ Z ４ 、 (vi)-S(=O)(=NZ ５ )Z ２ 、 (vii)-S(=NZ ５ )(=NZ ６ )Z ２ 、 ( ) ( ) ( ) ( ) ( ) ５ )!: ３ : ４ (ix)-CH ２ -C(=O)OH (x) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl); and (xi) unsubstituted or substituted C ２ -C ６ alkenyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z １ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ and -C(=O)OZ ２ (independently selected from the group consisting of selected from the group consisting of: R １０ａ and R １０ｂ together with the nitrogen to which they are attached form an unsubstituted or substituted 4-8 membered heterocyclic ring; R １０ｂ teeth, (i) hydrogen, and (ii) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents is cyano, OZ １ , and C ２ -C ６ alkynyl) selected from the group consisting of: Each Z １ teeth, (i) hydrogen, (ii) C １ -C ６ Alkyl, (iii) unsubstituted or substituted C ２ -C ６ alkenyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z １ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4-8 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 are independently selected from the group consisting of: Each Z ２ teeth, (i) Unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl); (ii) unsubstituted or substituted C ２ -C ６ alkenyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z １ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4- to 8-membered heterocycle, -OZ １ , -C(=O)OZ ３ (Independently selected from the group consisting of: (iii) C ２ -C ６ Alkynyl, (iv) C ３ -C ６ Cycloalkyl, (v) C ３ -C ６ Cycloalkenyl, (vi) C １ -C ６ Haloalkyl, (vii) unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of: (viii) unsubstituted or substituted C ３ -C ６ Cycloalkyl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of are independently selected from the group consisting of: Each Z ３ and Z ４ teeth, (i) hydrogen, (ii)-S(=O) ２ Z ２ 、 (iii) unsubstituted or substituted C １ -C ６ Alkyl, where one or more of the substituents are (a) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents is (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 (wherein one or more of the substituents is (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 (Independently selected from the group consisting of: (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents is (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) Independently selected from the group consisting of: (iii) C ２ -C ６ Alkenyl, (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 are independently selected from the group consisting of: Each Z ５ and Z ６ teeth, (i) hydrogen, (ii) C １ -C ６ Alkyl, and (iii) C ３ -C ６ Cycloalkyl are independently selected from the group consisting of:

2. Formula II: 【Chemistry 2】 or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein Y is N, and Y １ is N and Y ２ is CR ３ａ or Y is N, and Y １ is CR ３ａ And Y ２ is N; or Y is C, and Y １ is NR ３ｂ And Y ２ is N; or Y is C, and Y １ is N and Y ２ is NR ３ｃ and R １ teeth, (i) hydrogen, (ii)-C(=O)Z ２ (iii)S(O) ２ ﺺ ２ 、 (iv) unsubstituted or substituted C １ -C ６ Alkyl, where one or more of the substituents are (a) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents is (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 (wherein one or more of the substituents is (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 (Independently selected from the group consisting of: (c) C ２ -C ６ Alkynyl Independently selected from the group consisting of: (v) unsubstituted or substituted C ６ -C １０ Aryl, wherein one or more of the substituents are (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 、 (')-SZ １ 、 (h)-SF ５ , and (i) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of Independently selected from the group consisting of: (vi) Unsubstituted or substituted 5- to 9-membered heteroaryl, wherein one or more of the substituents is (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 、 (g) oxo, and (h) unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of Independently selected from the group consisting of: (vii) unsubstituted or substituted C ３ -C ６ Cycloalkyl, where one or more of the substituents are (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 Independently selected from the group consisting of: (viii) unsubstituted or substituted C ３ -C ６ A heterocycle, wherein one or more of the substituents are (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) oxo Independently selected from the group consisting of: (ix)-S(=O) ２ Z ２ , and (x)-C(=O)Z ２ selected from the group consisting of: R ２ teeth, (i) hydrogen, (ii) C １ -C ６ Alkyl, (iii) a halogen, and (iv) unsubstituted or substituted C １ -C ６ Alkynyl, wherein one or more of the substituents are (a) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents is (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 (independently selected from the group consisting of: (b) Unsubstituted or substituted C ３ -C ６ Cycloalkyl (wherein one or more of the substituents is (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 (independently selected from the group consisting of Independently selected from the group consisting of is selected from the group consisting of R ３ａ , R ３ｂ , and R ３ｃ teeth, (i) hydrogen, (ii) unsubstituted or substituted C １ -C ６ Alkyl, where one or more of the substituents are cyano, C ３ -C ６ Cycloalkyl, and unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ Independently selected from the group consisting of (iii) C ３ -C ６ Cycloalkyl are independently selected from the group consisting of: R ４ , R ５ , R ８ , and R ９ is hydrogen and C １ -C ６ independently selected from the group consisting of alkyl; R ６ teeth, (i)-(CH ２ ) ｍ -NR １０ａ R １０ｂ 、 (ii) -C(=O)NZ ３ Z ４ , and (iii) an unsubstituted or substituted 4- to 8-membered heterocycle, wherein one or more of the substituents is (a) C １ -C ６ Alkyl, (b)-C(=O)Z ２ (c)-C(=O)OZ ２ 、 (d)-C(=O)NZ ３ Z ４ 、 (e)-S(=O) ２ Z ２ 、 (f) -S(=O) ２ New Zealand ３ Z ４ , and (g) halogens. is selected from the group consisting of R ７ teeth, (i) hydrogen, and (ii) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl) or R ６ and R ７ together with the carbons to which they are attached form an unsubstituted or substituted 4-8 membered heterocycle, where one or more of the substituents is １ -C ６ Alkyl, -C(=O)Z ２ , -S(=O) ２ Z ２ and oxo); m is 0 or 1; R １０ａ teeth, (i)-C(=O)Z ２ (ii)-C(=O)OZ ２ 、 (iii)-C(=O)NZ ３ Z ４ 、 (iv)-S(=O) ２ Z ２ 、 (v)-S(=O) ２ NZ ３ Z ４ 、 (vi)-S(=O)(=NZ ５ )Z ２ 、 (vii)-S(=NZ ５ )(=NZ ６ )Z ２ 、 (viii)-S(=O)(=NZ ５ ) New Zealand ３ Z ４ , and (ix) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl) selected from the group consisting of: R １０ｂ teeth, (i) hydrogen, and (ii) unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl) selected from the group consisting of: Each Z １ teeth, (i) hydrogen, (ii) C １ -C ６ Alkyl, (iii) unsubstituted or substituted C ２ -C ６ alkenyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z １ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4-8 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 are independently selected from the group consisting of: Each Z ２ teeth, (i) Unsubstituted or substituted C １ -C ６ Alkyl (wherein one or more of the substituents are cyano and C ２ -C ６ alkynyl); (ii) unsubstituted or substituted C ２ -C ６ alkenyl (wherein one or more of the substituents is cyano, -S(=O) ２ Z １ , -S(=O) ２ New Zealand ３ Z ４ , halogen, -NZ ３ Z ４ , 4-8 membered heterocycles, (iii) C ２ -C ６ Alkynyl, (iv) C ３ -C ６ Cycloalkyl, (v) C ３ -C ６ Cycloalkenyl, (vi) C １ -C ６ Haloalkyl, (vii) unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of: (viii) unsubstituted or substituted C ３ -C ６ Cycloalkyl (wherein one or more of the substituents are halogen, C １ -C ６ Alkyl, and C １ -C ６ Haloalkyl, and -OZ １ (independently selected from the group consisting of are independently selected from the group consisting of: Each Z ３ and Z ４ teeth, (i) hydrogen, (ii)-S(=O) ２ Z ２ 、 (iii) unsubstituted or substituted C １ -C ６ Alkyl, where one or more of the substituents are (a) Unsubstituted or substituted C ６ -C １０ Aryl (wherein one or more of the substituents is (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 (wherein one or more of the substituents is (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 (Independently selected from the group consisting of: (c) unsubstituted or substituted 5- to 9-membered heteroaryl, where one or more of the substituents is (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) Independently selected from the group consisting of: (iv) C ２ -C ６ Alkenyl, (v) C ２ -C ６ Alkynyl, (vi) C ３ -C ６ Cycloalkyl, (vii) C ３ -C ６ Cycloalkenyl, and (viii) C １ -C ６ Haloalkyl are independently selected from the group consisting of: Each Z ５ and Z ６ teeth, (i) hydrogen, (ii) C １ -C ６ Alkyl, and (iii) C ３ -C ６ Cycloalkyl are independently selected from the group consisting of:

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

4. R ３ａ 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. Formula IV: 【Chemistry 4】 3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

6. R ３ｂ is hydrogen and C １ -C ６ 6. The compound of any one of claims 1, 2, or 5, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein the compound is selected from the group consisting of alkyl, aryl, arylsulfates, arylalkyl, arylsulfates, and arylsulfates.

7. Formula V: 【Chemistry 5】 3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

8. R ３ｃ is hydrogen and C １ -C ６ 10. The compound of any one of claims 1, 2, or 7, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein the compound is selected from the group consisting of alkyl.

9. R ６ is -(CH ２ ) ｍ -NR １０ａ R １０ｂ and m is 1; R ７ is hydrogen, R １０ｂ The compound of any one of claims 1 to 8, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein is hydrogen.

10. R １０ａ is -C(=O)Z ２ 10. The compound of any one of claims 1 to 9, wherein:

11. Z ２ is unsubstituted or substituted C ２ -C ６ alkenyl, one or more of the substituents being halogen, -NZ ３ Z ４ 11. The compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, wherein each of the rings is independently selected from the group consisting of: , 4-6 membered heterocycle.

12. Z ２ is unsubstituted C ２ -C ６ 12. The compound of claim 11, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, which is alkenyl.

13. R １ is unsubstituted or substituted C ６ -C １０ 13. The compound of any one of claims 1 to 12, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, which is aryl.

14. R １ is unsubstituted or substituted phenyl, one or more of the substituents being halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, and -OZ １ 14. The compound of claim 13, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, independently selected from the group consisting of:

15. Y ３ is nitrogen, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

16. N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (S)—N-((2-methyl-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (S)—N-((4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; (R)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide; and (S)—N-((4-(4-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)acrylamide 16. The compound of claim 15, selected from the group consisting of: or a tautomer, pharma- ceutically acceptable salt, or solvate thereof.

17. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

18. A compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17 for use as a medicament.

19. A compound according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17, for use in the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human.

20. The compound of any one of claims 1 to 16, or the pharmaceutical composition of claim 17, wherein the YAP / TAZ-TEAD activation-mediated disorder is selected from the group comprising cancer, fibrosis, and YAP / TAZ-TEAD activation-mediated congenital disorder.

21. The compound of any one of claims 1 to 16, or the pharmaceutical composition of claim 17, wherein the YAP / TAZ-TEAD activation mediated disorder is selected from lung cancer, breast cancer, head and neck cancer, esophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer (including but not limited to cholangiocarcinoma), skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesothelioma, and / or sarcoma.

22. The YAP / TAZ-TEAD activation mediated disorders include acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, craniopharyngioma, cyst adenocarcinoma, and sarcoma. Cancer, diffuse large B-cell lymphoma, hyperproliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell carcinoma, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphangioendothelial sarcoma, Lymphangiosarcoma, Lymphoblastic leukemia, Lymphoma (Hodgkin's and non-Hodgkin's), Malignant diseases and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, Lymphoid malignancies of T-cell or B-cell origin, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Mesothelioma, Multiple myeloma, Myeloid leukemia, Myeloma, Myxosarcoma, Neuroblastoma, NUT midline carcinoma (NMC), Non-small cell lung carcinoma, Oligodendroglioma, Oral cancer, Osteosarcoma, Papillary adenocarcinoma, Breast The compound according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17, selected from capitis carcinoma, pinealoma, polycythemia vera, rectal carcinoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, small cell lung carcinoma, solid tumors (carcinoma and sarcoma), small cell lung carcinoma, gastric carcinoma, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid carcinoma, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

23. A method for the prevention or treatment of a YAP / TAZ-TEAD activation mediated disorder in an animal, mammal or human, comprising administering to said animal, mammal or human in need of such prevention or treatment an effective dose of a compound according to any one of claims 1 to 16.

24. 24. The method of treating or preventing a YAP / TAZ-TEAD activation mediated disorder according to claim 23 in combination with one or more other medicaments selected from the group consisting of an EGFR inhibitor, a MEK inhibitor, an AXL inhibitor, a B-RAF inhibitor, and a RAS inhibitor, for a patient in need thereof.

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