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

FIELD OF THE INVENTION

The present disclosure relates to novel compounds. The present disclosure also relates to the compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, such as, for example, for the prevention or treatment of cancer or fibrosis. Methods for the prevention or treatment of the diseases comprising the use of the novel compounds are also disclosed herein.

The present disclosure furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds, as well as to the compositions or preparations for use as a medicine, for example for the prevention or treatment of diseases mediated by 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 OF THE INVENTION

Hippo signaling is critical to restrict organ size through inactivation of the YAP/TAZ-TEAD transcriptional complex. In several aggressive solid cancers, Hippo signaling is inactivated through loss-of-function mutations or deletions in the genes encoding the upstream regulators (e.g. NF2, MST1/2 or LATS1/2), unleashing constitutive YAP/TAZ-TEAD transcriptional activity leading to unbridled tumor growth and metastasis. Knock-out, knockdown or pharmacologic inactivation of YAP/TAZ-TEAD is sufficient to impair YAP/TAZ-TEAD 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.

The main physiologic function of the Hippo pathway is to restrict tissue growth in adult tissue and modulate cell proliferation, differentiation and migration in developing organs. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators and DNA-binding partners. In mammals, the Ste20-like kinases, MST1/2 (homologs of Drosophila Hippo) phosphorylate and activate Large Tumor Suppressor 1/2 (LATS1/2). NF2 is a scaffold for the core Hippo kinases, promoting LATS1/2 activation by tethering MST1/2 to LATS1/2 (Lallemand et al., 2003, Genes Dev., 17, 1090-1100; Zhang et al., 2010, Dev. Cell, 19(1), 27-38). The LATS kinases will in turn phosphorylate and inactivate two highly homologous transcriptional co-activators: Yes-associated Protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ) by cytoplasmic sequestration via 14-3-3 and by ubiquitin-mediated degradation induced by β-TRCP E3 ligase. When the Hippo pathway is inactive, YAP and TAZ translocate in the nucleus to bind to the TEAD transcription factor family to induce expression of a specific signature promoting matrix remodeling, cell proliferation, survival and migration. TEAD1-4 can also bind to VGLL4 in the nucleus and act as a transcriptional repressor. VGLL4 is not structurally related to YAP/TAZ, but competes with YAP/TAZ based on a partially overlapping binding site on TEAD (Johnson et al., 2014, Nat. Rev. Drug Discov., 13, 63-79).

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

In fruit flies, loss of function of Hippo or Warts kinases (MST1/2 or LATS1/2 in mammals), or overexpression of Yorkie (the Drosophila homolog of YAP and TAZ), results in a dramatic overgrowth of the cuticle, as a result of dysregulated cell proliferation and resistance to apoptosis, leading to increased organ size. In mice, YAP overexpression, loss of MST1/2 or LATS1/2 kinase activities, or loss of NF2 leads to TEAD target gene up-regulation and progenitor cell expansion, resulting in liver and cardiac overgrowth and ultimately cancer formation in the liver, the small intestine and in skin. In contrast, a serine to alanine mutation at position 94 in YAP, that is unable to bind to TEAD, is not oncogenic (Zhao et al., 2008, Genes Dev., 22, 1962-1971). Likewise, a dominant-negative TEAD mutant that is unable to bind DNA, overcomes YAP-driven liver tumorigenesis. In addition, NF2 mutant liver carcinoma was greatly suppressed by heterozygous loss of Yap (Zhang et al., 2010, Dev. Cell, 19, 27-38). Finally, verteporfin, a small molecule that inhibits YAP-TEAD association significantly suppressed the oncogenic activity of YAP in these models (Liu-Chittenden et al., 2012, Genes Dev., 26, 1300-1305).

Gene amplification of YAP1 (encoding for YAP) and WWTR1 (encoding for 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 cancer and YAP/TAZ promote the acquisition of several important cancer cell phenotypes, such as proliferation, resistance to apoptosis, invasion, and immune-suppression (e.g. by attracting myeloid derived suppressor cells (Wang et al., 2016, Cancer Discov., 6, 80-95)). In addition, gene fusions with YAP1 have been identified in several cancer types including ependymomas, vascular cancers, cervical carcinomas and porocarcinomas, which results in constitutive activation of YAP-TEAD, and are oncogenic in mice (Szulzewsky et al., 2020, Genes Dev., 34: 1-14). In addition, several germline or somatic mutations in components of the Hippo pathway associated with various cancer types have been discovered in targeted and whole-genome sequencing studies. The best studied example is the NF2 locus, mutated with a high frequency in neurofibromatosis. Loss of NF2 and LATS2 are also frequently observed in schwannomas. Another tumor type that is commonly (in about 70% of all cases) associated with constitutive YAP-TEAD activation through genetic inactivation of NF2, LATS1/2, MST1/2 or SAV1, is malignant mesothelioma (Bueno et al., 2016, Nat Genet 48, 407-416). Recent studies have shown that several mesothelioma cell lines with NF2 loss-of-function mutations exhibit a decrease in YAP phosphorylation and an increase in YAP-TEAD reporter activity. The YAP-TEAD transcription and viability of NF2 mutant mesothelioma cell lines (but not WT mesothelioma) are sensitive to YAP siRNA (an effect which can be rescued by overexpression of siRNA resistant YAP) and to treatment with verteporfin, a YAP antagonist (Zhang et al., 2017, J. Cell Mol. Med., 21: 2663-2676).

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

In summary, YAP/TAZ activation has been shown to drive tumorigenesis and YAP/TAZ is hyperactivated in many different types of cancer in humans (often through loss-of-function mutations in upstream negative regulators). Genetic deletion or pharmacologic inhibition of YAP/TAZ has been shown to suppress tumor development and progression in different types of cancer. Therefore, it is believed that deregulation of the Hippo tumor suppressor pathway is a major event in the development of a wide range of cancer types and malignancies. Hence, pharmacological targeting of the Hippo cascade through inhibition of YAP, TAZ, TEAD, and/or the YAP/TAZ-TEAD protein-protein interaction would be a valuable approach for the treatment of cancers that harbor functional alterations of this pathway.

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

Neurofibromatosis type 2 is characterized by nervous system tumors including schwannomas, meningiomas, and ependymomas. Neurofibromatosis type 2 is an inheritable disorder caused by the inactivation of NF2 (Striedinger et al., 2008, Neoplasia 10, 1204-1210). Loss of NF2 leads to constitutive activation of YAP/TAZ-TEAD. The Sturge-Weber syndrome is a congenital eurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. The Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ which leads to activation of YAP/TAZ-TEAD transcription (Shirley et al., 2013, NEJM, 368, 1971-1979). Therefore, several congenital disorders, characterized by constitutive YAP/TAZ-TEAD activation could be treated with inhibitors of YAP/TAZ-TEAD.

A few publications describe inhibitors of the YAP-TEAD transcriptional activation. Inventiva highlighted YAP-TEAD protein-protein interaction inhibitors in WO 2020/070181, WO2018/185266, and WO 2017/064277. The General Hospital Corporation, Boston described autopalmitoylation inhibitors in WO 2017/053706. Vivace Therapeutics, Inc. disclosed non-fused tricyclic (WO 2018/204532), benzosulfonyl (WO2019/040380), benzocarbonyl (WO 2019/113236), oxadiazole (WO 2019/222431), and bicyclic (WO 2020/097389) compounds that modulate the interaction between YAP/TAZ and TEAD. The Regents of the University of California and Vivace Therapeutics, Inc. described tricyclic compounds that inhibit the Hippo-YAP signaling pathway in WO 2013/188138 and WO 2017/058716, respectively. Kyowa Hakko Kirin Co., Ltd. revealed alpha,beta-unsaturated amide compounds that display anti-cancer activity in WO 2018/235926 and US 2019/0010136. Genentech, Inc. disclosed carboxamide and sulfonamide derivatives useful as inhibitors of the YAP-TEAD protein-protein interaction in WO2019/232216 and WO 2020/051099. Dana-Farber Cancer Institute, Inc. highlighted inhibitors of TEAD transcription factors in WO 2020/081572. The Trustees of Indiana University described small-molecules that bind within the hydrophobic palmitate-binding pocket of TEADs in WO2020/087063. Wenchao Lu, et al. published vinylsulfonamides as covalent TEAD autopalmitoylation inhibitors (2019, European Journal of Medicinal Chemistry, 184, p. 111767). Korean Research Institute of Chemical Technology disclosed benzo[cd]indol-2(1H)-one derivatives that inhibit YAP-TEAD binding in WO 2020/096416.

However, there is still a need for new, alternative and/or better therapeutics for the prevention or treatment of diseases mediated by the YAP/TAZ-TEAD activation, such as cancer and fibrosis among potentially other indications. Therapeutics with enhanced potency, less side-effects, a higher activity, a lower toxicity or better pharmacokinetic or -dynamic properties or combinations thereof would be very welcome.

The present disclosure provides a class of novel compounds which can be used as inhibitors of the YAP/TAZ-TEAD activation mediated diseases.

SUMMARY OF THE INVENTION

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

The present disclosure provides new compounds which have been shown to possess inhibitory activity on the YAP/TAZ-TEAD transcription. The present disclosure furthermore demonstrates that these compounds efficiently inhibit the activity of YAP/TAZ-TEAD transcription. Therefore, 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, for example, lung cancer, breast cancer, head and neck cancer, oesophageal 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, mesotheliomas, and/or sarcomas (ii) fibrosis, and (iii) YAP/TAZ-TEAD activation related congenital disorders, among others.

In some aspects, the compounds described herein 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, for example, 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, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinomas, 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

The present disclosure furthermore relates to the use of such compounds as medicines and to their use for the manufacture of medicaments, more in particular for treating and/or preventing YAP/TAZ-TEAD activation mediated diseases, in particular (i) cancer, more specifically, for example, lung cancer, breast cancer, head and neck cancer, oesophageal 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, mesotheliomas, and/or sarcomas and (ii) fibrosis in animals or mammals, more in particular in humans.

The present disclosure also relates to methods for the preparation of the compounds described herein and to pharmaceutical compositions comprising them, e.g., in an effective amount.

In some embodiments, the disclosure relates to the compounds of the invention for use as a medicine, to the use of such compounds as medicines and to their use for the manufacture of medicaments, more in particular for treating and/or preventing YAP/TAZ-TEAD activation mediated diseases more specifically for the treatment and/or prevention of, e.g., 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, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinomas, 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

The present disclosure also relates to a method of treatment or prevention of TEAD activation mediated disorders in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof.

The present disclosure also relates to methods of preparing the compounds described herein comprising, e.g., the steps for synthesis of the compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION
Definitions

The term “YAP/TAZ-TEAD activation mediated diseases” refers to diseases in which hippo signaling is inactivated and whereby YAP/TAZ-TEAD activation is contributing, driving, sustaining, enabling or the like such disease. This might be through loss-of-function mutations or deletions in the genes encoding the upstream regulators of YAP/TAZ-TEAD (e.g. NF2, MST1/2, LATS1/2, FAT1 or SAV1), unleashing constitutive YAP-TEAD transcriptional activity leading to unbridled tumor growth and metastasis of some cancers. This might also be through YAP1 or WWTR1 (TAZ) gene amplifications, gene fusions or activating mutations, or YAP/TAZ overexpression or hyperactivity, among others. YAP/TAZ-TEAD activation mediated diseases therefore refers to cancer, but also includes fibrosis and certain congenital disorders. Cancers that are included in YAP/TAZ-TEAD mediated diseases are, without being limited thereto, lung cancer, breast cancer, head and neck cancer, oesophageal 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, mesotheliomas, and/or sarcomas. Also included are (i) squamous cell carcinomas of the lung, cervix, ovaries, head and neck, oesophagus, and/or skin, or (ii) cancers that originate from neuroectoderm-derived tissues, such as ependymomas, meningiomas, schwannomas, peripheral nerve-sheet tumors and/or neuroblastomas, or (iii) vascular cancers, such as epithelioid haemangioendotheliomas. Fibrotic diseases or fibrosis that is included in YAP/TAZ-TEAD mediated diseases are, without being limited thereto, liver fibrosis, lung fibrosis and heart fibrosis. Congenital disorders that are included in YAP/TAZ-TEAD mediated diseases are, without being limited thereto, Sturge-Weber syndrome and Neurofibromatosis type 2.

YAP/TAZ-TEAD mediated diseases also includes cancers that have developed resistance to prior treatments such has EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors and others.

The term “treat” or “treating” as used herein is intended to refer to administration of a compound or composition to a subject for the purpose of effecting a therapeutic benefit or prophylactic benefit through inhibition of the YAP/TAZ-TEAD transcription. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through YAP/TAZ-TEAD transcription. By “therapeutic benefit” is meant eradication, amelioration, reversing, alleviating, inhibiting the progress of or lessening the severity of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

The term “subject” as used herein, refers to an animal, for example a mammal, such as a human, a patient, who has been the object of treatment, observation or experiment or who is in need of such treatment.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “antagonist” or “inhibitor” as used herein in reference to inhibitors of the YAP/TAZ-TEAD activation, refers to a compound capable of producing, depending on the circumstance, a functional antagonism of YAP/TAZ-TEAD activation.

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.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the 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. Where an indefinite or definite article is used when referring to a singular noun e.g. “a” or “an”, “the”, this includes a plural of that noun unless something else is specifically stated.

Similarly it should be appreciated that in the description of exemplary embodiments of the disclosure, various features of the disclosure are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.

In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.

The term “leaving group” or “LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

The term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See, e.g.: “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 assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.

The term “alkyl” or “C_1-18alkyl” as used herein means C₁-C₁₈normal, secondary, or tertiary, linear, branched or straight hydrocarbon with no site of unsaturation. Examples are 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 particular embodiments, the term alkyl refers to C_1-12alkyl (C_1-12hydrocarbons), yet more in particular to C_1-9alkyl (C_1-9hydrocarbons), yet more in particular to C_1-6alkyl (C_1-6hydrocarbons) as further defined herein above.

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

The term “alkoxy” or “alkyloxy”, as a group or part of a group, refers to a group having the formula —OR^bwherein R^bis C_1-6alkyl as defined herein above. Non-limiting examples of suitable C_1-6alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

The term “haloalkoxy”, as a group or part of a group, refers to a group of formula —O—R^c, wherein R^cis 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, 4,4,4-trichlorobutoxy.

The term “cycloalkyl” or “C_3-18cycloalkyl” as used herein and unless otherwise stated means a saturated hydrocarbon monovalent group having from 3 to 18 carbon atoms consisting of or comprising a C_3-10monocyclic or C_7-18polycyclic saturated hydrocarbon, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like. In particular embodiments, the term cycloalkyl refers to C_3-12cycloalkyl (saturated cyclic C_3-12hydrocarbons), yet more in particular to C_3-9cycloalkyl (saturated cyclic C_3-9hydrocarbons), still more in particular to C_3-6cycloalkyl (saturated cyclic C_3-6hydrocarbons) as further defined herein above. For the avoidance of doubt, fused systems of a cycloalkyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

The term “alkenyl” or “C_2-18alkenyl” as used herein is C₂-C₁₈normal, secondary or tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂). The double bond may be in the cis or trans configuration. In particular embodiments, the term alkenyl refers to C_2-12alkenyl (C_2-12hydrocarbons), yet more in particular to C_2-9alkenyl (C_2-9hydrocarbons), still more in particular to C_2-6alkenyl (C_2-6hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond.

The term “alkenyloxy”, as a group or part of a group, refers to a group having the formula —OR^dwherein R^dis alkenyl as defined herein above.

The term “cycloalkenyl” as used herein refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond and consisting of or comprising a C_5-10monocyclic or C_7-18polycyclic hydrocarbon. Examples include, but are not limited to: cyclopentenyl (—C₅H₇), cyclopentenylpropylene, methylcyclohexenylene and cyclohexenyl (—C₆H₉). The double bond may be in the cis or trans configuration. In particular embodiments, the term cycloalkenyl refers to C_5-12cycloalkenyl (cyclic C_5-12hydrocarbons), yet more in particular to C_5-9cycloalkenyl (cyclic C_5-9hydrocarbons), still more in particular to C_5-6cycloalkenyl (cyclic C_5-6hydrocarbons) as further defined herein above with at least one site of unsaturation, namely a carbon-carbon, sp2 double bond. For the avoidance of doubt, fused systems of a cycloalkenyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkenyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkenyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

The term “alkynyl” or “C_2-18alkynyl” as used herein refers to C₂-C₁₈normal, secondary, tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (—C≡CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, —CH₂C≡CH). In particular embodiments, the term alkynyl refers to C_2-12alkynyl (C_2-12hydrocarbons), yet more in particular to C_2-9alkynyl (C_2-9hydrocarbons) yet more in particular to C_2-6alkynyl (C_2-6hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond.

The term “alkynyloxy”, as a group or part of a group, refers to a group having the formula —OR^ewherein R^eis alkynyl as defined herein above.

The term “cycloalkynyl” as used herein refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond and consisting of or comprising a C_5-10monocyclic or C_7-18polycyclic hydrocarbon. Examples include, but are not limited to: cyclohept-1-yne, 3-ethyl-cyclohept-1-ynylene, 4-cyclohept-1-yn-methylene and ethylene-cyclohept-1-yne. In particular embodiments, the term cycloalkynyl refers to C_5-10cycloalkynyl (cyclic C_5-10hydrocarbons), yet more in particular to C_5-9cycloalkynyl (cyclic C_5-9hydrocarbons), still more in particular to C_5-6cycloalkynyl (cyclic C_5-6hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. For the avoidance of doubt, fused systems of a cycloalkynyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

The term “alkylene” as used herein each refer to a saturated, branched or straight chain hydrocarbon group of 1-18 carbon atoms (more in particular C_1-12, C_1-9or C_1-6carbon atoms), and having two monovalent group centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene include, but are not limited to: methylene (—CH₂—), 1,2-ethyl (—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), and the like.

The term “alkenylene” as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C_2-12, C_2-9or C_2-6carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.

The term “alkynylene” as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C_2-12, C_2-9or C_2-6carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

The term “heteroalkyl” as used herein refers to an alkyl wherein one or more carbon atoms are replaced by one or more atoms selected from the group comprising oxygen, nitrogen or sulphur atom. The term heteroalkyl thus comprises —O—R^b, —NR^o—R^b, —R^a—O—R^b, and —S—R^b, wherein R^ais alkylene, R^bis alkyl, and R^ois hydrogen or alky as defined herein. In particular embodiments, the term refers to C_1-12heteroalkyl, C_1-9heteroalkyl or C_1-6heteroalkyl. In some embodiments heteroalkyl is selected from the group comprising alkyloxy, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl.

The term “heteroalkenyl” as used herein refers to an acyclic alkenyl wherein one or more carbon atoms are replaced by one or more atoms selected from oxygen, nitrogen or sulphur atom. The term heteroalkenyl thus comprises —O—R^d, —NH—(R^d), —N(R^d))₂, —N(R^b)(R^d), and —S—R^dwherein R^bis alkyl and R^dis alkenyl as defined herein. In particular embodiments, the term refers to C_2-12heteroalkenyl, C_2-9heteroalkenyl or C_2-6heteroalkenyl. In some embodiments heteroalkenyl is selected from the group comprising alkenyloxy, alkenyl-oxy-alkenyl, (mono or di-)alkenylamino, (mono or di-)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl,

The term “heteroalkynyl” as used herein refers to an acyclic alkynyl wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom. The term heteroalkynyl thus comprises but is not limited to —O—R^d, —N(R^d)₂, NHR^d, —N(R^b)(R^e), —N(R^d)(R^e), and —S—R^dwherein R^bis alkyl, R^eis alkynyl and R^dis alkenyl as defined herein. In particular embodiments, the term refers to C_2-12heteroalkynyl, C_2-9heteroalkynyl or C_2-6heteroalkynyl. In some embodiments the term heteroalkynyl is selected from the group comprising alkynyloxy, alkynyl-oxy-alkynyl, (mono or di-)alkynylamino, (mono or di-)alkynyl-amino-alkynyl, alkynylthio, alkynyl-thio-alkynyl,

The term “heteroalkylene” as used herein refers to an alkylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms.

The term “heteroalkenylene” as used herein refers to an alkenylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms.

The term “heteroalkynylene” as used herein refers to an alkynylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atom.

The term “aryl” as used herein means an aromatic hydrocarbon of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like. In particular embodiments, the term aryl refers to a 6-14 carbon atoms membered aromatic cycle, yet more in particular refers to a 6-10 carbon atoms membered aromatic cycle. Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofurane, dihydrobenzothiophene and the like are considered as heterocycle according to the disclosure. Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

The term “aryloxy”, as a group or part of a group, refers to a group having the formula —OR^gwherein R^gis aryl as defined herein above.

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

The term “arylalkyloxy”, as a group or part of a group, refers to a group having the formula —O—R^a-R^gwherein R^gis aryl, and R^ais alkylene as defined herein above.

The term “arylalkenyl” or “arylalkenyl-” as used herein refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylalkenyl group comprises 6 to 20 carbon atoms, e.g. the alkenyl moiety of the arylalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

The term “arylalkynyl” or “arylalkynyl-” as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylalkynyl group comprises 6 to 20 carbon atoms, e.g. the alkynyl moiety of the arylalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

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

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

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

The term “heterocycle” or “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system of 3 to 18 atoms including at least one N, O, S, or P (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms). 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 optionally be oxidized and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C═O. The heterocycle may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocyclyls or heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Fused systems of a heterocycle or heterocyclyl with an aryl ring are considered as heterocycle or heterocyclyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycle or heterocyclyl with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

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

The term “heteroaryl” refers to an aromatic ring system of 5 to 18 atoms including at least one N, O, S, or P, containing 1 or 2 rings which can be fused together or linked covalently, each ring typically containing 5 to 6 atoms; at least one of said rings is aromatic, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C═O. Fused systems of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a heteroaryl ring with a heterocycle are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a hetero aryl ring with an aryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non-limiting examples of such heteroaryl, 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-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, 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, cinnolinyl, quinazolinyl, quinoxalinyl; in some embodiments, said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl and thiazolyl; in some embodiments, said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, indolyl and benzimidazolyl.

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

Heteroaryl and heterocycle or heterocyclyl as used herein includes by way of example and not limitation these groups described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular 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.

The term “heterocyclyloxy” or “heterocycleoxy”, as a group or part of a group, refers to a group having the formula —O—Rⁱwherein Rⁱis heterocyclyl as defined herein above.

The term “heterocyclylalkyloxy” or “heterocyclealkoxy”, as a group or part of a group, refers to a group having the formula —O—R^a-Rⁱwherein Rⁱis heterocyclyl, and R^ais alkyl as defined herein above.

The term “heteroaryloxy”, as a group or part of a group, refers to a group having the formula —O—R^kwherein R^kis heteroaryl as defined herein above.

The term “heteroarylalkyloxy”, as a group or part of a group, refers to a group having the formula —O—R^a-Rⁱwherein Rⁱis heteroaryl, and R^ais alkyl as defined herein above.

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

The term “heterocyclyl-alkenyl” or “heterocycle-alkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heterocyclyl. The heterocyclyl-alkenyl or heterocycle-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety is 2 to 6 carbon atoms and the heterocyclyl moiety is 3 to 14 atoms.

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, is replaced with a heterocyclyl. The heterocyclyl-alkynyl or heterocycle-alkynyl group can comprise 6 to 20 atoms, e.g. the alkynyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms.

The term “heterocyclyl-heteroalkyl” or “heterocycle-heteroalkyl” as a group or part of a group refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl. The heterocyclyl-heteroalkyl or heterocycle-heteroalkyl group can comprise 6 to 20 atoms, e.g. the heteroalkyl moiety can comprise 1 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. In some embodiments heterocyclyl-heteroalkyl or heterocycle-heteroalkyl is selected from the group comprising heterocyclyl-O-alkyl, heterocyclylalkyl-O-alkyl, heterocyclyl-NH-alkyl, heterocyclyl-N(alkyl)₂, heterocyclylalkyl-NH-alkyl, heterocyclylalkyl-N-(alkyl)₂, heterocyclyl-S-alkyl, and heterocyclylalkyl-S-alkyl.

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

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

The term “heteroaryl-alkyl” as a group or part of a group refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl. An example of a heteroaryl-alkyl group is 2-pyridyl-methylene. The heteroaryl-alkyl group can comprise 6 to 20 atoms, e.g. the alkyl moiety of the heteroaryl-alkyl group can comprise 1 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.

The term “heteroaryl-alkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl. The heteroaryl-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety of the heteroaryl-alkenyl group can comprise 2 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.

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 comprises 6 to 20 atoms, e.g. the alkynyl moiety of the heteroaryl-alkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.

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

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

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

By way of example, carbon bonded heteroaryl or heterocyclic rings (or heterocycles) can be bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded 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 bonded heterocyclic rings are bonded at position 1 of an 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, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ß-carboline. Still more typically, nitrogen bonded heteroaryls or heterocyclyls include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

As used herein and unless otherwise stated, the terms “alkoxy”, “cyclo-alkoxy”, “aryloxy”, “arylalkyloxy”, “heteroaryloxy” “heterocyclyloxy”, “alkylthio”, “cycloalkylthio”, “arylthio”, “arylalkylthio”, “heteroarylthio” and “heterocyclylthio” refer to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl heteroaryl, or heterocyclyl (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like. The same definitions will apply for alkenyl and alkynyl instead of alkyl.

The term “alkylthio”, as a group or part of a group, refers to a group having the formula —S—R^bwherein R^bis alkyl as defined herein above. Non-limiting examples of alkylthio groups include methylthio (—SCH₃), ethylthio (—SCH₂CH₃), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.

The term “alkenylthio”, as a group or part of a group, refers to a group having the formula —S—R^dwherein R^dis alkenyl as defined herein above.

The term “alkynylthio”, as a group or part of a group, refers to a group having the formula —S—R^ewherein R^eis alkynyl as defined herein above.

The term “arylthio”, as a group or part of a group, refers to a group having the formula —S—R^gwherein R^gis aryl as defined herein above.

The term “arylalkylthio”, as a group or part of a group, refers to a group having the formula —S—R^a-R^gwherein R^ais alkylene and R^gis aryl as defined herein above.

The term “heterocyclylthio”, as a group or part of a group, refers to a group having the formula —S—Rⁱwherein Rⁱis heterocyclyl as defined herein above.

The term “heteroarylthio”, as a group or part of a group, refers to a group having the formula —S—R^kwherein R^kis heteroaryl as defined herein above.

The term “heterocyclylalkylthio”, as a group or part of a group, refers to a group having the formula —S—R^a-Rⁱwherein R^ais alkylene and Rⁱis heterocyclyl as defined herein above.

The term “heteroarylalkylthio”, as a group or part of a group, refers to a group having the formula —S—R^a-R^kwherein R^ais alkylene and R^kis heteroaryl as defined herein above.

The term “mono- or di-alkylamino”, as a group or part of a group, refers to a group of formula —N(R^o)(R^b) wherein R^ois hydrogen, or alkyl, R^bis alkyl. Thus, alkylamino include mono-alkyl amino group (e.g. mono-alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-alkylamino group 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-1-propylamino, n-butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n-propylamino, ethyl-1-propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di-n-butylamino, di-i-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

The term “mono- or di-arylamino”, as a group or part of a group, refers to a group of formula —N(R^q)(R^r) wherein R^qand R^rare each independently selected from hydrogen, aryl, or alkyl, wherein at least one of R^qor R^ris aryl.

The term “mono- or di-heteroarylamino”, as a group or part of a group, refers to a group of formula —N(R^u)(R^v) wherein R^uand R^vare each independently selected from hydrogen, heteroaryl, or alkyl, wherein at least one of R^uor R^vis heteroaryl as defined herein.

The term “mono- or di-heterocyclylamino”, as a group or part of a group, refers to a group of formula —N(R^w)(R^x) wherein R^wand R^xare each independently selected from hydrogen, heterocyclyl, or alkyl, wherein at least one of R^wor R^xis heterocyclyl as defined herein.

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

The terminology regarding a chemical group “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” as used herein, refers to a group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom and thus includes, depending on the group to which is referred, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, heteroarylheteroalkynyl, among others. This term therefore comprises, depending on the group to which is referred, as an example alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-heteroalkyl, heterocyclyl-heteroalkyl, heteroaryl-alkoxy, heterocyclyl-alkoxy, among others. As an example, the terminology “alkyl which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” therefore refers to heteroalkyl, meaning an alkyl which comprises one or more heteroatoms in the hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain. Examples of heteroalkyl include methoxy, methylthio, ethoxy, propoxy, CH₃—O—CH₂—, CH₃—S—CH₂—, CH₃—CH₂—O—CH₂—, CH₃—NH—, (CH₃)₂—N—, (CH₃)₂—CH₂—NH—CH₂—CH₂—, among many other examples. As an example, the terminology “arylalkylene which optionally includes one or more heteroatoms in the alkylene chain, said heteroatoms being selected from the atoms consisting of O, S, and N” therefore refers to arylheteroalkylene, meaning an arylalkylene which comprises one or more heteroatoms in the hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain. “Arylheteroalkylene” thus includes aryloxy, arylalkoxy, aryl-alkyl-NH— and the like and examples are phenyloxy, benzyloxy, aryl-CH₂—S—CH₂—, aryl-CH₂—O—CH₂—, aryl-NH—CH₂— among many other examples. The same counts for “heteroalkenylene”, “heteroalkynylene”, and other terms used herein when referred to “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N”.

The terminology regarding a chemical group “wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said group can be taken together to form a ═O or ═S” as used herein, refers to a group where two or more hydrogen atoms on a carbon atom or heteroatom of said group are taken together to form ═O or ═S. As an example, the terminology refers to “an alkyl wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl can be taken together to form a ═O or ═S”, 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—.

The combination for a group “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” and “wherein optionally two or more hydrogen atoms on a carbon atom or heteroatom of said group can be taken together to form a ═O or ═S” can combine the two aspects described herein above and includes, if the group referred to is alkyl, among other examples 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—.

The term “single bond” as used herein for a linking group i.e. in a way that a certain linking group is selected from a single bond, etc. in the formulas herein, refers to a molecule wherein the linking group is not present and therefore refers to compounds with a direct linkage via a single bond between the two moieties being linked by the linking group.

As used herein with respect to a substituting group, and unless otherwise stated, the terms “substituted” such as in “substituted alkyl”, “substituted alkenyl”, substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted heterocyclyl”, “substituted arylalkyl”, “substituted heteroaryl-alkyl”, “substituted heterocyclyl-alkyl” and the like refer to the chemical structures defined herein, and wherein the said alkyl, alkenyl, alkynyl, group and/or the said aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more substituents (preferable 1, 2, 3, 4, 5 or 6), meaning that one or more hydrogen atoms are each independently replaced with at least one substituent. Typical substituents include, but are not limited to and in a particular embodiment said substituents are being 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; and each Z is independently —H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, protecting group or prodrug moiety, while two Z bonded to a nitrogen atom can be taken together with the nitrogen atom to which they are bonded to form a heteroaryl, or heterocyclyl. Alkyl(ene), alkenyl(ene), and alkynyl(ene) groups may also be similarly substituted.

Any substituent designation that is found in more than one site in a compound of this disclosure shall be independently selected.

Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.

As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this disclosure with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.

The term “heteroatom(s)” as used herein means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.

The term “hydroxy” as used herein means —OH.

The term “carbonyl” as used herein means carbon atom bonded to oxygen with a double bond, i.e., C═O.

The term “amino” as used herein means the —NH₂group.

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

The present disclosure furthermore relates to the compounds for use as medicines and to their use for the manufacture of medicaments for treating and/or preventing cancer or fibrosis. The present disclosure relates to the compounds for use as medicines for treating and/or preventing YAP/TAZ-TEAD activation mediated diseases such as cancer or fibrosis in animals, mammals, more in particular in humans. The disclosure also relates to methods for the preparation of all such compounds and to pharmaceutical compositions comprising them in an effective amount. The present disclosure also relates to a method of treatment or prevention of cancer or fibrosis in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof. The present disclosure also relates to the compounds for veterinary use and to their use as medicines for the prevention or treatment of diseases in a non-human mammal, such as cancer and fibrosis in non-human mammals.

In one embodiment, the disclosure provides a compound of Formula I:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
  - Z is selected from the group consisting of ═N—, ═N⁺—, and ═C—;
  - Q¹is ═N— or ═CX¹—;
  - Q²is ═N— or ═CX²—;
  - Q³is ═N— or ═CX³—;
  - X¹, X², and X³are independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) halogen,
  - (iii) cyano,
  - (iv) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of Z¹,
  - (v) C₁-C₆haloalkyl,
  - (vi) —OZ¹, and
  - (vii) —NZ³Z⁴;
- when Z is ═C—, R¹is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) halogen,
  - (iii) cyano,
  - (iv) C₁-C₆alkyl,
  - (v) C₁-C₆haloalkyl,
  - (vi) —OZ¹, and
  - (vii) —NZ³Z⁴;
- when Z is ═N— or ═N⁺—, R¹is —O⁻ or absent;
- R²is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) C₁-C₆alkyl,
  - (iii) —(CH₂)_n—R^3a,
  - (iv) —O—(CH₂)_n—R^3a,
  - (v) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of:
    - i. hydrogen,
    - ii. unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
      - 1. halogen,
      - 2. hydroxy,
      - 3. cyano,
      - 4. —OZ¹,
      - 5. —SZ¹,
      - 6. —NZ³Z⁴,
      - 7. —C(═O)Z²
      - 8. —C(═O)OH,
      - 9. —C(═O)OZ²,
      - 10. —C(═O)NZ³Z⁴,
      - 11. —NZ⁵C(═O)Z²,
      - 12. —NZ⁵C(═O)OZ²,
      - 13. —NZ⁵C(═O)NZ³Z⁴,
      - 14. —S(═O)₂Z⁸,
      - 15. —S(═O)₂NZ³Z⁴,
      - 16. —S(═O)(═NZ⁶)Z²,
      - 17. —S(═Z⁶)(═NZ⁷)Z²,
      - 18. —S(═O)(═NZ⁶)NZ³Z⁴,
      - 19. —NZ⁵S(═O)₂Z²,
      - 20. —NZ⁵S(═O)₂NZ³Z⁴,
      - 21. —NZ⁵S(═O)(═NZ⁶)Z²,
      - 22. —NZ⁵S(═NZ⁶)(═NZ⁷)Z², and
      - 23. —NZ⁵S(═O)(═NZ⁶)NZ³Z⁴,
    - iii. —C(═O)Z²
    - iv. —C(═O)OZ²,
    - v. —C(═O)NZ³Z⁴,
    - vi. —S(═O)₂Z⁸,
    - vii. —S(═O)₂NZ³Z⁴,
    - viii. —S(═O)(═NZ⁶)Z²,
    - ix. —S(═Z⁶)(═NZ⁷)Z²,
    - x. —S(═O)(═NZ⁶)NZ³Z⁴, and
  - (vi) —(CH₂)—NR^3aR^3b;
- n is 0 or 1; R^3ais selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) —OZ¹,
    - (d) —SZ¹,
    - (e) —NZ³Z⁴,
    - (f) —C(═O)Z²
    - (g) —C(═O)OH,
    - (h) —C(═O)OZ²,
    - (i) —C(═O)NZ³Z⁴,
    - (j) —NZ⁵C(═O)Z²,
    - (k) —NZ⁵C(═O)OZ²,
    - (l) —NZ⁵C(═O)NZ³Z⁴,
    - (m) —S(═O)₂Z⁸,
    - (n) —S(═O)₂NZ³Z⁴,
    - (o) —S(═O)(═NZ⁶)Z²,
    - (p) —S(═Z⁶)(═NZ⁷)Z²,
    - (q) —S(═O)(═NZ⁶)NZ³Z⁴,
    - (r) —NZ⁵S(═O)₂Z²,
    - (s) —NZ⁵S(═O)₂NZ³Z⁴,
    - (t) —NZ⁵S(═O)(═NZ⁶)Z²,
    - (u) —NZ⁵S(═NZ⁶)(═NZ⁷)Z², and
    - (v) —NZ⁵S(═O)(═NZ⁶)NZ³Z⁴,
  - (iii) —C(═O)Z²,
  - (iv) —C(═O)OZ²,
  - (v) —C(═O)NZ³Z⁴,
  - (vi) —S(═O)₂Z⁸,
  - (vii) —S(═O)₂NZ³Z⁴,
  - (viii) —S(═O)(═NZ⁶)Z²,
  - (ix) —S(═Z⁶)(═NZ⁷)Z²,
  - (x) —S(═O)(═NZ⁶)NZ³Z⁴, and
  - (xi) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, C₂-C₈alkenyl, and C₁-C₆alkyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O;
- R^3bis selected from the group consisting of hydrogen and C₁-C₆alkyl;
- R⁴is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
    - (a) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
      - (1) halogen,
      - (2) cyano,
      - (3) C₁-C₆alkyl,
      - (4) C₃-C₆cycloalkyl,
      - (5) C₁-C₆haloalkyl,
      - (6) —OZ¹,
      - (7) C₂-C₆alkenyl, and
      - (8) C₂-C₆alkynyl,
    - (b) unsubstituted or substituted C₃-C₆cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
      - (1) halogen,
      - (2) cyano,
      - (3) C₁-C₆alkyl,
      - (4) C₃-C₆cycloalkyl,
      - (5) C₁-C₆haloalkyl, and
      - (6) —OZ¹,
    - (c) C₂-C₆alkynyl, and
    - (d) unsubstituted or substituted 3- to 6-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, C₂-C₈alkenyl, and C₁-C₆alkyl,
  - (ii) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl,
    - (f) —OZ¹, and
    - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹,
  - (iii) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein zero or more of the heteroaryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl,
    - (f) —OZ¹, and
    - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹,
  - (iv) unsubstituted or substituted C₃-C₆cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl, and
    - (f) —OZ¹,
  - (v) unsubstituted or substituted 3- to 6-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl, and
    - (f) —OZ¹,
  - (vi) —S(═O)₂Z², and
  - (vii) —C(═O)Z²;
- each Z¹is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
    - a. cyano,
    - b. —S(═O)₂Z⁸,
    - c. C₃-C₈cycloalkyl,
    - d. —C(═O)OH,
    - e. —S(═O)₂Z⁸,
    - f. —NZ³Z⁴,
    - g. halogen,
    - h. unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O,
    - i. unsubstituted or substituted 3- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heteroaryl carbons can be oxidized to form a C═O, and
    - j. unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and cyano,
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of:
    - a. cyano,
    - b. —S(═O)₂Z⁸,
    - c. halogen, and
    - d. unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
      - i. cyano,
      - ii. —S(═O)₂Z⁸,
      - iii. C₃-C₈cycloalkyl,
      - iv. —C(═O)OH,
      - v. —S(═O)₂Z⁸,
      - vi. —NZ³Z⁴,
      - vii. halogen,
      - viii. unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O,
      - ix. unsubstituted or substituted 3- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heteroaryl carbons can be oxidized to form a C═O, and
      - x. unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆haloalkyl, cyano, —S(═O)₂Z⁸, —NZ³Z⁴, and unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) C₂-C₆alkynyl,
  - (v) C₃-C₆cycloalkyl,
  - (vi) C₃-C₆cycloalkenyl,
  - (vii) unsubstituted or substituted C₃-C₈cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (viii) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (ix) unsubstituted or substituted 3- to 8-membered heteroaryl, wherein zero or more of the heteroaryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and
  - (x) unsubstituted or substituted 3- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl;
- each Z²is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of C₂-C₆alkenyl, cyano, —C(═O)OH, —S(═O)₂Z⁸, halogen, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) C₂-C₆alkynyl,
  - (v) C₃-C₆cycloalkyl, and
  - (vi) C₃-C₆cycloalkenyl;
- each Z³is independently selected from the group consisting of:
  - (i) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of C₂-C₆alkenyl, cyano, —C(═O)OH, —S(═O)₂Z⁸, halogen, —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (ii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iii) unsubstituted or substituted C₂-C₆alkynyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, OZ¹, —S(═O)₂Z⁸, —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) unsubstituted or substituted C₃—C cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and
  - (v) unsubstituted or substituted C₃—C cycloalkenyl, wherein zero or more of the cycloalkenyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O;
- each Z⁴, Z⁵, Z⁶and Z⁷is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) C₁-C₆alkyl, and
  - (iii) C₃-C₆cycloalkyl;
- each Z⁸is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, and C₁-C₆alkyl,
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃—C cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) halogen, and
  - (v) hydroxy.

In another embodiment, the disclosure provides the compound of Formula II:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: Q¹, Q², Q³, X¹, X², X³, R², R^3a, R^3b, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

In another embodiment, the disclosure provides the compound of Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula III:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: Q¹, Q², Q³, X¹, X², X³, R², R^3a, R^3b, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula III, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q²and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

In another embodiment, the disclosure provides the compound of Formula III, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula III, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula IV:

[Image Omitted]

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: X¹, X², X³, R², R^3a, R^3b, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, X², and X³are independently selected from the group consisting of —H, —OH, substituted or unsubstituted C₁-C₆alkyl (e.g., methyl), and —O-Methyl. In another embodiment, the disclosure provides the compound of Formula IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, X², and X³are independently selected from the group consisting of —H, —OH, and —O-Methyl.

In another embodiment, the disclosure provides the compound of Formula IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula IV, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula V:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: X¹, X², X³, R², R^3a, R^3b, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, X², and X³are independently selected from the group consisting of —H, —OH, and —O-Methyl.

In another embodiment, the disclosure provides the compound of Formula V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula V, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula VI:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: R², R^3a, R^3b, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula VI, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula VI, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula VII:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: R², R^3a, R^3b, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula VII or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula VII, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula VIII:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein: Q¹, Q², Q³, X¹, X², X³, R^3a, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula VIII, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

In another embodiment, the disclosure provides the compound of Formula VIII, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula VIII, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula IX:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², Q³, X¹, X², X³, R^3a, R⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, Z⁸are as defined in connection with Formula I.

In another embodiment, the disclosure provides the compound of Formula IX, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

In another embodiment, the disclosure provides the compound of Formula IX, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

In another embodiment, the disclosure provides the compound of Formula IX, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

In another embodiment, the disclosure provides the compound of Formula X:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
  - Z is selected from the group consisting of ═N—, ═N⁺—, and ═C—;
  - X¹is selected from the group consisting of —H, —O(C₁-C₆alkyl), substituted or unsubstituted C₁-C₆alkyl (e.g., methyl), and —OH;
  - when Z is ═N— or ═N⁺—, R¹is —O—, or absent;
  - when Z is ═C—, R¹is —OR⁶, or unsubstituted or substituted C₂-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R⁶;
  - R²is selected from the group consisting of:
  - (i) —OR³,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R³, and
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of R⁴;
  - R³is selected from the group consisting of:
  - (i) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R⁴,
  - (ii) —C(═O)R⁴, and
  - (iii) —NHR⁴;
  - R⁴is selected from the group consisting of:
  - (i) —C(═O)R⁵,
  - (ii) —S(═O)₂R⁵,
  - (iii) —OH, and
  - (iv) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C₁-C₆alkyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O; R⁵is selected from the group consisting of:
  - (i) —C₁-C₆alkyl,
  - (ii) —C₂-C₆alkenyl,
  - (iii) —O(C₁-C₆alkyl),
  - (iv) —NH—C₁-C₆alkyl,
  - (v) —OH, and
  - (vi) unsubstituted or substituted C₃-C₆cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C₁-C₆alkyl, and zero or more of the cycloalkyl carbons can be oxidized to form a C═O;
  - R⁶is selected from the group consisting of unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R⁷, wherein
  - R⁷is selected from the group consisting of
  - (i) unsubstituted or substituted 3- to 6-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of C₁-C₆alkyl, and zero or more of the heteroaryl carbons can be oxidized to form a C═O, and
  - (ii) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C₁-C₆alkyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O.

In another embodiment, the disclosure provides the compound of Formula X, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, is selected from the group consisting of —H, —OH, substituted or unsubstituted C₁-C₆alkyl (e.g., methyl), and —O-Methyl. In another embodiment, the disclosure provides the compound of Formula X, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, is selected from the group consisting of —H, —OH, and —O-Methyl.

In another embodiment, the disclosure provides the compound of Formula X, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z, is ═N—.

In another embodiment, the disclosure provides the compound of Formula X, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z, is ═C—.

In another embodiment, the disclosure provides the compound of Formula X, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R²is C₁alkyl substituted with one R³substituent, and the one R³substituent is —NHR⁴.

In another embodiment, the disclosure provides a compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)propionamide;

N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)methanesulfonamide;

N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)propionamide;

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)- or (S)—N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)propionamide;

N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)methanesulfonamide;

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)methanesulfonamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetic acid;

N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)- or (S)—N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)- or (S)-methyl ((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)cyclopropanecarboxamide;

N-(methylsulfamoyl)-1-[1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,5-naphthyridin-3-yl]methanamine;

(E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylic acid;

N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)oxy)acetic acid; and

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)oxetan-3-amine.

In another embodiment, the disclosure provides a compound, or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)—N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(S)—N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)—N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(S)—N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

Methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

(R)-methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

(S)-methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

(S)—N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

In another embodiment, the disclosure provides a compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide;

(2S)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)pyrrolidine-2-carboxamide;

(2R)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)pyrrolidine-2-carboxamide;

1-methyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)-1H-imidazole-5-carboxamide;

1-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-2-one;

N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide;

N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

2-phenyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-acryloyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)glycine;

N-acetyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)glycine;

3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

(R)- or (S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isobutyramide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)benzamide;

1-(4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)prop-2-en-1-one;

N-((6-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

1-methyl-3-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)urea;

N-((7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide;

N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((7-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((7-chloro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((1-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide;

N-((6-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)acetamide;

N-((6-cyclopropyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-cyano-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxamide;

N-((6-(difluoromethoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-(difluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

N-((6-ethynyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

In another embodiment, the disclosure provides a compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(S)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

(R)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

(S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

(S)—N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

In another embodiment, the disclosure provides a compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

(S)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

Preferred or particular statements (features) and embodiments of the compounds of this disclosure are set herein below. Each statement, aspect and embodiment of the disclosure so defined may be combined with any other statement, aspect and/or embodiment, unless clearly indicated to the contrary. In particular, any feature indicated as being preferred, particular or advantageous may be combined with any other features or statements indicated as being preferred, particular or advantageous. Hereto, the present disclosure is in particular captured by any one or any combination of one or more of the below numbered statements and embodiments, with any other statement, aspect and/or embodiment (which are not numbered).

Embodiment 1: A compound of Formula I:

[Image Omitted]

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

- Z is selected from the group consisting of ═N—, ═N⁺—, and ═C—;
- Q¹is ═N— or ═CX¹—;
- Q²is ═N— or ═CX²—;
- Q³is ═N— or ═CX³—;
- X¹, X², and X³are independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) halogen,
  - (iii) cyano,
  - (iv) C₁-C₆alkyl,
  - (v) C₁-C₆haloalkyl,
  - (vi) —OZ¹, and
  - (vii) —NZ³Z⁴;
- when Z is ═C—, R¹is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) halogen,
  - (iii) cyano,
  - (iv) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of Z¹,
  - (v) C₁-C₆haloalkyl,
  - (vi) —OZ¹, and
  - (vii) —NZ³Z⁴;
- when Z is ═N— or ═N⁺—, R¹is —O— or absent;
- R²is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) C₁-C₆alkyl,
  - (iii) —(CH₂)_n—R^3a,
  - (iv) —O—(CH₂)_n—R^3a,
  - (v) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of:
    - i. hydrogen,
    - ii. unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
      - 1. halogen,
      - 2. hydroxy,
      - 3. cyano,
      - 4. —OZ¹,
      - 5. —SZ¹,
      - 6. —NZ³Z⁴,
      - 7. —C(═O)Z²
      - 8. —C(═O)OH,
      - 9. —C(═O)OZ²,
      - 10. —C(═O)NZ³Z⁴,
      - 11. —NZ⁵C(═O)Z²,
      - 12. —NZ⁵C(═O)OZ²,
      - 13. —NZ⁵C(═O)NZ³Z⁴,
      - 14. —S(═O)₂Z⁸,
      - 15. —S(═O)₂NZ³Z⁴,
      - 16. —S(═O)(═NZ⁶)Z²,
      - 17. —S(═Z⁶)(═NZ⁷)Z²,
      - 18. —S(═O)(═NZ⁶)NZ³Z⁴,
      - 19. —NZ⁵S(═O)₂Z²,
      - 20. —NZ⁵S(═O)₂NZ³Z⁴,
      - 21. —NZ⁵S(═O)(═NZ⁶)Z²,
      - 22. —NZ⁵S(═NZ⁶)(═NZ⁷)Z², and
      - 23. —NZ⁵S(═O)(═NZ⁶)NZ³Z⁴,
    - iii. —C(═O)Z²
    - iv. —C(═O)OZ²,
    - v. —C(═O)NZ³Z⁴,
    - vi. —S(═O)₂Z⁸,
    - vii. —S(═O)₂NZ³Z⁴,
    - viii. —S(═O)(═NZ⁶)Z²,
    - ix. —S(═Z⁶)(═NZ⁷)Z²,
    - x. —S(═O)(═NZ⁶)NZ³Z⁴, and
  - (vi) —(CH₂)—NR^3aR^3b;
- n is 0 or 1;
- R^3ais selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) —OZ¹,
    - (d) —SZ¹,
    - (e) —NZ³Z⁴,
    - (f) —C(═O)Z²
    - (g) —C(═O)OH,
    - (h) —C(═O)OZ²,
    - (i) —C(═O)NZ³Z⁴,
    - (j) —NZ⁵C(═O)Z²,
    - (k) —NZ⁵C(═O)OZ²,
    - (l) —NZ⁵C(═O)NZ³Z⁴,
    - (m) —S(═O)₂Z⁸,
    - (n) —S(═O)₂NZ³Z⁴,
    - (o) —S(═O)(═NZ⁶)Z²,
    - (p) —S(═Z⁶)(═NZ⁷)Z²,
    - (q) —S(═O)(═NZ⁶)NZ³Z⁴,
    - (r) —NZ⁵S(═O)₂Z²,
    - (s) —NZ⁵S(═O)₂NZ³Z⁴,
    - (t) —NZ⁵S(═O)(═NZ⁶)Z²,
    - (u) —NZ⁵S(═NZ⁶)(═NZ⁷)Z², and
    - (v) —NZ⁵S(═O)(═NZ⁶)NZ³Z⁴,
    - (iii) —C(═O)Z²,
    - (iv) —C(═O)OZ²,
    - (v) —C(═O)NZ³Z⁴,
    - (vi) —S(═O)₂Z⁸,
    - (vii) —S(═O)₂NZ³Z⁴,
    - (viii) —S(═O)(═NZ⁶)Z²,
    - (ix) —S(═Z⁶)(═NZ⁷)Z²,
    - (x) —S(═O)(═NZ⁶)NZ³Z⁴, and
    - (xi) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, C₂-C₈alkenyl, and C₁-C₆alkyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O;
- R^3bis selected from the group consisting of hydrogen and C₁-C₆alkyl;
- R⁴is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
    - (a) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
      - (1) halogen,
      - (2) cyano,
      - (3) C₁-C₆alkyl,
      - (4) C₃-C₆cycloalkyl,
      - (5) C₁-C₆haloalkyl,
      - (6) —OZ¹,
      - (7) C₂-C₆alkenyl, and
      - (8) C₂-C₆alkynyl,
    - (b) unsubstituted or substituted C₃-C₆cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
      - (7) halogen,
      - (8) cyano,
      - (9) C₁-C₆alkyl,
      - (10) C₃-C₆cycloalkyl,
      - (11) C₁-C₆haloalkyl, and
      - (12) —OZ¹,
    - (c) C₂-C₆alkynyl, and
    - (d) unsubstituted or substituted 3- to 6-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, C₂—C alkenyl, and C₁-C₆alkyl,
  - (viii) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl,
    - (f) —OZ¹, and
    - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹,
  - (ix) unsubstituted or substituted 5- to 9-membered heteroaryl, wherein zero or more of the heteroaryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl,
    - (f) —OZ¹, and
    - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹,
  - (x) unsubstituted or substituted C₃-C₆cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl, and
    - (f) —OZ¹,
  - (xi) unsubstituted or substituted 3- to 6-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:
    - (a) halogen,
    - (b) cyano,
    - (c) C₁-C₆alkyl,
    - (d) C₃-C₆cycloalkyl,
    - (e) C₁-C₆haloalkyl, and
    - (f) —OZ¹,
  - (xii) —S(═O)₂Z², and
  - (xiii) —C(═O)Z²;
- each Z¹is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
    - a. cyano,
    - b. —S(═O)₂Z⁸,
    - c. C₃-C₈cycloalkyl,
    - d. —C(═O)OH,
    - e. —S(═O)₂Z⁸,
    - f. —NZ³Z⁴,
    - g. halogen,
    - h. unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O,
    - i. unsubstituted or substituted 3- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₂-C₆alkenyl, and zero or more of the heteroaryl carbons can be oxidized to form a C═O, and
    - j. unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and cyano,
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of:
    - a. cyano,
    - b. —S(═O)₂Z⁸,
    - c. halogen, and
    - d. unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of:
      - i. cyano,
      - ii. —S(═O)₂Z⁸
      - iii. C₃-C₈cycloalkyl,
      - iv. —C(═O)OH,
      - v. —S(═O)₂Z⁸,
      - vi. —NZ³Z⁴,
      - vii. halogen,
      - viii. unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆Alkyl, and C₂-C₆alkenyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O,
      - ix. unsubstituted or substituted 3- to 9-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆Alkyl, and C₂-C₆alkenyl, and zero or more of the heteroaryl carbons can be oxidized to form a C═O, and
      - x. unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆haloalkyl, cyano, —S(═O)₂Z⁸, —NZ³Z⁴, and unsubstituted or substituted 3- to 8-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of halogen, C₁-C₆Alkyl, and C₂-C₆alkenyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) C₂-C₆alkynyl,
  - (v) C₃-C₆cycloalkenyl,
  - (vi) unsubstituted or substituted C₃-C₈cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (vii) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (viii) unsubstituted or substituted 3- to 8-membered heteroaryl, wherein zero or more of the heteroaryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆Alkyl, and C₂-C₆alkenyl, and
  - (ix) unsubstituted or substituted 3- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆Alkyl, and C₂-C₆alkenyl;
- each Z²is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of C₂-C₆alkenyl, cyano, —C(═O)OH, —S(═O)₂Z⁸, halogen, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) C₂-C₆alkynyl,
  - (v) C₃-C₆cycloalkyl, and
  - (vi) C₃-C₆cycloalkenyl;
- each Z³is independently selected from the group consisting of:
  - (i) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of C₂-C₆alkenyl, cyano, —C(═O)OH, —S(═O)₂Z⁸, halogen, —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (ii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iii) unsubstituted or substituted C₂-C₆alkynyl, wherein one or more substituents are independently selected from the group consisting of cyano, —S(═O)₂Z⁸, halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of cyano, OZ¹, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) unsubstituted or substituted C₃—C cycloalkyl, wherein zero or more of the cycloalkyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O, and
  - (v) unsubstituted or substituted C₃—C cycloalkenyl, wherein zero or more of the cycloalkenyl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, cyano, and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, —S(═O)₂Z⁸, —NZ³Z⁴and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O;
- each Z⁴, Z⁵, Z⁶and Z⁷is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) C₁-C₆alkyl, and
  - (iii) C₃-C₆cycloalkyl;
- each Z⁸is independently selected from the group consisting of:
  - (i) hydrogen,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of halogen, cyano, and C₁-C₆alkyl,
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of halogen and unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of —N(unsubstituted or substituted C₁-C₆alkyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkenyl)Z⁴, —N(unsubstituted or substituted C₂-C₆alkynyl)Z⁴, —N(unsubstituted or substituted C₃—C cycloalkyl)Z⁴, —N(unsubstituted or substituted C₃-C₆cycloalkenyl)Z⁴, and 4- to 8-membered heterocycle, wherein zero or more of the heterocycle carbons can be oxidized to form a C═O,
  - (iv) halogen, and
  - (v) hydroxy.

Embodiment 2: The compound of embodiment 1 of Formula II:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 3: The compound of embodiment 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

Embodiment 4: The compound of embodiment 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 5: The compound of embodiment 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 6: The compound of embodiment 1 of Formula III:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 7: The compound of embodiment 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

Embodiment 8: The compound of embodiment 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 9: The compound of embodiment 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 10: The compound of embodiment 1 of Formula IV:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 11: The compound of embodiment 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, X², and X³are independently selected from the group consisting of —H, —OH, substituted or unsubstituted C₁-C₆alkyl (e.g., methyl) and —O-Methyl.

Embodiment 12: The compound of embodiment 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 13: The compound of embodiment 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 14: The compound of embodiment 1 of Formula V:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 15: The compound of embodiment 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, X², and X³are independently selected from the group consisting of —H, —OH, and —O-Methyl.

Embodiment 16: The compound of embodiment 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 17: The compound of embodiment 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 18: The compound of embodiment 1 of Formula VI:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 19: The compound of embodiment 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 20: The compound of embodiment 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 21: The compound of embodiment 1 of Formula VII:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 22: The compound of embodiment 21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 23: The compound of embodiment 21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 24: The compound of embodiment 1 of Formula VIII:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 25: The compound of embodiment 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

Embodiment 26: The compound of embodiment 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 27: The compound of embodiment 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 28: The compound of embodiment 1 of Formula IX:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

Embodiment 29: The compound of embodiment 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Q¹, Q², and Q³are ═CX¹—, ═CX²—, and ═CX³— respectively.

Embodiment 30: The compound of embodiment 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of:

- (a) halogen,
- (b) cyano,
- (c) C₁-C₆alkyl,
- (d) C₃-C₆cycloalkyl,
- (e) C₁-C₆haloalkyl,
- (f) —OZ¹, and
- (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

Embodiment 31: The compound of embodiment 28, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R⁴is substituted C₆aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are C₁haloalkyl.

Embodiment 32: A compound of Formula X:

[Image Omitted]

- or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
- Z is selected from the group consisting of ═N—, ═N⁺—, and ═C—;
- X¹is selected from the group consisting of —H, —O(C₁-C₆alkyl), substituted or unsubstituted C₁-C₆alkyl (e.g., methyl) and —OH;
- when Z is ═N— or ═N⁺—, R¹is —O—, or absent;
- when Z is ═C—, R¹is —OR⁶, or unsubstituted or substituted C₂-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R⁶;
- R²is selected from the group consisting of:
  - (i) —OR³,
  - (ii) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R³, and
  - (iii) unsubstituted or substituted C₂-C₆alkenyl, wherein one or more substituents are independently selected from the group consisting of R⁴;
- R³is selected from the group consisting of:
  - (i) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R⁴,
  - (ii) —C(═O)R⁴, and
  - (iii) —NHR⁴;
- R⁴is selected from the group consisting of:
  - (i) —C(═O)R⁵,
  - (ii) —S(═O)₂R⁵,
  - (iii) —OH, and
  - (iv) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C₁-C₆Alkyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O;
- R⁵is selected from the group consisting of:
  - (i) —C₁-C₆alkyl,
  - (ii) —C₂-C₆alkenyl,
  - (iii) —O(C₁-C₆alkyl),
  - (iv) —NH—C₁-C₆alkyl,
  - (v) —OH, and
  - (vi) unsubstituted or substituted C₃-C₆cycloalkyl, wherein one or more substituents are independently selected from the group consisting of C₁-C₆Alkyl, and zero or more of the cycloalkyl carbons can be oxidized to form a C═O;
- R⁶is selected from the group consisting of:
  - (i) unsubstituted or substituted C₁-C₆alkyl, wherein one or more substituents are independently selected from the group consisting of R⁶(ii) and R⁶(iii),
  - (ii) unsubstituted or substituted 3- to 6-membered heteroaryl, wherein one or more substituents are independently selected from the group consisting of C₁-C₆Alkyl, and zero or more of the heteroaryl carbons can be oxidized to form a C═O, and
  - (iii) unsubstituted or substituted 3- to 6-membered heterocycle, wherein one or more substituents are independently selected from the group consisting of C₁-C₆Alkyl, and zero or more of the heterocycle carbons can be oxidized to form a C═O.

Embodiment 33: The compound of embodiment 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein X¹, is selected from the group consisting of —H, —OH, substituted or unsubstituted C₁-C₆alkyl (e.g., methyl) and —O-Methyl.

Embodiment 34: The compound of embodiment 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z, is ═N—.

Embodiment 35: The compound of embodiment 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein Z, is ═C—.

Embodiment 36: The compound of embodiment 32, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein R²is C₁alkyl substituted with one R³substituent, and the one R³substituent is —NHR⁴.

Embodiment 37: A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)propionamide;

N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)methanesulfonamide;

N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)propionamide;

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

R)- or (S)—N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)propionamide;

N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)methanesulfonamide;

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)methanesulfonamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetic acid;

N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)- or (S)—N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)- or (S)-methyl ((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)cyclopropanecarboxamide;

N-(methylsulfamoyl)-1-[1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,5-naphthyridin-3-yl]methanamine;

(E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylic acid;

N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)oxy)acetic acid; and

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)oxetan-3-amine.

Embodiment 38: A compound, or a tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)—N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(S)—N-((5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(R)—N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

(S)—N-((5-((3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide;

Methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

(R)-methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

(S)-methyl-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)carbamate;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide;

N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

(S)—N-((6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

Embodiment 39. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide;

(2S)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)pyrrolidine-2-carboxamide;

(2R)-5-oxo-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)pyrrolidine-2-carboxamide;

1-methyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)-1H-imidazole-5-carboxamide;

1-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-2-one;

N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide;

N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acrylamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

(R)- or (S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

2-phenyl-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-acryloyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)glycine;

N-acetyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)glycine;

3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

(R)- or (S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isobutyramide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)benzamide;

1-(4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)prop-2-en-1-one;

N-((6-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

1-methyl-3-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)urea;

N-((7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide;

N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)- or (S)—N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((7-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((7-chloro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((1-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide;

N-((6-ethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)acetamide;

N-((6-cyclopropyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-cyano-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxamide;

N-((6-(difluoromethoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-(difluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

N-((6-ethynyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

Embodiment 40. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(S)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide-2,2,2-d3;

3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

(R)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

(S)-3,3,3-trifluoro-N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propanamide;

N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

(S)—N-((3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

Embodiment 41. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, selected from the group consisting of:

N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(S)—N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide;

(R)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide; and

(S)—N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide.

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

Embodiment 43: The compound of any one of embodiments 1-41, or the pharmaceutical composition of embodiment 42, for use as a medicine.

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

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

Embodiment 46: The compound of embodiment 44, or a pharmaceutical composition according to embodiment 44, wherein the YAP/TAZ-TEAD activation mediated disorder is selected from lung cancer, breast cancer, head and neck cancer, oesophageal 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, mesotheliomas, and/or sarcomas.

Embodiment 47: The compound of embodiment 44, or a pharmaceutical composition according to embodiment 44, wherein the YAP/TAZ-TEAD activation mediated disorder is selected from 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, bronchogenic carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinomas, 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Embodiment 48: 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 for such prevention or treatment an effective dose of the compounds of any one of embodiments 1-41.

Embodiment 49: The method of Embodiment 48, further comprising administering one or more additional medicines selected from the group consisting of EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, and RAS inhibitors.

More generally, the disclosure relates to the compounds of the formulae described herein and embodiments, statements and aspects thereof being useful as agents having biological activity or as diagnostic agents. Any of the uses mentioned with respect to the present disclosure may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.

Compounds of the present disclosure are small molecule YAP/TAZ-TEAD inhibitors. Small molecule YAP/TAZ-TEAD inhibitors are useful, e.g., for the treatment of cancer, including with no limitations, lung cancer, breast cancer, head and neck cancer, oesophageal 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, mesotheliomas, and/or sarcomas. In other embodiments, small molecule YAP/TAZ-TEAD inhibitors are useful for the treatment of cancers characterized by squamous cell carcinomas of the lung, cervix, ovaries, head and neck, oesophagus, and/or skin. In other embodiments, small molecule YAP/TAZ-TEAD inhibitors are useful for the treatment of cancers that originate from neuroectoderm-derived tissues, such as ependymomas, meningiomas, schwannomas, peripheral nerve-sheet tumors and/or neuroblastomas. In other embodiments, small molecule YAP/TAZ-TEAD inhibitors are useful for the treatment of vascular cancers, such as epithelioid haemangioendotheliomas, or for the treatment of supratentorial ependymomas or porocarcinomas. In some embodiments, the solid tumors have gain-of-function gene amplifications, gene fusions or activating mutations in the YAP1 or WWTR1 (TAZ) genes. In some embodiments the solid tumors have loss-of-function mutations or deletions in the NF2, LATS1/2, BAP1, FAT1, SAV1, and/or MST1/2 genes. In some embodiments solid tumors have gain-of-function mutations in the GNAQ and/or GNA11 genes, e.g. in uveal melanoma. In some embodiments, solid cancer are characterized by constitutive nuclear presence of YAP and/or TAZ. In some embodiments, solid cancers are characterized by the overexpression of YAP/TAZ-TEAD signature genes, including but not limited to CTGF, CYR61, AMOTL2, and/or ANKRD1.

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

Small molecule YAP/TAZ-TEAD inhibitors may also be useful when combined, upon simultaneous administration, or subsequent administration, with other agents used for the treatment of cancer. This may include, for instance, the co-treatment with inhibitors or monoclonal antibodies targeting receptor tyrosine kinases such as EGFR (afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab) or AXL (crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, dubermatinib), to components of the RAS-MAPK signaling cascade, including inhibitors of RAS itself (such as AMG510, MRTX849, BI1701963, ARS1620), inhibitors of B-RAF (sorafinib tosylate, dabrafenib, vemurafenib, regorafenib), or MEK1/2 (trametinib, selumetinib, cobimetinib, mirdametinib).

Small molecule YAP/TAZ-TEAD inhibitors may also be useful to treat a metastasized cancer. In some instances, the metastasized cancer is selected from metastasized 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 sarcoma, head and neck cancer, prostate cancer, and meningioma.

In some embodiments, the cancer treated could be malignant pleural mesothelioma or lung cancer.

In some embodiments, the compounds of the disclosure can be used for the treatment of 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 myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, 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 (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

Malignant Pleural Mesothelioma

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

Lung Cancer

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

In some embodiments, small molecule YAP/TAZ-TEAD inhibitors are useful, e.g., for the treatment of congenital disorders. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription 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 loss-of-function mutations or deletions in the NF2 gene. Exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port-Wine stain, and Neurofibromatosis. In some embodiments the congenital disease is Neurofibromatosis, including but not limited to Neurofibromatosis type 2.

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

The compounds of the disclosure can inhibit YAP/TAZ-TEAD transcription activation. The compounds have been shown to inhibit YAP/TAZ-TEAD transcription activity in cellular models and in an animal model. The compounds have also been shown to have an inhibitory effect on cancer cell lines that are dependent on YAP/TAZ-TEAD transcription activity and on the growth of cancer in a xenograft cancer model.

The compounds of the disclosure can optionally be bound covalently to an insoluble matrix and used for affinity chromatography (separations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl are useful in hydrophobic affinity separations).

When using one or more derivatives of the formulae as defined herein:

- the active ingredients of the compound(s) may be administered to the animal or mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
- the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription in humans and other mammals (such as cancer, fibrosis and certain congenital disorders), preferably is a YAP/TAZ-TEAD transcription inhibiting amount of the compounds of the formulae, statements, aspects and embodiments as defined herein and corresponds to an amount which ensures a plasma level that is able to inhibit the YAP/TAZ-TEAD activation and is between 1 μg/ml and 100 mg/ml.

Suitable dosages of the compounds or compositions of the disclosure should be used to treat or prevent the targeted diseases in a subject. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.

According to a particular embodiment of the disclosure, the compounds of the disclosure may be employed in combination with other therapeutic agents for the treatment or prophylaxis of diseases mediated by activity of YAP/TAZ-TEAD transcription in humans and other mammals (such as cancer, fibrosis and certain congenital disorders). The disclosure therefore relates to the use of a composition comprising:

- (a) one or more compounds of the formulae and aspects, statements and embodiments herein, and
- (b) one or more further therapeutic or preventive agents that are 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 compound or composition can be administered concurrently with, prior to, or subsequent to the one or more additional therapeutic agents, which are different from the compound described herein and may be useful as, e.g., combination therapies.

Examples of such further therapeutic agents for use in combinations include agents that are inhibitors of:

- EGFR (such as afatinib, erlotinib hydrochloride, osimertinib, gefitinib, dacomitinib, neratinib, canertinib, cetuximab),
- AXL (such as crizotinib, cabozantinib, gilteritinib, sitravatinib, bemcentinib, dubermatinib),
- components of the RAS-MAPK signaling cascade, including inhibitors of RAS itself (such as AMG510, MRTX849, BI1701963, ARS1620),
- B-RAF (such as sorafinib tosylate, dabrafenib, vemurafenib, regorafenib), or
- MEK1/2 (trametinib, selumetinib, cobimetinib, mirdametinib).

The pharmaceutical composition or combined preparation according to this disclosure may contain the compounds of the present disclosure over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the content of the derivatives of the present disclosure of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.

Those of skill in the art will also recognize that the compounds of the disclosure may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the disclosure is not limited to any particular protonation state—any and all protonated forms of the compounds are intended to fall within the scope of the disclosure.

The term “pharmaceutically acceptable salts” as used herein means the therapeutically active non-toxic salt forms which the compounds of formulae herein are able to form. Therefore, the compounds of this disclosure optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na⁺, Li⁺, K⁺, Ca²⁺ and Mg²⁺. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the disclosure may bear multiple positive or negative charges. The net charge of the compounds of the disclosure may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Typical counter ions 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 counter ion is not a critical feature of the disclosure, and that the disclosure encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the disclosure is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this disclosure. Examples of metal salts which are prepared in this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvates which the compounds of formulae herein as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise compounds of the disclosure in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this disclosure are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

The compounds of the disclosure also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the disclosure include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX₄⁺ (wherein X is C₁-C₄alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na⁺ and NX₄⁺ (wherein X typically is independently selected from H or a C₁-C₄alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present disclosure.

As used herein and unless otherwise stated, the term “enantiomer” means each individual optically active form of a compound of the disclosure, having an optical purity or enantiomeric excess (as determined by methods standard 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%.

The term “isomers” as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or trans-configuration.

Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term “stereoisomerically pure” or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (e.g. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms “enantiomerically pure” and “diastereomerically pure” should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.

Separation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of a compound of the disclosure can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compound. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like. (“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).

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

The present disclosure also includes isotopically labelled compounds, which are identical to those recited in the formulas recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of the present disclosure and pharmaceutically acceptable salts of said compounds or which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the formulas of this disclosure may generally be prepared by carrying out the procedures disclosed in the examples and preparations described herein, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. Also encompassed within the disclosure are modifications of the compounds of formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof using PROTAC technology (Schapira M. et al, Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, the PROTAC technology designs a bifunctional small molecule, one end of which is a compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof, and the other end of which is connected with a ligand of E3 ubiquitin ligase through a connecting chain, to form a target-induced protein degradation complex. Because this degradation has a catalytic effect, a lower dosage can achieve efficient degradation. The compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof can be connected via a linker arm (e.g. long-chain ethylene glycol with the length of 2-10, long-chain propylene glycol with the length of 2-10 and long-chain fatty alkane with the length of 2-10) to a ligand of E3 ubiquitin ligase such as e.g. thalidomide analogs.

The compounds of the disclosure may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.

Subsequently, the term “pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, e.g. the compositions of this disclosure can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.

Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present disclosure. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, e.g. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present disclosure may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.

Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present dislclosure are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C₁₀-C₂₂), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable from coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl group having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl-choline and their mixtures.

Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives 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 non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.

Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C_8-22alkyl (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl.

A more detailed description of surface-active agents suitable for this purpose may be found for instance in “McCutcheon's Detergents and Emulsifiers Annual” (MC Publishing Crop., Ridgewood, New Jersey, 1981), “Tensid-Taschenbucw’, 2 d ed. (Hanser Verlag, Vienna, 1981) and “Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981).

Compounds of the disclosure and their pharmaceutically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.

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

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 solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g. mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w 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 PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.

The oily phase of the emulsions of this disclosure may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

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

Formulations suitable for topical administration to the eye also include eye drops wherein 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% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

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

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.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

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.

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

Compounds of the disclosure can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the disclosure (“controlled release formulations”) in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given disclosed compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the disclosure can be prepared according to conventional methods.

Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.

In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.

Another embodiment of this disclosure relates to various precursor or “pro-drug” forms of the compounds of the present disclosure. It may be desirable to formulate the compounds of the present disclosure in the form of a chemical species which itself is not significantly biologically-active, but which when delivered to the animal, mammal or human will undergo a chemical reaction catalyzed by the normal function of the body of the fish, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing a compound as defined herein. The term “pro-drug” thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.

The pro-drugs of the compounds of the present disclosure can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms. In the present case, however, the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a C—C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used. The counterpart of the active pharmaceutical ingredient in the pro-drug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.

For the purpose of the present disclosure the term “therapeutically suitable pro-drug” is defined herein as “a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal, mammal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome”.

More specifically the term “prodrug”, as used herein, relates to an inactive or significantly less active derivative of a compound such as represented by the structural formulae herein described, which undergoes spontaneous or enzymatic transformation within the body in order to release the pharmacologically active form of the compound. For a comprehensive review, reference is made to Rautio J. et al. (“Prodrugs: design and clinical applications” Nature Reviews Drug Discovery, 2008, doi: 10.1038/nrd2468).

The compounds of the disclosure can be prepared while using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present disclosure.

EXAMPLES
General Syntheses

Abbreviations that may be used in the instant specification, particularly in the schemes and examples, are as follows: AIBN—Azobisisobutyronitrile, aq—Aqueous solution, ACN—acetonitrile, Ac₂O—Acetic anhydride, AcOH—Acetic acid, AcCl—Acetyl chloride, B₂Pin₂-Bis(pinacolato)diboron, BF₃·OEt₂—Boron trifluoride diethyl etherate, BINAP—(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), Bn—benzyl, Boc—tert-butyloxycarbonyl, Boc₂O—Di-tert-butyl dicarbonate, BrettPhos—2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, BrettPhos Pd G3—[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, tBuOH—tert-Butanol, Bz—benzoyl, CDI—1,1′-Carbonyldiimidazole, Conc—Concentrated, mCPBA—meta-Chloroperoxybenzoic acid, CMBP—(Tributylphosphoranylidene)acetonitrile, Cu(OAc)₂—Copper(II)acetate, d—day, DAST—Diethylaminosulfur trifluoride, DBU—1,8-Diazabicyclo[5.4.0]undec-7-ene, DCM—Dichloromethane, DCE—1,2-Dichloroethane, DIAD—Diisopropyl azodicarboxylate, DIPEA—Diisopropyl ethyl amine, DMA—N,N-Dimethylacetamide, DMAP—N,N-Dimethylpyridin-4-amine, DMEM—Dulbecco's Modified Eagle's Medium, DMF—N,N-Dimethylformamide, DMF-DMA—N,N-Dimethylformamide dimethyl acetal, DMP—Dess-Martin periodinane, DMS—dimethylsulfide, DMSO—Dimethyl sulfoxide, DMSO-d₆—Deuterated dimethyl sulfoxide, DPPA—Diphenyl phosphoryl azide, DPPF—1,1′-Ferrocenediyl-bis(diphenylphosphine), EDA—Ethyl diazoacetate, EDC—1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, Et₃N—Triethylamine, Et₃SiH—Triethylsilane, EtOH—Ethanol, EtOAc—Ethyl acetate, Et₂O—Diethyl ether, Eq.—Equivalent, FA—Formic acid, g—gram, h—Hour, HATU—O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HCl—Hydrogen chloride, HEPES—4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HMPA—hexamethylphosphoramide, HPLC—High performance liquid chromatography, IPA—2-propanol, KHMDS—Potassium bis(trimethylsilyl)amide, LAH—Lithium aluminum hydride, LiHMDS—Lithium bis(trimethylsilyl)amide, LDA—Lithium diisopropylamide, LG—Leaving group, L—liter, LC/MS—liquid chromatography/mass spectrometry, Me—methyl, Me₃SI—Trimethylsulfonium iodide, MeI—iodomethane, MeOH—Methanol, MsCl—Methanesulfonyl chloride, min—Minute, mg—Milligram, mL—Milliliter, m/z—Mass-to-charge ratio, NaOAc—sodium acetate, NBS—N-Bromosuccinimide, n-BuLi—n-Butyllithium, NHS—N-Hydroxysuccinimide, Pd(amphos)Cl₂—Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), PCy₃—Tricyclohexylphosphine, Pd(PPh₃)₂Cl₂—Bis(triphenylphosphine)palladium(II)dichloride, Pd(PPh₃)₄—Tetrakis(triphenylphosphine)palladium, Pd₂(dba)₃—Tris(dibenzylideneacetone) dipalladium, Pd(dppf)Cl₂—(1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, Pd(dppf)Cl₂·DCM—(1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with DCM, Pd(OAc)₂—Palladium(II) acetate, PG—protecting group, PMB—para-methoxybenzyl, PPh₃—Triphenylphosphine, ppm—Parts per million, Pet ether—Petroleum ether, PMA—phosphomolybdic acid in EtOH, p-TSA—para-toluenesulfonic acid, Py—pyridine, Raney Ni—Raney nickel, Rf—Retention factor, RLU—Relative light unit, RT—Room temperature, sat—Saturated, SCX—Strong cation exchange, SFC—supercritical fluid chromatography, S-phos—2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, TBAF—Tetra-n-butylammonium fluoride, TBN—tert-Butyl nitrite, t-Bu—tert-butyl, t-BuOH—tert-butyl alcohol, t-BuONO—tert-butyl nitrite, TEA—Triethylamine, THF—Tetrahydrofuran, THP—Tetrahydropyranyl, TFA—Trifluoroacetic acid, TFAA—Trifluoroacetic anhydride, TLC—Thin layer chromatography, TMS—Trimethylsilyl, TMSN₃—Trimethylsilyl azide, TMSI—Trimethylsilyl iodide, T₃P—Propanephosphonic acid anhydride, TPP—Triphenylphosphine, UPLC—ultra high performance liquid chromatography, UV—ultraviolet light, Xanthphos—4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, XPhos—2-Dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl, XPhos-Pd-G2—Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), ZnEt₂—Diethylzinc.

Compounds of the present invention may be prepared according to the general procedure outlined in Scheme 1.

[Image Omitted]

- J is a protecting group (—OPG);
- L and Y are independently: —N═ or —C(H)═;
- A is selected from the group consisting of:
  - (a) halogen,
  - (b) cyano,
  - (c) C₁-C₆alkyl,
  - (d) C₃-C₆cycloalkyl,
  - (e) C₁-C₆haloalkyl,
  - (f) —OZ¹, and
  - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.
    
    All other variables are as described for the compounds of the present invention and its embodiments and formulae.

Alternatively, compounds of the invention may be synthesized according to Scheme 2.

[Image Omitted]

- L and Y are independently: —N═ or —C(H)═.
- A is selected from the group consisting of:
  - (a) halogen,
  - (b) cyano,
  - (c) C₁-C₆alkyl,
  - (d) C₃-C₆cycloalkyl,
  - (e) C₁-C₆haloalkyl,
  - (f) —OZ¹, and
  - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.
    
    All other variables are as described for the compounds of the present invention and its embodiments and formulae.

Alternatively, compounds of the invention may be synthesized according to Scheme 3.

[Image Omitted]

- L and Y are independently: —N═ or —C(H)═.
- X is selected from the group consisting of:
  - (i) hydrogen,
  - (ii) halogen,
  - (iii) cyano,
  - (iv) C₁-C₆alkyl,
  - (v) C₁-C₆haloalkyl,
  - (vi) —OZ¹, and
  - (vii) —NZ³Z⁴.
- A is selected from the group consisting of:
  - (a) halogen,
  - (b) cyano,
  - (c) C₁-C₆alkyl,
  - (d) C₃-C₆cycloalkyl,
  - (e) C₁-C₆haloalkyl,
  - (f) —OZ¹, and
  - (g) unsubstituted or substituted C₆-C₁₀aryl, wherein zero or more of the aryl carbons can be oxidized to form a C═O, and one or more substituents are independently selected from the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆haloalkyl, and —OZ¹.

All other variables are as described for the compounds of the present invention and its embodiments and formulae.

Alternatively, compounds of the invention may be synthesized according to Scheme 4.

[Image Omitted]

Variables L, Y, A, R^aand R^zare as described for the compounds of the present invention and its embodiments and formulae.

Alternatively, compounds of the invention may be synthesized according to Scheme 5.

[Image Omitted]

Variables R^aand R^zare as described for the compounds of the present invention and its embodiments and formulae.

The general schemes depicted above should be considered as non-limiting examples. It will be understood that compounds of the invention may be obtained through other methods which are known to people skilled in the art.

TABLE 1

Structures of compounds of the disclosure and their respective compound numbers.

Cpd.

No.
Structure
Name

1

[Image Omitted]

N-((5-(pyridin-3-yloxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)propionamide

2

[Image Omitted]

N-((5-(pyridin-3-yloxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)methanesulfonamide

3

[Image Omitted]

N-((5-(pyridin-3-yloxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

4

[Image Omitted]

N-((5-((2,6-dioxo-1,2,3,6- tetrahydropyrimidin-4-yl)methoxy)-1- (4-(trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

5

[Image Omitted]

N-((5-((2,6-dioxo-1,2,3,6- tetrahydropyrimidin-4-yl)methoxy)-1- (4-(trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)propionamide

6

[Image Omitted]

N-((5-((2-oxo-1,2-dihydropyridin-4- yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

6-En1

[Image Omitted]

(R)- or (S)-N-((5-((2-oxo-1,2- dihydropyridin-4-yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

6-En2

[Image Omitted]

(R)- or (S)-N-((5-((2-oxo-1,2- dihydropyridin-4-yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

7

[Image Omitted]

N-((5-((2-oxo-1,2-dihydropyridin-4- yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)propionamide

8

[Image Omitted]

N-((5-((2,6-dioxo-1,2,3,6- tetrahydropyrimidin-4-yl)methoxy)-1- (4-(trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl) methanesulfonamide

9

[Image Omitted]

N-((5-((2-oxo-1,2-dihydropyridin-4- yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl) methanesulfonamide

10

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)acrylamide

10-En1

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acrylamide

10-En2

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acrylamide

11

[Image Omitted]

N-((5-(2-(3,5-dioxopiperazin-1- yl)ethyl)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl) acrylamide

12

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)acetamide

12-En1

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

12-En2

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

13

[Image Omitted]

2-(1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)acetic acid

14

[Image Omitted]

N-((5-((3-methyl-2,6-dioxo-1,2,3,6- tetrahydropyrimidin-4-yl)methoxy)-1- (4-(trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

14-En1

[Image Omitted]

(R)- or (S)-N-((5-((3-methyl-2,6- dioxo-1,2,3,6-tetrahydropyrimidin-4- yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

14-En2

[Image Omitted]

(R)- or (S)-N-((5-((3-methyl-2,6- dioxo-1,2,3,6-tetrahydropyrimidin-4- yl)methoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroquinolin-3- yl)methyl)acrylamide

15-En1

[Image Omitted]

(R)- or (S)-methyl ((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)carbamate

15-En2

[Image Omitted]

(R)- or (S)-methyl ((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)carbamate

16

[Image Omitted]

7-(acetamidomethyl)-5-(4- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,5-naphthyridine 1-oxide

17

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)propionamide

17-En1

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)propionamide

17-En2

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)propionamide

18

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3- yl)methyl)cyclopropanecarboxamide

19

[Image Omitted]

N-(methylsulfamoyl)-1-[1-[4- (trifluoromethyl)phenyl]-3,4-dihydro- 2H-1,5-naphthyridin-3- yl]methanamine

20

[Image Omitted]

(E)-3-(1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)acrylic acid

21

[Image Omitted]

N-((6-methoxy-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acrylamide

22

[Image Omitted]

N-((6-methoxy-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

22-En1

[Image Omitted]

(R)- or (S)-N-((6-methoxy-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

22-En2

[Image Omitted]

(R)- or (S)-N-((6-methoxy-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

23

[Image Omitted]

N-((6-hydroxy-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

24

[Image Omitted]

2-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)oxy)acetic acid

25

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)oxetan-3-amine

26

[Image Omitted]

N-((6-methyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

26-En1

[Image Omitted]

(R)- or (S)-N-((6-methyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

26-En2

[Image Omitted]

(R)- or (S)-N-((6-methyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

27

[Image Omitted]

N-((5-oxo-1-(4- (trifluoromethyl)phenyl)-1,2,3,4,5,6- hexahydro-1,6-naphthyridin-3- yl)methyl)acetamide

28

[Image Omitted]

(2S)-5-oxo-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)pyrrolidine-2-carboxamide

29

[Image Omitted]

(2R)-5-oxo-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)pyrrolidine-2-carboxamide

30

[Image Omitted]

1-methyl-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)-1H-imidazole-5- carboxamide

31

[Image Omitted]

1-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)pyrrolidin-2-one

32

[Image Omitted]

N-((8-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)acetamide

33

[Image Omitted]

N-((8-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)acrylamide

34

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)acetamide-2,2,2-d3

34-En1

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide-2,2,2-d3

34-En2

[Image Omitted]

(R)- or (S)-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide-2,2,2-d3

35

[Image Omitted]

2-phenyl-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

36

[Image Omitted]

N-acryloyl-N-((8-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroisoquinolin-6- yl)methyl)glycine

37

[Image Omitted]

N-acetyl-N-((8-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroisoquinolin-6- yl)methyl)glycine

38

[Image Omitted]

3,3,3-trifluoro-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)propanamide

38-En1

[Image Omitted]

(R)- or (S)-3,3,3-trifluoro-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)propanamide

38-En2

[Image Omitted]

(R)- or (S)-3,3,3-trifluoro-N-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)propanamide

39

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)isobutyramide

40

[Image Omitted]

N-((1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)benzamide

41

[Image Omitted]

1-(4-(1-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydroquinolin-3- yl)piperazin-1-yl)prop-2-en-1-one

42

[Image Omitted]

N-((6-(trifluoromethyl)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

43

[Image Omitted]

1-methyl-3-((1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)urea

44

[Image Omitted]

N-((7-bromo-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

45

[Image Omitted]

N-((6-amino-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

46

[Image Omitted]

N-((2-methyl-8-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydroisoquinolin-6- yl)methyl)acetamide

47

[Image Omitted]

N-((3-methyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

47-En1

[Image Omitted]

(R)- or (S)-N-((3-methyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

47-En2

[Image Omitted]

(R)- or (S)-N-((3-methyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

48

[Image Omitted]

N-((5-methyl-6-oxo-1-(4- (trifluoromethyl)phenyl)-1,2,3,4,5,6- hexahydro-1,5-naphthyridin-3- yl)methyl)acetamide

49

[Image Omitted]

N-((7-amino-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

50

[Image Omitted]

N-((7-fluoro-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

51

[Image Omitted]

N-((7-chloro-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

52

[Image Omitted]

N-((6-(dimethylamino)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

53

[Image Omitted]

N-((1-(5-(trifluoromethyl)pyridin-2-yl)- 1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)acetamide

54

[Image Omitted]

N-((6-methyl-5-oxo-1-(4- (trifluoromethyl)phenyl)-1,2,3,4,5,6- hexahydro-1,6-naphthyridin-3- yl)methyl)acetamide

55

[Image Omitted]

N-((6-ethyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

56

[Image Omitted]

N-((5-(4-(trifluoromethyl)phenyl)- 5,6,7,8-tetrahydropyrido[2,3- b]pyrazin-7-yl)methyl) acetamide

57

[Image Omitted]

N-((6-cyclopropyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

58

[Image Omitted]

N-((6-cyano-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

59

[Image Omitted]

7-(acetamidomethyl)-5-(4- (trifluoromethyl)phenyl)-5,6,7,8- tetrahydro-1,5-naphthyridine-2- carboxamide

60

[Image Omitted]

N-((6-(difluoromethoxy)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

61

[Image Omitted]

N-((6-(difluoromethyl)-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

62

[Image Omitted]

N-((6-bromo-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

63

[Image Omitted]

N-((6-ethynyl-1-(4- (trifluoromethyl)phenyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3- yl)methyl)acetamide

Compounds having an asymmetric carbon atom marked with an ″*″ were isolated as a single (R)- or (S)-enantiomer, but the absolute stereochemistry of these compounds has not been determined.

These examples are provided for the purpose of illustrating the present disclosure and by no means should be interpreted to limit the scope of the present disclosure.

Part A: Experimental Chemistry Procedures

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

The reactions were, if necessary, carried out under an inert atmosphere (mostly argon and N₂). The number of equivalents of reagents and the amounts of solvents employed as well as the reaction temperatures and times can vary slightly between different reactions carried out by analogous methods. The work-up and purification methods were adapted according to the characteristic properties of each compound and can vary slightly for analogous methods. The yields of the compounds prepared are not optimized. The indication “equivalents” (“eq.” or “eq” or “equiv.”) means molar equivalents, “RT” or “rt” means room temperature (23±7° C.), “M” are indications of concentration in mol/l, “sol.” means solution, “conc.” means concentrated. The mixing ratios of solvents are usually stated in the volume/volume ratio. To perform reactions under microwave radiation a CEM Microwave (Discover SP) was employed (Heating rate: 2-6° C./see; 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 agitation: electromagnetic stirring; Air Cooling: ≥25 psi (20 L/min flow); System control: Synergy™ software). Key analytical characterization was carried out by means of ¹H-NMR spectroscopy and/or mass spectrometry (MS, m/z for [M+H]+ and/or [M−H]−) for all the exemplary compounds and selected intermediate products. In certain cases, where e.g. regioisomers and/or diatereomers could be/were formed during the reaction, additional analytics, such as, e.g. ¹³C NMR and NOE (nuclear overhauser effect) NMR experiments were in some cases performed. Analytical instruments employed were e.g. for NMR analysis a BRUKER AVANCE 400 MHz (Software Topspin) or a VARIAN MR 400 MHz (VNMRJ Sofware) machine was employed. For LC/MS analysis, e.g. an Acquity UPLC H-Class, Mass: Acquity SQD2 detector (ESI), an Acquity UPLC, Mass: Quatro premierXE Detector (ESI), an Acquity UPLC, Mass: Waters Xevo TQ-S Detector (ESI/ESCI), or an Alliance Waters 2695, Mass: Quattromicro™ (ESCI) multimode ionization was employed. Analytical HPLCs were measured e.g. on Alliance Waters 2695. Analytical SFC were performed e.g. on a PIC solution (Software: SFC PIC Lab Online), a WATERS-X5 (Software MASSLYNX), or a WATERS-UPC2 (Empower). Preparative HPLC separations were performed e.g. on a Waters 2545 (Software Empower), a Gilson (Software Trilution), or a Shimadzu (Software LC Solution). Preparative SFC were performed e.g. on a Waters Thar SFC-80 (Software Chromscope), Waters Thar SFC-150 (Software Chromscope), Waters Thar SFC-200 (Software Chromscope), or a PIC SFC-175 (Software SFC PIC Lab Online). Structures of example compounds that contain stereocenters are drawn and named with absolute stereochemistry, if known. In the case of unknown absolute stereochemistry the compounds can be either racemic, a mixture of diatereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia 1 and Dia 2 means that diastereoisomers were separated but the stereochemistry is unknown. En 1 and En 2 means that both enantiomers were separated but the absolute configuration is unknown. No suffix given after the compound code means that a compound containing stereocenters was obtained as a racemic mixture or a mixture of diatereomers, respectively, unless the chemical name of the compound specifies the exact stereochemistry. The LC/MS analysis mentioned in the experimental part were also performed on an Alliance 15 Waters 2695 HPLC (equipped with a PDA detector) connected to a mass spectrometer Waters Quattromicro (ESCI, multimode ionization) or Waters H-Class Acquity UPLC connected to a QDa or SQD2 mass spectrometer. The separations were performed with 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 to 30-35° C. and the PDA acquisition wavelength was set in the range of 210-400 nm (Acquisition Software: MassLynx). Elutions were carried out with the methods described in the following tables. For Method L1, L2, L4, L6 and L7 Solvent A: FA LC-MS grade 0.05% in milliQ water. Solvent B: ACN LC-MS grade. Column temp=35° C. For Method L3 Solvent A: NH₄HCO₃5 mM in milliQ water. Solvent B: ACN LC-MS grade. Column temp=35° C. For Method L5, Solvent A: TFA LC-MS grade 0.05% in milliQ water. Solvent B: TFA LC-MS grade in ACN. Column temp=35° C. For Method L8 Solvent A: NH₄HCO₃10 mM in milliQ water. Solvent B: ACN LC-MS grade. Column temp=35° C.

HPLC
Time
Solvents
Flow

Method
System
(min)
A (%)
B (%)
(mL/min)
Column

L1
Waters Acquity
0.0
97
3
0.6
Acquity BEH C18 (0.05%

UPLC
0.4
97
3
0.6
FA in solvents A and B)

3.2
2
98
0.6

3.8
2
98
0.6

4.2
97
3
0.6

4.5
97
3
0.6

L2
Waters Acquity
0.0
97
3
0.6
Acquity BEH C18 (0.05%

UPLC
0.4
97
3
0.6
FA in solvents A and B)

2.0
2
98
0.6

3.4
2
98
0.6

3.5
97
3
0.6

4.0
97
3
0.6

L3
Waters Alliance
0.0
95
5
1.3
X-Bridge C18 (5 mM

2695 HPLC
0.5
95
5
1.3
NH₄HCO₃in solvents A and

1.0
85
15
1.3
B)

4.0
2
98
1.3

7.0
2
98
1.3

7.5
95
5
1.3

8.0
95
5
1.3

L4
Waters Acquity
0.0
97
3
0.6
Acquity BEH C18 (0.05%

UPLC
0.4
97
3
0.6
FA in solvents A and B)

2.5
2
98
0.6

3.5
2
98
0.6

3.6
97
3
0.6

4.0
97
3
0.6

L5
Waters Acquity
0.0
97
3
0.6
Acquity BEH C18 (0.05%

UPLC
0.4
97
3
0.6
TFA in solvents A and B)

2.5
2
98
0.6

3.4
2
98
0.6

3.5
97
3
0.6

4.0
97
3
0.6

L6
Waters Acquity
0.0
97
3
0.6
Acquity BEH C18 (0.05%

UPLC
2.5
97
3
0.6
FA in solvents A and B)

7.5
2
98
0.6

9.5
2
98
0.6

9.6
97
3
0.6

10.0
97
3
0.6

L7
Waters Acquity
0.0
97
3
0.55
Acquity BEH C18 (0.05% FA

UPLC
8.5
0
100
0.55
in solvents A and B)

9.0
0
100
0.55

9.5
97
3
0.55

10.0
97
3
0.55

L8
Waters Acquity
0.0
95
5
1.0
X-Bridge C18 (10 mM

UPLC
1.0
95
5
1.0
NH₄HCO₃in solvents A and

3.0
85
15
1.0
B)

7.0
45
55
1.0

11.0
2
98
1.0

16.0
2
98
1.0

16.1
95
5
1.0

20.0
95
5
1.0

The SFC analysis mentioned in the experimental part was performed on a WATERS Acquity UPLC (Empower-3 Software) equipped with an Acquity PDA and an Acquity QDa Detector. The separations were performed using the columns and conditions described in the following table.

S1
Column: Chiralpak AD-H (5 μm, 4.6 × 250 mm): % CO₂: 85; co-solvent: 15 (MeOH);

Flow: 3 g/min; ABPR: 1800 psi; Temperature: 30° C.

S2
Column: Chiralpak AD-H (5 μm, 4.6 × 250 mm) or (5 μM, 4.6 ×150 mm): % CO₂: 90; co-

solvent: 10 (MeOH); Flow: 3 g/min; ABPR: 1800 psi; Temperature: 30° C.

S3
Column: Chiralpak IG (5 μm, 4.6 × 250 mm): % CO₂: 70; co-solvent: 30 (MeOH);

Flow: 3 g/min; ABPR: 1500 psi; Temperature: 30° C.

S4
Column: Chiralpak AD-H (5 μm, 4.6 × 250 mm): % CO₂: 80; co-solvent: 20 (MeOH);

Flow: 3 g/min; ABPR: 1500 psi; Temperature: 30° C.

S5
Column: Chiralpak IC (5 μm, 4.6 × 150 mm): % CO₂: 60; co-solvent: 40 (MeOH);

Flow: 3 g/min; ABPR: 1500 psi; Temperature: 30° C.

S6
Column: Chiralpak AD-H (5 μm, 4.6 × 150 mm): % CO₂: 75; co-solvent: 25 (MeOH);

Flow: 3 g/min; ABPR: 1500 psi; Temperature: 30° C.

S7
Column: (R,R) Whelk-01 (3.5 μm, 4.6 × 150 mm): % CO₂: 90; co-solvent: 10 (iPrOH);

Flow: 3 g/min; ABPR: 1500 psi; Temperature: 30° C.

S8
Column: Chiralpak AD-H (5 μm, 4.6 × 250 mm): % CO₂: 80; co-solvent: 20 (1:1

MeOH/ACN); Flow: 3 g/min; ABPR: 1500 psi; Temperature: 30° C.

Preparative HPLC purifications mentioned in this experimental part have been carried out on a Waters 2545 (Empower software, 2996 PDA detector, 2707 autosampler), a Gilson (Software Trilution, 171 DAD detector, GX-271 autosampler), or a Shimadzu (Software LC Solution, CMB-20A detector, SIL-10AP autosampler). The separations were carried out with columns and solvents described in the following table. Gradient systems for each individual compound were employed using the solvents mentioned in the table. Detection wavelengths were fixed at 210 and 254 nm.

H1
Column: X-Select Phenyl Hexyl (5 μm, 19 × 250 mm); Solvent A: 0.1% FA in Water;

Solvent B: ACN; Flow: 16 mL/min.

H2
Column: Luna C18 (5 μm, 21 × 250 mm); Solvent A: 0.1% FA in Water; Solvent B:

ACN; Flow: 16 mL/min.

H3
Column: X-Select C18 (5 μm, 19 × 250 mm); Solvent A: 0.1% FA in Water; Solvent

B: ACN; Flow: 17 mL/min.

H4
Column: Princeton Sphere C18 (5 μm, 20 × 250 mm); Solvent A: 0.1% FA in Water;

Solvent B: ACN; Flow: 15 mL/min.

H5
Column: X-Select CSH C18 (5 μm, 19 × 250 mm); Solvent A: 0.1% FA in Water;

Solvent B: ACN; Flow: 17 mL/min.

H6
Column: X-Bridge C18 (5 μm, 19 × 250 mm); Solvent A: 0.1% TFA in Water;

Solvent B: ACN; Flow: 15 mL/min.

H7
Column: YMC HydroSphere C18 (5 μm, 20 × 250 mm); Solvent A: 0.1% FA in

Water; Solvent B: ACN; Flow: 18 mL/min.

H8
Column: UniHybride C18 (8 μm, 20 × 150 mm); Solvent A: 0.1% FA in Water;

Solvent B: ACN; Flow: 19 mL/min.

H9
Column: Unisil PhenylHexyl C18 (10 μm, 50 × 150 mm) or (10 μm, 25 × 150 mm);

Solvent A: 0.1% FA in Water Solvent B: ACN; Flow: 20 mL/min.

H10
Column: Princeton C18 (5 μm, 21 × 250 mm); Solvent A: 0.1% FA in Water Solvent

B: ACN; Flow: 20 mL/min.

H11
Column: X-Bridge C18 (5 μm, 19 × 150 mm); Solvent A: 0.1% FA in Water Solvent

B: ACN; Flow: 14 mL/min.

H12
Column: X-Select CSH C18 (5 μm, 25 × 250 mm) or (5 μm, 19 × 250 mm); Solvent A:

0.1% TFA in Water; Solvent B: ACN; Flow: 14 mL/min.

H13
Column: Acquity UPLC BEH (1.7 μm, 2 × 100 mm); Solvent A: 0.1% TFA in Water;

Solvent B: ACN; Flow: 14 mL/min.

H14
Column: X-Select CSH C18 (5 μm, 19 × 250 mm); Solvent A: NH₄HCO₃in Water;

Solvent B: ACN; Flow: 15 mL/min.

Preparative SFC purifications mentioned in this experimental part have been carried out with the following system: a Thar SCF-200 (Software Chromscope) equipped with a UV/PDA detector and a modifier stream injection mode. The separations were performed using the columns and conditions were carried out with the methods described in the following table.

Detection wavelengths were fixed at 224 nm.

K1
Chiralpak IG (5 μm, 30 × 250 mm); % CO₂: 70; % co-solvent: 30 (MeOH); Flow: 90

g/min; ABPR: 100 bar; Temperature: 30° C.

K2
Chiralpak AD-H (5 μm, 30 × 250 mm); % CO₂: 80; % co-solvent: 20 (MeOH); Flow:

60 g/min; ABPR: 100 bar; Temperature: 30° C.

K3
Chiralpak AD-H (5 μm, 30 × 250 mm); % CO₂: 90; % co-solvent: 10 (MeOH); Flow:

90 g/min; ABPR: 100 bar; Temperature: 30° C.

K4
Chiralpak AD-H (5 μm, 21 × 250 mm); % CO₂: 75; % co-solvent: 25 (MeOH); Flow:

70 g/min; ABPR: 100 bar; Temperature: 30° C.

K5
Chiral ART Amylose-C NEO (5 μm, 30 × 250 mm); % CO₂: 85; % co-solvent: 15 (1:1

MeOH/ACN); Flow: 90 g/min; ABPR: 100 bar; Temperature: 30° C.

Example 1: Synthesis of N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide (Cpd. No. 3)

[Image Omitted]

Step-1: A solution of 1-methoxy-2-methyl-3-nitrobenzene (20.0 g, 119.64 mmol) in chloroform (200 mL) was treated with AIBN (3.929 mg, 23.92 mmol) and NBS (23.45 g, 177.99 mmol) at room temperature. The reaction mixture was stirred at 75° C. for 16 h and the reaction was monitored by TLC (mobile phase: 20% EtOAc in pet ether, Rf: 0.45, detection: UV). The reaction mixture was cooled to room temperature, diluted with H₂O (500 mL) and extracted with DCM (2×400 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (30.0 g), which was triturated with pentane to afford 2-(bromomethyl)-1-methoxy-3-nitrobenzene as yellow solid (23.0 g). ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.53-7.55 (dd, 1H), 7.40-7.44 (t, 1H), 7.14-7.16 (d, 1H), 4.83 (s, 2H), 3.98 (s, 3H).

Step-2: A solution of ethyl 2-cyanoacetate (21.21 g, 187.75 mmol) in THF (1700 mL) was cooled to 0° C., treated with LiHMDS (188 mL, 187.75 mmol) and stirred at 0° C. for 30 min before being treated with a solution of 2-(bromomethyl)-1-methoxy-3-nitrobenzene (23.0 g, 93.87 mmol) in THF (600 ml). The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 30% EtOAc in Pet ether, Rf: 0.40, detection: UV). The reaction mixture was quenched with aqueous NH₄Cl (2.0 L) at 0° C. and the product was extracted with EtOAc (3×750.0 ml). The combined organic layer was washed with brine (800 mL), dried over Na₂SO₄and concentrated to afford the crude product (35 g, LC/MS: 20%). The crude product was purified by silica gel column chromatography using 15% EtOAc in pet ether as eluent. The collected fraction was concentrated under reduced pressure to afford ethyl 2-cyano-3-(2-methoxy-6-nitrophenyl)propanoate as a brown liquid (20.0 g, LC/MS: 95%). (LC/MS; m/z 279.2 [M+H]⁺).

Step-3: A solution of ethyl 2-cyano-3-(2-methoxy-6-nitrophenyl)propanoate (20 g, 71.87 mmol) in acetic acid (200.0 mL) was treated with Fe powder (20.1 g, 359. 37 mmol) at 100° C. and stirred at 100° C. for 2 h. Progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in Pet ether, Rf: 0.26, detection: UV). The reaction mixture was diluted with EtOAc, filtered through a pad of Celite and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO₃(3×300 mL), brine (500 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown solid (15 g, LC/MS: 50%). The crude product was triturated with pentane to afford 5-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-carbonitrile as an off white solid (7.5 g, LC/MS: 72%). (LC/MS; m/z 203.3 [M+H]⁺).

Step-4: A solution of 5-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-carbonitrile (7.50 g, 37.09 mmol) in MeOH (195 mL) was treated with NiCl₂·6H₂O (5.29 g, 22.25 mmol), (Boc)₂O (10.22 mL, 44.50 mmol) and NaBH₄(8.14 g, 222.53 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 30% EtOAc in Pet ether, Rf: 0.50, detection: UV). The resulting solution was concentrated, diluted with EtOAc (300 mL) and filtered through a pad of Celite. The filtrate was washed with H₂O (200 mL) and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (7.5 g, LC/MS: 45%). The crude product was triturated with pet ether to afford tert-butyl ((5-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as an off white solid (5.0 g, LC/MS: 60%). (LC/MS; m/z 307.4 [M+H]⁺).

Step-5: A solution of tert-butyl ((5-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (5.0 g, 16.32 mmol) in 1,4-dioxane (65.0 mL) was treated with 1-iodo-4-(trifluoromethyl)benzene (8.87 g, 32.64 mmol), potassium carbonate (6.75 g, 48.96 mmol), CuI (621 mg, 3.26 mmol) and (±)-trans-1,2-diaminocyclohexane (464 mg, 3.26 mmol) at room temperature. The reaction mixture was stirred at 120° C. for 16 h in a sealed tube. Progress of the reaction mixture was monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.63, detection: UV). The resulting solution was diluted with H₂O (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (9.0 g, LC/MS: 34%). The crude product was purified by column chromatography using silica gel and 10% EtOAc in pet ether as an eluent to afford tert-butyl ((5-methoxy-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as an off white solid (2.7 g, LC/MS: 90%). (LC/MS; m/z 451.4 [M+H]⁺).

Step-6: A solution of tert-butyl ((5-methoxy-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (2.7 g, 5.99 mmol) in THF (20 mL) was cooled to 0° C., treated with 1M BH₃. THF complex (26.0 mL, 26.64 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 3 h at 0° C. and monitored by TLC (mobile phase: 30% EtOAc in Pet ether, Rf: 0.54, detection: UV). The reaction mixture was cooled to 0° C. and quenched with aqueous NH₄Cl (80 mL), filtered through a pad of Celite and the filtrate was extracted with EtOAc (3×70 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure and the residue was triturated with n-pentane to afford tert-butyl ((5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as an off white solid (2.0 g, LC/MS: 96%). (LC/MS; m/z 437.4 [M+H]⁺).

Step-7: A solution of tert-butyl ((5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (2.0 g, 4.58 mmol) in DCM (20.0 mL) was treated with BBr₃(23 mL, 22.91 mmol, 1M solution in DCM) at 0° C. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.03, detection: UV). The resulting solution was cooled to 0° C., quenched with saturated sodium bicarbonate and extracted with 20% IPA in chloroform (5×50 mL). The combined organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (1.5 g, LC/MS: 81%). The crude product was triturated with n-pentane to afford 3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-ol as a dark brown solid (1.1 g, LC/MS: 86%). (LC/MS; m/z 323.3 [M+H]⁺).

Step-8: A solution of tert-butyl ((5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (1.1 g, 3.41 mmol) in DCM (11 mL) was treated with TEA (0.70 mL, 5.11 mmol) and (Boc)₂O (0.74 mL, 3.24 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.24, detection: UV). The resulting solution was diluted with H₂O (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (1.2 g, LC/MS: 84%). The crude product was purified by silica gel column chromatography using 25% EtOAc in pet ether as eluent to afford tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as a yellow solid (900 mg, LC/MS: 99%). (LC/MS; m/z 423.2 [M+H]⁺).

Step-9: A solution of tert-butyl ((5-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (650 mg, 1.53 mmol) in DMSO (6.5 mL) was treated with potassium phosphate (979 mg, 4.61 mmol) and 3-iodopyridine (630 mg, 3.07 mmol). The reaction mixture was degassed by bubbling Argon for 10 min and then treated with CuI (29 mg, 0.154 mmol) and picolinic acid (38 mg, 0.308 mmol) at room temperature. The reaction mixture was stirred for 1 h under microwave irradiation at 120° C. and monitored by TLC (mobile phase: 30% EtOAc in Pet ether, Rf: 0.35, detection: UV). The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (3×75 ml). The combined organic layer was washed with brine (80 mL), dried over Na₂SO₄and concentrated to afford the crude product (800 mg, LC/MS: 49%). The crude product was purified by flash chromatography using a 24 g silica column and 20% EtOAc in pet ether as eluent to afford tert-butyl ((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (Int-1) as an off white solid (400 mg, LC/MS: 97%). (LC/MS; m/z 500.2 [M+H]⁺).

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

Step-11: A solution of (5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methanamine (100 mg, 0.250 mmol) in DCM (4.5 mL) was treated with a solution of TEA (38 mg, 0.376 mmol) in DCM (0.25 mL) and a solution of acryloyl chloride (23 mg, 0.250 mmol) in DCM (0.25 mL) under nitrogen atmosphere at 0° C. and stirred for 30 min. Progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM. Rf: 0.32. detection: UV). The reaction mixture was diluted with ice cold water (10 mL) and extracted with DCM (3×15 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (85 mg, LC/MS: 86%). The crude product was purified by preparative HPLC method H1 and the fractions were concentrated under reduced pressure to afford N-((5-(pyridin-3-yloxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide (Cpd. No. 3) as an off-white solid (44.8 mg, LC/MS: 99.5%). (LC/MS; m/z 454.4 [M+H]⁺).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 3: Cpd. No. 1 (using propionyl chloride in step 11), Cpd. No. 2 (using mesyl chloride in step 11).

Example 2: Synthesis of N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide (Cpd. No. 4)

[Image Omitted]

Step-1: A solution of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (5 g, 31.14 mmol) in ACN (100 mL) was treated with Et₃N (6.3 g, 62.28 mmol) and benzoyl chloride (8.7 g, 62.28 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.5, detection: UV). The resulting reaction mixture was concentrated under reduced pressure and the residue was triturated with ACN (50 mL) and dried under reduced pressure to afford 6-(chloromethyl)pyrimidine-2,4-diyldibenzoate (7 g, LC/MS: 98%). (LC/MS; m/z 503.2 [M+H]⁺).

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

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

Step-4: A solution of 6-(((3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl)oxy)methyl)pyrimidine-2,4(1H,3H)-dione TFA salt (110 mg, 0.246 mmol) in 1,4-dioxane (4.0 mL) was treated with a solution of NaHCO₃(82 mg, 0.986 mmol) in H₂O (0.5 mL) and a solution of acryloyl chloride (22.30 mg, 0.246 mmol) in 1,4-dioxane (0.5 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM. Rf: 0.32. detection: UV). The resulting solution was diluted with ice cold H₂O (20 mL) and extracted with DCM (2×15 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (95 mg, LC/MS: 63%). The crude product was purified by preparative HPLC method H2 and the collected fraction was concentrated and lyophilized to afford N-((5-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide (Cpd. No. 4) as a light brown solid (17.4 mg, LC/MS: 99%). (LC/MS; m/z 501.4 [M+H]⁺).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 4: Cpd. No. 5 (using propionyl chloride and Et₃N in DCM in step 4), Cpd. No. 6, Cpd. No. 7 (using propionyl chloride and Et₃N in DCM in step 4), Cpd. No. 8 (using mesyl chloride in step 4), Cpd. No. 9 (using mesyl chloride in step 4), Cpd. No. 14.

The racemic compound Cpd. No. 6 (220 mg) was purified by preparative SFC method K1 to afford Cpd. No. 6-En1 (66 mg) and Cpd. No. 6-En2 (63 mg), each as an off-white solid.

The chiral purity of each enantiomer was assessed by analytical SFC method S3: Cpd. No. 6-En1 (99.4% ee) and Cpd. No. 6-En2 (92% ee).

The following single enantiomers were isolated in a manner similar (use of appropriate purification methods known to the person skilled in the art) to Cpd. No. 6-En1 and Cpd. No. 6-En2: Cpd. No. 14-En1 (99.9% ee), Cpd. No. 14-En2 (99.8% ee).

Example 3: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide (Cpd. No. 10)

[Image Omitted]

Step-1: A solution of tert-butyl (2-formylpyridin-3-yl)carbamate (3.0 g, 13.49 mmol) in DCM (60 mL) was treated with (carbethoxymethylene)triphenylphosphorane (19.39 g, 26.99 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 20% EtOAc in pet ether, Rf: 0.35. detection: UV). The reaction mixture was quenched with water (100 mL) and extracted with DCM (2×80 mL). The organic layer was washed with brine (60 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (5.0 g, LC/MS: 57%). The crude product was purified by flash chromatography using an 80 g silica column and 15% EtOAc in pet ether as an eluent to afford ethyl (E)-3-(3-((tert-butoxycarbonyl)amino)pyridin-2-yl)acrylate as a pale brown semi solid (3.0 g, LC/MS: 99%). (LC/MS; m/z 293.3 [M+H]⁺).

Step-2: A solution of ethyl (E)-3-(3-((tert-butoxycarbonyl)amino)pyridin-2-yl)acrylate (3.0 g, 10.27 mmol) in EtOH (60 mL) was treated with 10% Pd/C (1.5 g) at room temperature. The reaction mixture was stirred at room temperature for 2 h under H₂balloon. The reaction was monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.40. detection: UV). The reaction mixture was filtered through a Celite pad and washed with EtOH (100 mL). The filtrate was concentrated under reduced pressure to afford 3-(3-((tert-butoxycarbonyl)amino)pyridin-2-yl)propanoate as a colorless gum (2.8 g, LC/MS: 99%). (LC/MS; m/z 295.4 [M+H]⁺).

Step-3: A solution of ethyl 3-(3-((tert-butoxycarbonyl)amino)pyridin-2-yl)propanoate (2.8 g, 9.52 mmol) in DCM (28 mL) was treated with TFA (14 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.20. detection: UV). The reaction mixture was concentrated under reduced pressure and the residue was diluted with saturated aqueous NaHCO₃(50 mL) (pH 7-8) and extracted with 10% MeOH in DCM (6×50 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford 3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white solid (1.4 g, LC/MS: 99%). (LC/MS; m/z 149.2 [M+H]⁺).

Step-4: A solution of 3,4-dihydro-1,5-naphthyridin-2(1H)-one (2.0 g, 13.51 mmol) in DMF (20 mL) was treated with NaH (0.6 g, 27.02 mmol, 60%) at 0° C. and the mixture was stirred for 30 min at room temperature. Benzyl chloride (1.7 g, 13.51 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 4 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.42. detection: UV). The resulting solution was quenched with cooled water (100 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (3.0 g, LC/MS: 80%). The crude product was purified by flash chromatography using an 80 g column (silica) and 2% MeOH in DCM as an eluent to afford 1-benzyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a pale-yellow solid (2.6 g, LC/MS: 82%). (LC/MS; m/z 239.2 [M+H]⁺).

Step-5: A solution of 1-benzyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2.6 g, 10.92 mmol) in THF (52 mL) was treated with LiHMDS (1.0 M in THF) (22 mL, 21.84 mmol) at −78° C. Ethyl chloroformate (1.18 mL, 12.01 mmol) was added at −78° C. and the reaction mixture was stirred for 30 min at −78° C. The reaction was monitored by TLC (mobile phase: 70% EtOAc in Pet ether, Rf: 0.37. detection: UV). The reaction mixture was warmed to room temperature, quenched with saturated aqueous NH₄Cl (100 mL) and extracted with EtOAc (2×80 mL). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (3.0 g, LC/MS: 63%). The crude product was purified by flash chromatography using an 80 g silica gel column 50% EtOAc in pet ether as eluent to afford ethyl 1-benzyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate as a pale-yellow solid (2.5 g, LC/MS: 76%). (LC/MS; m/z 311.0 [M+H]⁺).

Step-6: A solution of ethyl 1-benzyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (2.5 g, 10.50 mmol) in THF (25 mL) was treated with 2M BH₃·DMS in THF (20 mL, 52.52 mmol) at 0° C. The reaction mixture was heated to 70° C. and stirred for 90 min. The reaction was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.52. detection: UV). The reaction mixture was cooled to 0° C., quenched with MeOH (30 mL). The reaction mixture was heated to 70° C. and stirred for 6 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.13. detection: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure and the residue was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford as a brown gum (2.5 g, LC/MS: 77%). The crude product was purified by flash chromatography using an 80 g silica gel column and 10% MeOH in DCM as eluent to afford (1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (Int-2) as a pale brown gum (1.5 g, LC/MS: 87%). (LC/MS; m/z 255.3 [M+H]⁺).

Step-7: A solution of Int-2 (1.5 g, 5.90 mmol) in THF (30 mL) was treated with phthalimide (1.3 g, 8.85 mmol), TPP (2.3 g, 8.85 mmol) and DIAD (1.73 mL, 8.85 mmol) at 0° C. The reaction mixture was heated to 70° C. and stirred for 16 h and monitored by TLC (mobile phase: 5% MeOH in DCM. Rf: 0.52. detection: UV). The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2×80 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (5.0 g, LC/MS: 48%). The crude product was purified by reverse phase chromatography using a 120 g C18 column and 20% ACN in H₂O as an eluent to afford 2-((1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isoindoline-1,3-dione as a pale brown solid (1.0 g, LC/MS: 82%). (LC/MS; m/z 384.0 [M+H]⁺).

Step-8: A solution of 2-((1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isoindoline-1,3-dione (1.0 g, 2.61 mmol) in MeOH (1.0 mL) was treated with ammonium formate (1.07 g, 16.97 mmol) and 10% Pd/C (1.5 g) at room temperature. The reaction mixture was stirred for 16 h at 70° C. and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf; 0.33, detection: UV). The reaction mixture was cooled to room temperature and filtered through a Celite pad and rinsed with MeOH (150 mL). The filtrate was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted EtOAc (2×50 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (800 mg, LC/MS: 35%). The crude product was purified by reverse phase column chromatography using a 40 g C18 column and 40% ACN in H₂O as an eluent to afford 2-((1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isoindoline-1,3-dione as a pale brown solid (270 mg, LC/MS: 94%). (LC/MS; m/z 294.3 [M+H]⁺).

Step-9: A solution of 2-((1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isoindoline-1,3-dione (260 mg, 0.64 mmol) in 1,4 dioxane (6 mL) was treated with Cs₂CO₃(720.99 mg, 2.21 mmol). The reaction mixture was degassed by bubbling argon for 5 min, then Pd₂(dba)₃(48.75 mg, 0.053 mmol), X-Phos (50.68 mg, 0.106 mmol) and 1-iodo-4-(trifluoromethyl)benzene (289.64 mg, 1.06 mmol) were added and the reaction mixture was heated to 100° C. by microwave irradiation for 1 h. The reaction was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.39. detection: UV). The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (500 mg, LC/MS: 39%). The crude product was purified by flash chromatography using a 24 g silica gel column and 50% EtOAc in pet ether as eluent to afford 2-((1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)isoindoline-1,3-dione as a pale brown gum (190 mg, LC/MS: 98%). (LC/MS; m/z 437.3 [M+H]⁺).

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

Step-11: A solution of (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanamine (110 mg, 0.35 mmol) in DCM (5.0 mL) was cooled to 0° C. and treated with a solution of TEA (0.25 mL, 1.79 mmol) and a solution of acryloyl chloride (0.029 mL, 0.35 mmol) in DCM (2.0 mL) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.54. detection: UV). The reaction mixture was diluted with H₂O (40 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a pale-yellow gum (150 mg, LC/MS: 81%). The crude product was purified by preparative HPLC method H3 and the collected fractions were concentrated under reduced pressure and lyophilized to afford N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acrylamide (Cpd. No. 10) as a white solid (36.5 mg, LC/MS: 99.2%). (LC/MS; m/z 362.5 [M+H]⁺). Chiral SFC purification: Cpd. No. 10 (308 mg) was purified by preparative SFC method K2 to afford Cpd. No. 10-En1 (109 mg) and Cpd. No. 10-En2 (80 mg), each as an off-white solid. The chiral purity of each enantiomer was assessed by analytical SFC method S1: Cpd. No. 10-En1 (99.9% ee) and Cpd. No. 10-En2 (99.7% ee).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 10: Cpd. No. 12 (using acetyl chloride in step 11).

The following single enantiomers were isolated in a manner similar (use of appropriate purification methods known to the person skilled in the art) to Cpd. No. 10-En1 and Cpd. No. 10-En2: Cpd. No. 12-En1 (99.9% ee), Cpd. No. 12-En2 (99.2% ee), Cpd. No. 15-En1 (96% ee), Cpd. No. 15-En2 (99.6% ee).

Example 4: Synthesis of 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetic acid (Cpd. No. 13)

[Image Omitted]

Step-1: A solution of Int-2 (1.0 g, 3.932 mmol) in DCM (18 mL) was treated with Et₃N (1.644 mL, 11.796 mmol) and a solution of methanesulfonyl chloride (0.493 g, 4.325 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.45, detection: UV). The reaction mixture was diluted with H₂O (20 mL) and extracted with DCM (2×20 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford (1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate as a pale brown semi solid (1.2 g, LC/MS: 93%). (LC/MS; m/z 333.5 [M+H]⁺).

Step-2: A solution of (1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (1.2 g, 3.610 mmol) in DMF (20 mL) was treated with Et₃N (0.753 mL, 5.415 mmol) and tetrabutylammonium cyanide (1.161 g, 4.332 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 50, detection: UV). The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown semi solid (2.1 g, LC/MS: 76%). The crude product was purified by column chromatography (silica gel) using 5% MeOH in DCM as eluent. The pure fraction was concentrated under reduced pressure to afford 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetonitrile as a brown semi solid (1.5 g, LC/MS: 78%). (LC/MS; m/z 264.2 [M+H]⁺).

Step-3: Freshly prepared HCl gas was bubbled through a solution of 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetonitrile (1.0 g, 3.797 mmol) in MeOH (20 mL) for 30 min at 0° C. The reaction mixture was then stirred at 75° C. for 16 h and monitored by TLC (mobile phase: 100% EtOAc, Rf: 50, detection: UV). The reaction mixture was concentrated and quenched with saturated aqueous NaHCO₃(50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄and concentrated to afford methyl 2-(1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetate as a brown semi solid (630 mg, LC/MS: 70%). (LC/MS; m/z 297.3 [M+H]⁺).

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

Step-5: A solution of methyl 2-(1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetate (350 mg, 1.697 mmol) in 1,4-dioxane (12 mL) was treated with Cs₂CO₃(2530.243 mg, 5.940 mmol) and degassed by bubbling argon for 5 min. Pd₂(dba)₃(77.699 mg, 0.085 mmol), X-Phos (80.897 mg, 0.170 mmol) and 1-iodo-4-(trifluoromethyl)benzene (738.564 mg, 2.715 mmol) were added and the mixture was heated to 100° C. by microwave irradiation for 1 h. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.50, detection: UV). The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted EtOAc (2×50 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (1.2 g, LC/MS: 30%). The crude product was purified by column chromatography (silica gel) using 3% MeOH in DCM as eluent. The pure fraction was concentrated under reduced pressure to afford methyl 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetate as a pale brown semi solid (390 mg, LC/MS: 66%). (LC/MS; m/z 351.3 [M+H]⁺).

Step-6: A stirred solution of methyl 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetate (380 mg, 1.085 mmol) in THF (4 mL) and water (4 mL) was treated with lithium hydroxide hydrate (91.029 mg, 2.169 mmol) at room temperature for 16 h. The reaction progress was monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.16, detection: UV). The reaction mixture was concentrated, diluted with water (1 mL), acidified with formic acid (3 drops, pH 2-3) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na₂SO₄and concentrated to afford a brown semi solid (365 mg, LC/MS: 64%). The crude product was purified by preparative HPLC method H2 and the pure fraction was concentrated under reduced pressure to afford 2-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acetic acid (Cpd. No. 13) as a white solid (115 mg, LC/MS: 98%). (LC/MS; m/z 337.3 [M+H]⁺).

Example 5: Synthesis of 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide (Cpd. No. 16)

[Image Omitted]

A stirred solution of Cpd. No. 12 (200 mg, 0.573 mmol) in DCM (8 mL) was cooled to 0° C. and treated with m-CPBA (118.28 mg, 0.687 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.53. detection: UV). The reaction mixture was diluted with H₂O (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a pale brown semi solid (LC/MS: 73%). The crude product was purified by preparative HPLC method H4 and the pure fraction was concentrated under reduced pressure to afford 7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridine 1-oxide as an off white solid (Cpd. No. 16) (35 mg, LC/MS: 99%). (LC/MS; m/z 366.2 [M+H]⁺).

Example 6: Synthesis of N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide (Cpd. No. 17)

[Image Omitted]

Step-1: A solution of titanium tetrachloride (14.365 mL, 131.485 mmol) in CCl₄(20 mL) was treated with THF (300 mL) at 0° C. and stirred for 15 minutes. After 15 minutes, a solution of 3-nitropicolinaldehyde (10 g, 65.742 mmol) in THF (100 mL) and a solution of diethyl malonate (10.029 mL, 65.742 mmol) in THF (100 mL) were added at 0° C. and stirred for 5 min. After 5 minutes, a solution of pyridine (21.199 mL, 262.969 mmol) in THF (100 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h under N₂atmosphere. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.58, detection: UV). The reaction mixture was quenched with ice cold water (600 mL) and extracted with EtOAc (2×600 mL). The combined organic layer was washed with saturated aqueous NaHCO₃(500 mL) and brine (500 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown liquid (24.5 g). The crude product was purified by flash column chromatography (silica) using a gradient of 0-100% EtOAc in hexane as an eluent. The pure fraction was concentrated under reduced pressure to afford diethyl 2-((3-nitropyridin-2-yl)methylene)malonate as a pale brown gum (20.9 g, LC/MS: 96%). (LC/MS; m/z 295.1 [M+H]⁺).

Step-2: A solution of diethyl 2-((3-nitropyridin-2-yl)methylene)malonate (20 g, 67.96 mmol) in MeOH (200 mL) was treated with NaBH₄(5 g, 135 mmol) portion wise at 0° C. The reaction mixture was allowed to warm to 25° C. and stirred for 3 h under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h and progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in pet ether. Rf: 0.63. detection: UV). The reaction mixture was quenched with saturated aqueous NH₄Cl (100 mL) and concentrated under reduced pressure. The remaining aqueous mixture was extracted with EtOAc (2×100 mL) and the combined organic layer was washed with brine (100 mL), dried over Na₂SO₄and concentrated under reduced pressure to a pale brown gum (20 g, LC/MS: 67%). The crude product was purified by column chromatography using silica gel and 40% ethyl acetate in pet ether as an eluent to afford diethyl 2-((3-nitropyridin-2-yl)methyl)malonate as a pale brown liquid (13 g, LC/MS: 93%). (LC/MS; m/z 297.2 [M+H]⁺).

Step-3: A solution of diethyl 2-((3-nitropyridin-2-yl)methyl)malonate (13 g, 43.87 mmol) in AcOH (130 mL) was treated with iron powder (12.2 g, 219.38 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 2 h under nitrogen atmosphere and monitored by TLC (mobile phase: 30% EtOAc in pet ether. Rf: 0.12. detection: UV). The reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed EtOAc (100 mL). The filtrate was concentrated under reduced pressure and the residue was basified (pH-8) with saturated aqueous NaHCO₃and extracted with EtOAc (2×300 mL). The combined organic layer was washed with brine (200 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford ethyl 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate as a white solid (6 g, LC/MS: 99%). (LC/MS; m/z 221.2 [M+H]⁺).

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

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

Step-6: A solution of Int-3 (1 g, 3.24 mmol) in DCM (15 mL) was treated with Et₃N (1.35 mL, 9.73 mmol) and methanesulfonyl chloride (0.31 mL, 3.89 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 100% EtOAc in Pet Ether. Rf: 0.38. detection: UV). The reaction mixture was allowed to cool to 0° C., quenched with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate as a brown gum (1.2 g, LC/MS: 91%). (LC/MS; m/z 387.2 [M+H]⁺).

Step-7: A solution of (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (1.2 g, 3.10 mmol) in DMF (12 mL) and H₂O (4 mL) was treated with NaN₃(0.76 g, 11.68 mmol) at room temperature. The reaction mixture was stirred for 16 h at 70° C. under nitrogen atmosphere. The reaction mixture was stirred at 70° C. for 16 h and progress of the reaction was monitored by TLC (mobile phase: 100% EtOAc. Rf: 0.48. detection: UV). The reaction mixture was allowed to cool to 0° C., quenched with ice-water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (2×50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford 3-(azidomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine as a brown gum (1 g, LC/MS: 82%). (LC/MS; m/z 334.2 [M+H]⁺).

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

Step-9: A solution of (1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanamine (250 mg, 0.81 mmol) in DCM (4 mL) was treated with Et₃N (0.28 mL, 2.03 mmol) and a solution of propionyl chloride (75 mg, 0.81 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and progress of the reaction was monitored by TLC (mobile phase: 10% MeOH in DCM. Rf: 0.5. detection: UV). The reaction mixture was diluted with DCM (50 mL), washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure to afford a yellow gum (260 mg, LC/MS: 73%). The crude product was purified by preparative HPLC method H5 and the collected fraction was concentrated under reduced pressure and lyophilized to afford N-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)propionamide (Cpd. No. 17) as an off-white solid (35 mg, LC/MS: 96%). (LC/MS; m/z 364.3 [M+H]⁺). Chiral SFC purification: Cpd. No. 17 (75 mg) was purified by preparative SFC method K3 to afford Cpd. No. 17-En1 (27 mg) and Cpd. No. 17-En2 (22 mg), each as a pale-yellow solid. The chiral purity of each enantiomer was assessed by analytical SFC method S4: Cpd. No. 17-En1 (99.8% ee), Cpd. No. 17-En2 (99% ee).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 17: Cpd. No. 18 (using cyclopropane carboxylic acid, HATU and DIPEA in DMF in step 9), Cpd. No. 19 (using MsCl in step 9), Cpd. No. 21 (using 6-methoxy-3-nitropicolinaldehyde in step 1 and acryloyl chloride in step 9), Cpd. No. 22 (using 6-methoxy-3-nitropicolinaldehyde in step 1 and AcCl in step 9), Cpd. No. 25 (using oxetan-3-one, NaCNBH₃and AcOH in DCE in step 9). Cpd. No. 28 (using (S)-5-oxopyrrolidine-2-carboxylic acid, HATU and DIPEA in DMF in step 9), Cpd. No. 29 (using (R)-5-oxopyrrolidine-2-carboxylic acid, HATU and DIPEA in DMF in step 9), Cpd. No. 30 (using 1-methyl-1H-imidazole-5-carboxylic acid, HATU and DIPEA in DMF in step 9), Cpd. No. 31 (using 4-chlorobutanoyl chloride in step 9, followed by cyclization with KotBu in THF), Cpd. No. 34 (using acetic-2,2,2-d3 anhydride, TEA and DMAP in step 9), Cpd. No. 35 (using 2-phenylacetyl chloride in step 9), Cpd. No. 38 (using 3,3,3-trifluoropropanoyl chloride in step 9), Cpd. No. 39 (using isobutyric acid, HATU and DIPEA in DMF in step 9), Cpd. No. 40 (using benzoyl chloride in step 9), Cpd. No. 43 (using methylcarbamic chloride in step 9), Cpd. No. 53 (using 2-bromo-5-(trifluoromethyl)pyridine in step 5).

The following single enantiomers were isolated in a manner similar (use of appropriate purification methods known to the person skilled in the art) to Cpd. No. 17-En1 and Cpd. No. 17-En2: Cpd. No. 22-En1 (99.8% ee), Cpd. No. 22-En2 (99.4% ee), Cpd. No. 34-En1 (99.8% ee), Cpd. No. 34-En2 (98% ee), Cpd. No. 38-En1 (99.4% ee), Cpd. No. 38-En2 (94% ee).

Example 7: Synthesis of (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylic acid (Cpd. No. 20)

[Image Omitted]

Step-1: A solution of Int-3 (500 mg, 1.62 mmol) in DCM (10 mL) was treated with DMP (1.37 g, 3.24 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in pet ether. Rf: 0.49. detection: PMA stain). The reaction mixture was quenched with saturated aqueous NaHCO₃and extracted with DCM (2×40 mL). The combined organic layer was washed with aqueous sodium thiosulfate (30 mL) and brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbaldehyde as a brown gum (500 mg, LC/MS: 37%). (LC/MS; m/z 307.3 [M+H]⁺).

Step-2: A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbaldehyde (500 mg, 1.63 mmol) in DCM (10 mL) was treated with ethyl (triphenylphosphoranylidene)acetate (1.13 g, 3.26 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in pet ether. Rf: 0.75, detection: UV). The reaction mixture was quenched with water (20 mL) and extracted with DCM (2×40 mL). The combined organic layer was washed with brine (40 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown liquid (500 mg, LC/MS: 31%). The crude product was purified by column chromatography using silica gel and 20% EtOAc in pet ether as an eluent to afford ethyl (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylate as a brown liquid (300 mg, LC/MS: 86%). (LC/MS; m/z 377.4 [M+H]⁺).

Step-3: A solution of ethyl (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylate (180 mg, 0.47 mmol) in MeOH (2 mL) and water (0.5 mL) was treated with a solution of sodium hydroxide (38 mg, 0.95 mmol) in water (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM. Rf: 0.22. detection: UV). The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), adjusted to pH-5 with addition of 1N HCl and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford a yellow gum (165 mg, LC/MS: 58%). The crude product was purified by preparative HPLC method H6 and the collected fraction was concentrated under reduced pressure to afford (E)-3-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)acrylic acid (Cpd. No. 20) as a pale yellow solid (26.3 mg, LC/MS: 95%). (LC/MS; m/z 349.3 [M+H]⁺).

Example 8: Synthesis of 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)oxy)acetic acid (Cpd. No. 24)

[Image Omitted]

Step-1: A stirred solution of 2-methyl-3-nitropyridine (20 g, 144.802 mmol) in MeOH (800 mL) was treated with dimethyl oxalate (153.894 g, 1303.215 mmol) and sodium methoxide (200 mL, 30% in MeOH) at room temperature. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere and monitored by TLC (30% EtOAc in pet ether, Rf: 0.4, detection: UV). The reaction mixture was quenched with water (3000 mL) and extracted with EtOAc (2×1250 mL). The combined organic layer was washed with brine (2×500 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford methyl 3-(3-nitropyridin-2-yl)-2-oxopropanoate as a dark orange solid (20 g, LC/MS: 94%). (LC/MS; m/z 225.2 [M+H]⁺).

Step-2: A stirred solution of methyl 3-(3-nitropyridin-2-yl)-2-oxopropanoate (6.0 g, 26.765 mmol) in THF (120 mL) was added (0.608 g, 16.059 mmol) at 0° C. The resulting reaction mixture was allowed to stir at room temperature for 16 h under nitrogen atmosphere and monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.3, detection: UV). The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2×300 mL). The combined organic layer was washed with brine (2×200 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford methyl 2-hydroxy-3-(3-nitropyridin-2-yl)propanoate as a dark brown gum (1.0 g, LC/MS: 71%). (LC/MS; m/z 227.1 [M+H]⁺).

Step-3: A solution of methyl 2-hydroxy-3-(3-nitropyridin-2-yl)propanoate (1.0 g, 4.421 mmol) in MeOH (20 mL) was treated with 10% Pd/C (0.5 g) at 26° C. under a nitrogen atmosphere. The reaction vessel was sealed and shaken vigorously under hydrogen pressure (50 psi) at room temp for 24 h. The progress of the reaction was monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.2, detection: UV). The reaction mass was filtered through a Celite pad and washed with 10% MeOH in DCM (2×150 mL). The filtrate was concentrated under reduced pressure to afford 3-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a brown solid (0.7 g, LC/MS: 73%). (LC/MS; m/z 165.0 [M+H]⁺).

Step-4: A stirred solution of 3-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one (700 mg, 4.264 mmol) in THF (7.0 mL) was added 1M BH₃in THF (42 mL, 42.640 mmol) at 0° C. The resulting reaction mixture was stirred at 70° C. for 16 h under nitrogen atmosphere and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.20, detection: UV). The reaction mixture was quenched with MeOH (100 mL) and refluxed for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with 10% MeOH in DCM (2×30 mL). The combined organic layer was washed with brine (50 mL) dried over sodium sulphate and concentrated to afford 1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol as a brown gum (700 mg, LC/MS: 51%). (LC/MS; m/z 151.0 [M+H]⁺).

Step-5: A stirred solution of 1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol (700 mg, 4.661 mmol) in 1,4-dioxane (14 mL) was treated with sodium tert-butoxide (1344 mg, 13.98 mmol) and degassed by bubbling argon for 10 min. X-Phos (444 mg, 0.932 mmol), Pd₂(dba)₃(426.820 mg, 0.466 mmol) and 1-iodo-4-(trifluoromethyl)benzene (1521.4 mg, 5.593 mmol) were added and the reaction mixture was stirred at 100° C. for 16 h in sealed tube. The reaction mixture was monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.38, detection: UV). The reaction mass was filtered through a pad of Celite and washed with EtOAc (2×30 mL). The filtrate was washed with water (50 mL) and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (800 mg, LC/MS: 40%). The crude product was purified by column chromatography using silica gel and 6% MeOH in DCM as eluent. The fractions were collected and concentrated under reduced pressure to afford 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol as a brown solid (300 mg, LC/MS: 84%). (LC/MS; m/z 295.3 [M+H]⁺).

Step-6: A stirred solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol (300 mg, 1.019 mmol) in toluene (4.0 mL) was treated with a solution of sodium hydroxide (1019.4 mg, 25.486 mmol) in water (2.0 mL), tetrahexylammonium hydrogen sulfate (13.8 mg, 0.031 mmol) and tert-butyl 2-bromoacetate (298.3 mg, 1.529 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.5, detection: UV). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine (40 mL), dried over sodium sulphate and concentrated under reduced pressure to afford methyl 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)oxy)acetate as a brown gum (300 mg, LC/MS: 50%). (LC/MS; m/z 409.4 [M+H]⁺).

Step-7: A solution of tert-butyl 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)oxy)acetate (290 mg, 0.710 mmol) in DCM (5.0 mL) was treated with TFA (1.0 mL)) at 0° C. The reaction mixture was stirred at room temperature for 4 h. The progress of reaction was monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.03, detection: UV). The reaction mixture was concentrated under reduced pressure to afford a brown gum (300 mg, LC/MS: 45%). The crude product was purified by preparative HPLC method H5. The pure fractions were combined and lyophilized to afford 2-((1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)oxy)acetic acid (Cpd. No. 24) as a brown semi-solid (15 mg, LC/MS: 99%). (LC/MS; m/z 353.3 [M+H]⁺).

Example 9: Synthesis of N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide (Cpd. No. 11)

[Image Omitted]

Step-1: A solution of Int-1 (1.0 g, 2.36 mmol) in DCM (20 mL) was cooled to 0° C. and treated with Et₃N (0.99 mL, 7.10 mmol), DMAP (0.058 g, 0.47 mmol) and Tf₂O (0.59 mL, 3.55 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 30% EtOAc in Pet ether, Rf: 0.62. detection: UV). The reaction mixture was diluted with H₂O (50 mL) and extracted with DCM (2×30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (1.5 g, LC/MS: 80%). The crude product was purified by flash chromatography using a 40 g silica column and 20% EtOAc in Pet ether as an eluent to afford 3-(((tert-butoxycarbonyl)amino)methyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl trifluoromethanesulfonate as a pale yellow gum (940 mg, LC/MS: 96%). (LC/MS; m/z 455.1 [M+H-Boc]⁺).

Step-2: In a glass screw-cap pressure vessel, a solution of 3-(((tert-butoxycarbonyl)amino)methyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl trifluoromethanesulfonate (940 mg, 1.69 mmol) in 1,4-dioxane (20 mL) was treated with LiCl (178.15 mg, 4.24 mmol). The reaction mixture was degassed by bubbling argon for 10 min, PdCl₂(PPh₃)₂(119.11 mg, 0.17 mmol) and tributyl(vinyl)stannane (0.99 mL, 3.39 mmol) were added, and the vessel was sealed with a Teflon screw-cap. The reaction mixture was heated and stirred at 100° C. for 16 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.5. detection: UV). The reaction mixture was cooled to room temperature and diluted with water (80 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (1.0 g, LC/MS: 85%). The crude product was purified by flash chromatography using a 40 g silica column and a gradient a gradient of EtOAc in pet ether as an eluent to afford tert-butyl ((1-(4-(trifluoromethyl)phenyl)-5-vinyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as an off white solid (0.7 g, LC/MS: 96%). (LC/MS; m/z 433.3 [M+H]⁺).

Step-3: A solution of tert-butyl ((1-(4-(trifluoromethyl)phenyl)-5-vinyl-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (900 mg, 2.08 mmol) in THF (10 mL) was treated with 1M BH₃. THF (3.12 mL, 3.12 mmol) at 0° C. and stirred for 1 h. The reaction mixture was quenched with H₂O (3.12 mL) at 0° C. and stirred for 1 h. Then, 20% aqueous NaOH (3.12 mL) and 30% aqueous H₂O₂solution (3.12 mL) were added at 0° C. and the mixture was stirred at 0° C. for 1 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.3, detection: UV). The resulting solution was diluted with H₂O (50 mL) and extracted with EtOAc (100 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (800 mg, LC/MS: 81%). The crude product was purified by flash chromatography using a 24 g silica column and 15% EtOAc in Pet ether as an eluent to afford tert-butyl ((5-(2-hydroxyethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as a pale yellow gum (500 mg, LC/MS: 94%). (LC/MS; m/z 451.3 [M+H]⁺).

Step-4: A stirred solution of tert-butyl ((5-(2-hydroxyethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (330 mg, 0.733 mmol) in DCM (6.0 mL) was treated with DMP (466 mg, 1.09 mmol) at 0° C. The resulting reaction mixture was allowed to warm to 26° C. and stirred for 2 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC (mobile phase: 20% EtOAc in Pet. ether, Rf: 0.58, detection: UV). The reaction mixture was allowed to cool to 0° C., quenched with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with saturated aqueous sodium bicarbonate (5×30 mL), brine (2×50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a pale yellow gum (500 mg, LC/MS: 30%). The crude product was purified by column chromatography using silica gel and a gradient of 0-20% EtOAc in pet. ether as eluent. The pure fraction was concentrated under reduced pressure to afford tert-butyl ((5-(2-oxoethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as a brown gum (150 mg, LC/MS: 66%). (LC/MS; m/z 449.3 [M+H]⁺).

Step-5: A stirred solution of tert-butyl ((5-(2-oxoethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (150 mg, 0.334 mmol) in DCE (2.0 mL) was treated with piperazine-2,6-dione (76.32 mg, 0.669 mmol) and AcOH (80 mg, 1.33 mmol) at 0° C. The reaction mixture was allowed to warm to 26° C. and stirred for 2 h under nitrogen atmosphere. Then sodium cyanoborohydride (105 mg, 1.67 mmol) was added portion-wise at 0° C. The resulting reaction mixture was allowed to warm to 26° C. and stirred for 2 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC (mobile phase: 30% EtOAc in Pet. ether, Rf: 0.46, detection: UV). The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (200 mg, LC/MS: 39%). The crude product was purified by column chromatography on silica gel 0-30% EtOAc in pet. ether as eluent. The pure fractions were combined and concentrated under reduced pressure to afford tert-butyl ((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate as a brown solid (120 mg, LC/MS: 52%). (LC/MS; m/z 547.3 [M+H]⁺).

Step-6: A stirred solution of tert-butyl ((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)carbamate (150 mg, 0.274 mmol) in DCM (2.0 mL) was treated with TFA (0.5 mL) at 0° C. The resulting reaction mixture was allowed to warm to 26° C. and stirred for 2 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in Pet. ether, Rf: 0.03, detection: UV). The reaction mixture was concentrated, and the residue was dissolved in DCM and concentrated to afford 4-(2-(3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl)ethyl)piperazine-2,6-dione as a brown gum (120 mg, LC/MS: 51%). (LC/MS; m/z 447.3 [M+H]⁺).

Step-7: A solution of 4-(2-(3-(aminomethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-5-yl)ethyl)piperazine-2,6-dione (120 mg, 0.214 mmol) in 1,4-dioxane (3.5 mL) was treated with a solution of NaHCO₃(90 mg, 1.071 mmol) in H₂O (1.0 mL) and a solution of acryloyl chloride (19 mg, 0.214 mmol) in 1,4-dioxane (0.5 mL) at 0° C. and stirred for 30 min. The progress of the reaction monitored by TLC (mobile phase: 10% MeOH in DCM. Rf: 0.32. detection: UV). The reaction mixture was diluted with ice cold water (10 mL) and extracted with DCM (3×15 mL). The combined organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (120 mg, LC/MS: 49%). The crude product was purified by preparative HPLC method H7 and the collected fractions were concentrated under reduced pressure to afford N-((5-(2-(3,5-dioxopiperazin-1-yl)ethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acrylamide (Cpd. No. 11) as an off-white solid (15 mg, LC/MS: 96%). (LC/MS; m/z 449.4 [M+H]⁺).

Example 10: Synthesis of N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 23)

[Image Omitted]

A solution of Cpd. No. 22 (340 mg, 0.89 mmol) in DMF (5 mL) and H₂O (0.1 mL) was treated with phosphoryl tribromide (2.05 g, 7.17 mmol) at 0° C. The resulting reaction mixture was stirred at 100° C. for 5 h and monitored by TLC (mobile phase: EtOAc. Rf: 0.28. detection: UV). The reaction mixture was diluted with cold water (40 mL) and extracted with EtOAc (2×90 mL). The combined organic layer was washed with cold water (2×30 mL), brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure and dried to afford a brown gum (280 mg, LC/MS: 38%). The crude product was purified by preparative HPLC method H8. The collected fraction was concentrated and lyophilized to afford N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 23) as an off-white solid (33 mg, LC/MS: 97%). (LC/MS; m/z 366.3 [M+H]⁺).

Example 11: Synthesis of N-((6-bromo-1-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (Cpd. No. 62) and N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 26)

[Image Omitted]

Step-1: A solution of Cpd. No. 12 (500 mg, 1.43 mmol) in DCM (10 mL) was treated with NBS (254.75 mg, 1.43 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 10% MeOH/DCM, Rf: 0.72, detection: UV). The reaction mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (1.0 g, LC/MS: 70%). The crude product was purified by flash chromatography (silica gel) using a gradient of 50-80% EtOAc in pet ether as eluent to afford N-((6-bromo-1-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (600 mg, LC/MS: 81%) as a brown gum. 100 mg of the sample was purified by prep-HPLC method H9 to afford N-((6-bromo-1-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (Cpd. No. 62) as an off white solid (62 mg, LC/MS: 99%). (LC/MS; m/z 428.2 [M+H]⁺).

Step-2: A solution of Cpd. No. 62 (120 mg, 0.28 mmol) in 1,4-dioxane (2 mL) and H₂O (0.5 mL) was treated with K₂CO₃(116.18 mg, 0.84 mmol) and trimethylboroxine (97.2 mg, 0.56 mmol) at room temperature. The mixture was degassed with argon for 10 min and PdCl₂(dppf) (20.4 mg, 0.028 mmol) was added. The reaction mixture was stirred at 100° C. for 12 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether. Rf: 0.34. detection: UV). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (100 mg, LC/MS: 52%). The crude product was purified by preparative HPLC method H10 to afford N-((6-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 26) as a pale yellow solid (25 mg, LC/MS: 97%). (LC/MS; m/z 364.3 [M+H]⁺).

Chiral SFC purification: Cpd. No. 26 (56 mg) was purified by preparative SFC method K4 to afford Cpd. No. 26-En1 (20 mg) and Cpd. No. 26-En2 (21 mg), each as an off white solid. The chiral purity of each enantiomer was assessed by analytical SFC method S6: Cpd. No. 26-En1 (99.8% ee), Cpd. No. 26-En2 (98.8% ee).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 26: Cpd. No. 42 (using methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, HMPA and CuI in DMF in step 2), Cpd. No. 55 (using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane in step 2 followed by alkene reduction using H₂and Pd/C in MeOH), Cpd. No. 57 (using cyclopropylboronic acid, Pd(OAc)₂, PCy₃and K3PO₄in toluene and water in step 2), Cpd. No. 58 (using CuCN in DMF in step 2), Cpd. No. 59 (using CuCN in DMF in step 2), Cpd. No. 63 (using TMS-acetylene, CuI, Et₃N and PdCl₂(PPh₃)₂in MeCN in step 2 followed by desilylation with K₂CO₃in MeOH).

Example 12: Synthesis of N-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 27)

[Image Omitted]

Step-1: A solution of ethyl 5-bromo-2-methylnicotinate (5.0 g, 20.48 mmol) and 1,3,5-triazine (1.8 g, 22.53 mmol) in dry DMSO (7.5 mL) was stirred at room temperature for 30 mi. t-BuOK (2.5 g, 22.53 mmol) and DMSO (15 mL) were added at room temperature, and the reaction mixture was stirred at 80° C. for 30 min. The mixture was cooled to room temperature, diluted with H₂O (30 mL) and AcOH (1.3 g, 22.53 mmol) and degassed with nitrogen for 16 h using a solution of 6N NaOH (300 mL) to scrub excess HCN in the exhaust. The reaction was monitored by TLC (mobile phase: 50% EtOAc in Pet ether, Rf: 0.3, detection: UV). The resulting solution was diluted with H₂O (100 mL), filtered, washed with n-pentane (80 mL) and dried under vacuum to afford the crude product (6.0 g, LC/MS: 49%). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in Pet ether as eluent to afford 3-bromo-1,6-naphthyridin-5(6H)-one (Int-4) as an off white solid (4.0 g, LC/MS: 91%). (LC/MS; m/z 225.2 [M+H]⁺).

Step-2: A solution of Int-4 (4 g, 17.77 mmol) in MeOH (70 mL) and DMF (15 mL) was treated with NaOAc (2.2 g, 26.66 mmol) and degassed with argon for 5 min followed by addition of DPPF (1.9 g, 2.99 mmol) and PdCl₂(dppf)·DCM (2.9 g, 3.55 mmol), before being degassed with argon for an additional 5 min. The reaction mixture was stirred at 80° C. for 24 h in a steel bomb under CO (50 psi) and monitored by TLC (mobile phase: 50% EtOAc in Pet ether, Rf: 0.25, detection: UV). The resulting solution was filtered through a pad of Celite and washed with 10% MeOH in DCM (150 mL). The filtrate was concentrated under reduced pressure, diluted with H₂O (200 mL) and extracted with 10% MeOH in DCM (350 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (3.0 g, LC/MS: 69%). The crude product was purified by flash chromatography (C18) using 20% ACN in H₂O as eluent to afford methyl 5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as an off white solid (1.4 g, LC/MS: 92%). (LC/MS; m/z 205.2 [M+H]⁺).

Step-3: A solution of methyl 5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (1.4 g, 6.86 mmol) in DMF (15 mL) was treated with Cs₂CO₃(4.5 g, 13.72 mmol) and PMB-Cl (1.3 g, 8.23 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.5, detection: UV). The resulting solution was diluted with ice cold H₂O (80 mL) and extracted with EtOAc (150 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (2.0 g, LC/MS: 61%). The crude product was purified by flash chromatography (silica gel) using 20% EtOAc in pet ether as eluent. The pure fractions were collected and concentrated under reduced pressure to afford methyl 6-(4-methoxybenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as an off white solid (1.4 g, LC/MS: 92%). (LC/MS; m/z 325.3 [M+H]⁺).

Step-4: A solution of methyl 6-(4-methoxybenzyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (1.4 g, 4.32 mmol) in EtOH (20 mL) was treated with Pd(OH)₂(0.7 g), stirred at 70° C. for 4 h under H₂(50 psi) and monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.26, detection: UV). The resulting solution was filtered through a pad of Celite and washed with MeOH (60 mL). The filtrate was concentrated under reduced pressure to afford the crude product (1.4 g, LC/MS: 48%). The crude product was purified by flash chromatography (silica gel) using 60% EtOAc in pet ether as eluent to afford methyl 6-(4-methoxybenzyl)-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate as an off white solid (850 mg, LC/MS: 66%). (LC/MS; m/z 329.3 [M+H]⁺).

Step-5: A solution of methyl 6-(4-methoxybenzyl)-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate (850 mg, 2.59 mmol) in dioxane (12 mL) was treated with Cs₂CO₃(2.1 g, 6.47 mmol) at room temperature and degassed with argon for 5 min, followed by addition of XPhos (247 mg, 0.52) and Pd₂(dba)₃(237 mg, 0.25 mmol). The mixture was degassed for 5 min and treated with 1-iodo-4-(trifluoromethyl)benzene (846 mg, 3.11 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 1 h under microwave irradiation and monitored by TLC (mobile phase: 70% EtOAc in Pet ether, Rf: 0.4, detection: UV). The resulting solution was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was washed with H₂O (80 mL) and the aqueous layer was extracted with EtOAc (80 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product (850 mg). The crude product was purified by flash chromatography (silica gel) using 40% EtOAc in pet ether as eluent. The fractions were collected and concentrated under reduced pressure to get methyl 6-(4-methoxybenzyl)-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate as a light brown gum (350 mg, LC/MS: 92%). (LC/MS; m/z 473.4 [M+H]⁺).

Step-6: A solution of methyl 6-(4-methoxybenzyl)-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate (350 mg, 0.74 mmol) in THF (10 mL) was treated with 2M LAH (0.56 mL, 1.11 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.2, detection: UV). The resulting solution was quenched with wet Na₂SO₄, diluted with EtOAc (50 mL), filtered through a celite bed and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure to afford 3-(hydroxymethyl)-6-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one (300 mg, LC/MS: 85%). (LC/MS; m/z 445.4 [M+H]⁺).

Step-7: A solution of 3-(hydroxymethyl)-6-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one (300 g, 0.67 mmol) in DCM (5 mL) was treated with Et₃N (102 mg, 1.01 mmol) and mesyl chloride (92 mg, 0.81 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.3, detection: UV). The resulting solution was diluted with H₂O (50 mL) and extracted with DCM (80 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford (6-(4-methoxybenzyl)-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl methanesulfonate (300 mg, LC/MS: 85%). (LC/MS; m/z 523.4 [M+H]⁺).

Step-8: A solution of (6-(4-methoxybenzyl)-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl methanesulfonate (300 mg, 0.57 mmol) in DMF (7 mL) and H₂O (3 mL) was treated with sodium azide (187 mg, 2.87 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 16 h and monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.55, detection: UV). The resulting solution was diluted with cooled H₂O (80 mL) and extracted with EtOAc (120 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (300 mg, LC/MS: 66%). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in pet ether as eluent to afford 3-(azidomethyl)-6-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one as a pale yellow gum (260 mg, LC/MS: 86%). (LC/MS; m/z 470.1 [M+H]⁺).

Step-9: A solution of 3-(azidomethyl)-6-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one (260 mg, 0.55 mmol) in MeOH (5 mL) was treated with 10% Pd/C (130 mg, 50% wt/wt) at room temperature. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.2, detection: UV). The resulting solution was filtered on bed of Celite and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to afford 3-(aminomethyl)-6-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one (200 mg, LC/MS: 88%). (LC/MS; m/z 444.4 [M+H]⁺).

Step-10: A solution of 3-(aminomethyl)-6-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one (200 mg, 0.45 mmol) in DCM (4 mL) was treated with Et₃N (137 mg, 1.35 mmol) and a solution of acetyl chloride (35 mg, 0.45 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.4, detection: UV). The resulting solution was diluted with cold H₂O (50 mL) and extracted with DCM (100 mL). The combined organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford N-((6-(4-methoxybenzyl)-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide (200 mg, LC/MS: 89%). (LC/MS; m/z 486.4 [M+H]⁺).

Step-11: N-((6-(4-methoxybenzyl)-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide (200 mg, 0.41 mmol) was treated with TFA (2 mL) at room temperature. The reaction mixture was stirred at 150° C. for 3 h under microwave irradiation and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.2, detection: UV). The resulting solution was concentrated under reduced pressure, diluted with H₂O (15 mL) and extracted with DCM (50 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (170 mg, LC/MS: 26%). The crude product was purified by preparative HPLC method H11 to afford N-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 27) as an off white solid (11 mg, LC/MS: 99%). (LC/MS; m/z 366.2 [M+H]⁺).

Example 13: Synthesis of N-((8-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) methyl) acetamide (Cpd. No. 32)

[Image Omitted]

Step-1: A solution of 6-bromoisoquinoline (20 g, 96.12 mmol) in MeOH (200 mL) and DMF (30 mL) was treated with NaOAc (11.82 g, 144.18 mmol) and DPPF (10.65 g, 19.22 mmol). The mixture was degassed with argon for 10 min, then Pd(dppf)Cl₂·DCM (15.68 g, 19.22 mmol) was added. The reaction mixture was stirred under CO (50 psi) in a steel bomb at 80° C. for 16 h and monitored by TLC (mobile phase: 10% EtOAc/Hexane. Rf: 0.33, detection: UV). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (20 g, LC/MS: 63%). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in pet ether as eluent to afford methyl isoquinoline-6-carboxylate as a brown solid (12 g, LC/MS: 97%). (LC/MS; m/z 188.1 [M+H]⁺).

Step-2: A solution of methyl isoquinoline-6-carboxylate (5 g, 26.71 mmol) in MeOH (50 mL) was treated with PtO₂(360 mg) and AcOH (1.0 mL) at room temperature. The reaction mixture was stirred for 16 h under H₂in a steel bomb (50 psi) at room temperature and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.23, detection: UV). The reaction mixture was filtered through a pad of Celite and washed with MeOH (200 mL). The filtrate was concentrated under reduced pressure to afford a brown gum (5.0 g, LC/MS: 70%). The crude product was purified by flash chromatography (silica gel) using 5% MeOH in DCM as eluent to afford methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate as a brown solid (3.0 g, LC/MS: 95%). (LC/MS; m/z 192.2 [M+H]⁺).

Step-3: A solution of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate (6.3 g, 32.94 mmol) in DCM (60 mL) was treated with Et₃N (13.86 mL, 98.83 mmol) and TFAA (5.53 mL, 39.53 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layer was washed with brine (2×50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (7.0 g, LC/MS: 71%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-35% EtOAc in pet ether as eluent to afford methyl 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as an off white solid (6.5 g, LC/MS: 90%). (LC/MS; m/z 288.2 [M+H]⁺).

Step-4: A solution of methyl 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (6.3 g, 21.93 mmol) in TFA (60 mL) was treated with H₂SO₄(3.0 mL) and NIS (7.36 g, 32.90 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (70 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (6.0 g, LC/MS: 44%). The crude product was purified by flash chromatography (C18) using 15-20% MeCN in water as eluent. Product containing fractions were combined, concentrated and extracted with EtOAc (3×50 mL). The combined organic extract was washed with water (3×50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford methyl 8-iodo-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as an off white solid (4.3 g, LC/MS: 84%). (LC/MS; m/z 413.8 [M+H]⁺).

Step-5: A solution of methyl 8-iodo-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (4.3 g, 10.40 mmol) in MeOH (40 mL) was treated with K₂CO₃(4.30 g, 31.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 50% EtOAC in pet-ether, Rf: 0.22, detection: UV). The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with 10% MeOH in DCM (2×100 mL). The combined organic layer was washed with brine (70 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford methyl 8-iodo-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Int-5) as a brown gum (4.0 g, LC/MS: 86%). (LC/MS; m/z 318.0 [M+H]⁺).

Step-6: A solution of Int-5 (4.0 g, 12.61 mmol) in DCM (40 mL) was treated with TEA (5.26 mL, 37.84 mmol) and (Boc)₂O (3.47 mL, 15.13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 50% EtOAc in pet-ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (5.0 g). The crude product was purified by flash chromatography (silica gel) to afford 2-(tert-butyl) 6-methyl 8-iodo-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate as a white solid (4.0 g, LC/MS: 70%). (LC/MS; m/z 418.0 [M+H]⁺).

Step-7: A solution of 2-(tert-butyl) 6-methyl 8-iodo-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate (4.0 g, 9.58 mmol) in 1,4-dioxane (40 mL) and H₂O (4.0 mL) was treated with (4-(trifluoromethyl) phenyl) boronic acid (2.18 g, 11.50 mmol) and K₂CO₃(3.96 mg, 28.76 mmol). The reaction mixture was degassed by bubbling argon for 5 min, then treated with Pd(dppf)Cl₂·DCM (391.13 mg, 0.47 mmol) and sealed with a Teflon screw-cap. The reaction mixture was stirred at 110° C. for 16 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether. Rf: 0.45, detection: UV). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with brine (80 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (5.0 g, LC/MS: 59%). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in pet ether as eluent to afford 2-(tert-butyl) 6-methyl 8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate as a brown solid (4.0 g, LC/MS: 70%). (LC/MS; m/z 380.0 [M+H⁺-tBu]⁺).

Step-8: A solution of 2-(tert-butyl) 6-methyl 8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate (4.0 g, 9.18 mmol) in THF (40 mL) was treated with 2.0 M LAH in THF (9.0 mL, 18.37 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.45, detection: UV). The reaction mixture was quenched with aqueous NH₄Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (70 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford tert-butyl 6-(hydroxymethyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Int-6) as a brown gum (3.3 g, LC/MS: 80%). (LC/MS; m/z 408.4 [M+H]⁺).

Step-9: A solution of Int-6 (500 mg, 1.22 mmol) in DCM (5.0 mL) was treated with TEA (0.51 mL, 3.68 mmol) and MsCl (0.11 mL, 1.47 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 50% EtOAc in pet-ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford tert-butyl 6-(((methyl sulfonyl) oxy) methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown gum (450 mg, LC/MS: 33%). (LC/MS; m/z 971.6 [2M+H]⁺).

Step-10: A solution of tert-butyl 6-(((methylsulfonyl)oxy) methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (500 mg, 1.03 mmol) in DMF (5 mL) and H₂O (0.5 mL) was treated with NaN₃(334.69 mg, 5.14 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 16 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether. Rf: 0.72, detection: UV). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with cold water (30 mL), brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford tert-butyl 6-(azido methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown gum (450 mg, LC/MS: 68%). (LC/MS; m/z 865.6 [2M+H]⁺).

Step-11: A solution of tert-butyl 6-(azidomethyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (450 mg, 1.04 mmol) in THF (5.0 mL) was treated with 2.0 M LAH in THF (1.5 mL, 3.12 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.45, detection: UV). The reaction mixture was quenched with aqueous NH₄Cl (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford tert-butyl 6-(aminomethyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown gum (450 mg, LC/MS: 57%). (LC/MS; m/z 407.3 [M+H]⁺).

Step-12: A solution of tert-butyl 6-(amino methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (450 mg, 1.10 mmol) in DCM (4.5 mL) was treated with Et₃N (0.46 mL, 3.32 mmol) and acetyl chloride (0.09 mL, 1.32 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.71, detection: UV). The mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (2×30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford tert-butyl 6-(acetamidomethyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown gum (400 mg, LC/MS: 52%). (LC/MS; m/z 897.6 [2M+H]⁺).

Step-13: A solution of tert-butyl 6-(acetamidomethyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (400 mg, 0.892 mmol) in DCM (4.0 mL) was treated with TFA (2.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.14, detection: UV). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL), basified with saturated aqueous NaHCO₃and extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (400 mg, LC/MS: 47%). The crude product was purified by preparative HPLC method H4 to afford N-((8-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) methyl) acetamide (Cpd. No. 32) as an off white solid (75 mg, LC/MS: 99.3%). (LC/MS; m/z 349.3 [M+H]⁺).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 32: Cpd. No. 33 (using acryloyl chloride in step 12).

Example 14: Synthesis of N-acryloyl-N-((8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl) glycine (Cpd. No. 36)

[Image Omitted]

Step-1: A solution of Int-6 (400 mg, 0.98 mmol) in DCM (5.0 mL) was treated with DMP (832.53 mg, 1.96 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and monitored by TLC (mobile phase: 50% EtOAc in pet-ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (500 mg). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-40% EtOAc in pet ether as eluent to afford tert-butyl 6-formyl-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown gum (300 mg, LC/MS: 88%).

Step-2: A solution of tert-butyl 6-formyl-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.74 mmol) in DCE (3 mL) and MeOH (0.5 mL) was treated with tert-butyl glycinate (97.06 mg, 0.74 mmol) and AcOH (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, then treated with NaCNBH₃(22.93 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for an additional 3 h and monitored by TLC (mobile phase: 50% EtOAc in pet-ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford tert-butyl 6-(((2-(tert-butoxy)-2-oxoethyl) amino) methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown gum (300 mg, LC/MS: 59%). (LC/MS; m/z 521.4 [M+H]⁺).

Step-3: A solution of tert-butyl 6-(((2-(tert-butoxy)-2-oxoethyl) amino) methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.57 mmol) in 1,4-dioxane (3 mL) and H₂O (3.0 mL: 0.3 mL) was treated with NaHCO₃(145.21 mg, 1.72 mmol) and acryloyl chloride (62.58 mg, 0.692 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.71, detection: UV). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (500 mg, LC/MS: 44%). The crude product was purified by flash chromatography (silica gel) using 20% EtOAc in pet ether as eluent to afford tert-butyl 6-((N-(2-(tert-butoxy)-2-oxoethyl)acrylamido)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown solid (300 mg, LC/MS: 57%). (LC/MS; m/z 575.4 [M+H]⁺).

Step-4: A solution of tert-butyl 6-((N-(2-(tert-butoxy)-2-oxoethyl) acrylamido) methyl)-8-(4-(trifluoromethyl) phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.522 mmol) in DCM (4.0 mL) was treated with TFA (2.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h and monitored by TLC (mobile phase: 5% MeOH in DCM. Rf: 0.14. detection: UV). The reaction mixture was concentrated under reduced pressure to afford a brown gum (280 mg, LC/MS: 60%). The crude product was purified by preparative HPLC method H12 to afford N-acryloyl-N-((8-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) methyl) glycine (Cpd. No. 36) as an off-white solid (15 mg, LC/MS: 98.7%). (LC/MS; m/z 419.2 [M+H]⁺).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 36: Cpd. No. 37 (using acetyl chloride in step 3).

Example 15: Synthesis of 1-(4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)prop-2-en-1-one (Cpd. No. 41)

[Image Omitted]

Step-1: A solution of 5-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-amine hydrogen chloride (Int-7, synthesized as described in International Publication No. WO 2022/72741) (250 mg, 0.61 mmol) in EtOH (5 mL) was treated with NaHCO₃(419 mg, 4.92 mmol) and N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine (213 mg, 0.92 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 4 h and monitored by TLC (50% EtOAc in pet ether, Rf: 0.4, detection: UV). The reaction mixture was diluted with H₂O (80 mL) and extracted with EtOAc (100 mL). The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (350 mg, LC/MS: 57%). The crude product was purified by flash chromatography (silica gel) using 20% EtOAc in pet. ether as eluent to afford 3-(4-benzylpiperazin-1-yl)-5-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline as a light brown gum (200 mg, LC/MS: 85%). (LC/MS; m/z 530.3 [M+H]⁺).

Step-2: A solution of 3-(4-benzylpiperazin-1-yl)-5-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.37 mmol) in MeOH (3 mL) was treated with 10% Pd/C (100 mg, 50% w/w) and Et₃N (0.2 mL) at room temperature. The reaction mixture stirred at room temperature for 16 h under H₂atmosphere and monitored by TLC (10% MeOH in DCM, Rf: 0.25, detection: UV). The reaction mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to afford 3-(piperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline (120 mg, LC/MS: 60%). (LC/MS; m/z 362.3 [M+H]⁺).

Step-3: A solution of 3-(piperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline (120 mg, 0.33 mmol) in DCM (3.5 mL) was treated with Et₃N (101 mg, 0.99 mmol) and a solution of acryloyl chloride (30 mg, 0.33 mmol) in DCM (0.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.5, detection: UV). The resulting solution was diluted with H₂O (20 mL) and extracted with DCM (2×40 mL). The combined organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (120 mg, LC/MS: 58%). The crude product was purified by preparative HPLC method H12 to afford 1-(4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)prop-2-en-1-one (Cpd. No. 41) as a pale brown gum (44.94 mg, LC/MS: 92%). (LC/MS; m/z 416.3 [M+H]⁺).

Example 16: Synthesis of N-((7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 44)

[Image Omitted]

Step-1: A solution of 5-bromo-2-methyl-3-nitropyridine (20 g, 92.157 mmol) in CCl₄(200 mL) was treated with AIBN (7.567 g, 46.079 mmol) and NBS (24.605 g, 138.236 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 16 h and monitored by TLC (mobile phase: 10% EtOAc in pet ether, Rf: 0.44, detection: UV). The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine (2×300 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (30 g, HPLC: 40%). The crude product was dissolved in pet ether, filtered and the filtrate was evaporated under reduced pressure to afford 5-bromo-2-(bromomethyl)-3-nitropyridine as a yellow liquid (23 g, HPLC: 40%).

Step-2: A solution of diethyl malonate (8.335 mL, 52.041 mmol) in THF (200 mL) was treated with sodium hydride (1.784 g, 74.345 mmol) at 0° C. and stirred for 30 min at room temperature. A solution of 5-bromo-2-(bromomethyl)-3-nitropyridine (22 g, 74.345 mmol) in THF (20 mL) was added at 0° C. The reaction mixture was stirred for 2 h and monitored by TLC (mobile phase: 10% EtOAc in pet ether, Rf: 0.37, detection: UV). The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (2×400 mL). The combined organic layer was washed with brine (2×400 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (24 g, LC/MS: 33%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-65% EtOAc in pet ether as eluent to afford diethyl 2-((5-bromo-3-nitropyridin-2-yl)methyl)malonate as a brown gum (10 g, LC/MS: 89%). (LC/MS; m/z 375.2 [M+H]⁺).

Step-3: A solution of diethyl 2-((5-bromo-3-nitropyridin-2-yl)methyl)malonate (10 g, 26.654 mmol) in AcOH (100 mL) was treated with Fe (7.443 g, 133.271 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 2 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.12, detection: UV). The reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with EtOAc (500 mL). The filtrate was concentrated under reduced pressure and the residue was diluted with aqueous NaHCO₃and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine (400 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford ethyl 7-bromo-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate as a white solid (7.8 g, LC/MS: 88%). (LC/MS; m/z 301.1 [M+H]⁺).

Step-4: A solution of ethyl 7-bromo-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (4.5 g, 15.044 mmol) in DCM (45 mL) was treated with (4-(trifluoromethyl)phenyl)boronic acid (5.715 g, 30.088 mmol), triethylamine (8.457 mL, 60.176 mmol) and Cu(OAC)₂(5.446 g, 30.088 mmol) at room temperature. The reaction mixture was stirred at room temperature for 7 h under oxygen atmosphere and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.58, detection: UV). The reaction mixture was quenched with water (60 mL) and extracted with DCM (2×60 mL). The combined organic layer was washed with brine (2×50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (4.9 g, LC/MS: 59%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-65% EtOAc in pet ether as eluent to afford ethyl 7-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate as an off-white solid (2.6 g, LC/MS: 82%). (LC/MS; m/z 443.2 [M+H]⁺).

Step-5: A solution of ethyl 7-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate (2.6 g, 5.866 mmol) in THF (26 mL) was treated with BH₃-DMS (2M in THF) (14.7 mL, 29.331 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 3 h under nitrogen atmosphere and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.18, detection: UV). The reaction mixture was quenched with MeOH and refluxed for 16 h before being concentrated, diluted with water (40 mL) and extracted with EtOAc (2×60 mL). The combined organic layer was washed with brine (2×40 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (2.8 g, LC/MS: 39%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-65% EtOAc in pet ether as eluent to afford (7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol as a yellow liquid (1.2 g, LC/MS: 96%). (LC/MS; m/z 389.2 [M+H]⁺).

Step-6: A solution of (7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (1.2 g, 3.099 mmol) in DCM (12 mL) was treated with Et₃N (1.307 mL, 9.298 mmol) and MsCl (0.296 mL, 3.719 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 70% EtOAc in Pet ether, Rf: 0.52, detection: UV). The reaction mixture was quenched with water (20 mL) and extracted with DCM (2×25 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford (7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate as a brown gum (1.3 g, LC/MS: 92%). (LC/MS; m/z 465.2 [M+H]⁺).

Step-7: A solution of (7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (1.3 g, 2.794 mmol) in DMF (13 mL) and water (13 mL) was treated with sodium azide (0.727 g, 11.176 mmol) at room temperature. The reaction mixture was stirred at 70° C. under nitrogen atmosphere for 16 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.77, detection: UV). The reaction mixture was cooled to 0° C., quenched with ice water (25 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (1.6 g, LC/MS: 53%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-65% EtOAc in pet. ether as eluent to afford 3-(azidomethyl)-7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine as a yellow liquid (1 g, LC/MS: 53%). (LC/MS; m/z 414.3 [M+H]⁺).

Step-8: A solution of 3-(azidomethyl)-7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (200 mg, 0.485 mmol) in THF (2 mL) was treated with PPh₃(381 mg, 1.45 mmol) and stirred at room temperature for 30 min. The reaction mixture was treated with H₂O (0.2 mL) and NH₄OH (0.2 mL) at 0° C. The resulting reaction mixture was allowed to warm to 26° C. and stirred for 16 h under nitrogen atmosphere and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.13, detection: UV). The reaction mixture was concentrated under reduced pressure to afford the crude product (600 mg, LC/MS: 52%). The crude product was purified by flash chromatography (C18) using 20% ACN in H₂O as eluent to afford (7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanamine as a brown gum (150 mg, LC/MS: 96%). (LC/MS; m/z 386.2 [M+H]⁺).

Step-9: A solution of (7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanamine (150 mg, 0.388 mmol) in DCM (3 mL) was treated with Et₃N (0.164 mL, 1.165 mmol) and acetyl chloride (0.030 mL, 0.427 mmol) at 0° C. The reaction mixture was stirred for 30 min at room temp under nitrogen atmosphere and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.63, detection: UV). The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (180 mg, LC/MS: 90%). The crude product was purified by preparative HPLC method H13 to afford N-((7-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd No. 44) as an off-white solid (97 mg, LC/MS: 99%). (LC/MS; m/z 430.1 [M+H]⁺).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 44: Cpd. No. 47 (using 6-bromo-2-methyl-3-nitropyridine in step 1 and diethyl 2-methylmalonate in step 2).

Chiral SFC purification: Cpd. No. 47 (110 mg) was purified by preparative SFC method K5 to afford Cpd. No. 47-En1 (39 mg) and Cpd. No. 47-En2 (40 mg), each as an off white solid. The chiral purity of each enantiomer was assessed by analytical SFC method S8: Cpd. No. 47-En1 (99.8% ee), Cpd. No. 47-En2 (99.8% ee).

Example 17: Synthesis of N-((6-amino-1-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (Cpd. No. 45) and N-((6-(dimethylamino)-1-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (Cpd. No. 52)

[Image Omitted]

Step-1: A solution of Cpd. No. 62 (120 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) was treated with tert-butyl carbamate (65.65 mg, 0.560 mmol), Cs₂CO₃(273.20 mg, 0.841 mmol) and X-phos (26.67 mg, 0.056 mmol). The reaction mixture was degassed with argon for 2 min, treated with X-phos-Pd-G2 (22.02 mg, 0.028 mmol) and sealed with a Teflon screw-cap. The reaction mixture was stirred at 80° C. for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.13, detection: UV). The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (200 mg, LC/MS: 21%). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in pet ether as eluent to afford tert-butyl (7-(acetamidomethyl)-5-(4-(trifluoromethyl) phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl) carbamate as a brown solid (100 mg, LC/MS: 70%). (LC/MS; m/z 465.2 [M+H]⁺).

Step-2: A solution of tert-butyl (7-(acetamidomethyl)-5-(4-(trifluoromethyl) phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl) carbamate (80 mg, 0.17 mmol) in DCM (1.0 mL) was treated with TFA (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.14, detection: UV). The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO₃and extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (80 mg, LC/MS: 57%). The crude product was purified by preparative HPLC method H4 to afford N-((6-amino-1-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (Cpd. No. 45) as a yellow solid (17 mg, LC/MS: 97%). (LC/MS; m/z 365.2 [M+H]⁺).

Step-3: A solution of Cpd. No. 45 (130 mg, 0.357 mmol) in THF (3.0 mL) and MeOH (0.5 mL) was treated with paraformaldehyde (107.03 mg, 3.56 mmol) and AcOH (0.1 mL). The reaction mixture was stirred at room temperature for 2 h, then NaCNBH₃(110.60 mg, 1.78 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.20, detection: UV). The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (LC/MS: 45%). The crude product was purified by preparative HPLC method H11 to afford N-((6-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) methyl) acetamide (Cpd. No. 52) as a green solid (26 mg, LC/MS: 95%). (LC/MS; m/z 393.2 [M+H]⁺).

Example 18: Synthesis of N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide (Cpd. No. 46)

[Image Omitted]

Step-1: A solution of Int-5 (1.8 g, 5.676 mmol mmol) in THF (20 mL) and MeOH (2.0 mL) was treated with paraformaldehyde (1.703 g, 56.760 mmol) and AcOH (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then treated with NaCNBH₃(1.760 g, 28.380 mmol). The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.33, detection: UV). The reaction mixture was concentrated, diluted with water (30 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (LC/MS: 53%). The crude product was purified by flash chromatography (silica gel) using 5-10% MeOH in DCM as eluent to afford methyl 8-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as a white gum (1.2 g, LC/MS: 49%). (LC/MS; m/z 332.2 [M+H]⁺).

Step-2: A solution of methyl 8-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (1.1 g, 3.32 mmol) in 1,4-dioxane (10 mL) and H₂O (1.0 mL) was treated with (4-(trifluoromethyl)phenyl)boronic acid (757.07 mg, 3.98 mmol) and K₂CO₃(1.37 g, 9.96 mmol). The reaction mixture was degassed with argon for 5 min, treated with Pd(dppf)Cl₂·DCM (135.52 mg, 0.166 mmol) and sealed with a Teflon screw-cap. The reaction mixture stirred at 110° C. for 16 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.19, detection: UV). The reaction mixture was cooled to room temperature, filtered and washed with EtOAc (50 mL). The filtrate was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (2.0 g). The crude product was purified by flash chromatography (C18) using a gradient of 55-80% ACN in water as eluent. Product containing fractions were combined, concentrated and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (3×50 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to afford methyl 2-methyl-8-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as an off-white gum (800 mg, LC/MS: 92%). (LC/MS; m/z 350.3 [M+H]⁺).

Step-3: A solution of methyl 2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (500 mg, 1.431 mmol) in THF (5.0 mL) was treated with 2.0 M LAH in THF (1.4 mL, 2.86 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.45, detection: UV). The reaction mixture was quenched with aqueous NH₄Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford 2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) methanol as a brown gum (500 mg, LC/MS: 95%). (LC/MS; m/z 322.3 [M+H]⁺).

Step-4: A solution of (2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) methanol (400 mg, 1.24 mmol) in ACN (4.0 mL) was treated with sulfuric acid (4.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 h and monitored by TLC (mobile phase: 10% MeOH in DCM, detection: UV). The reaction mixture was concentrated under reduced pressure, diluted with saturated NaHCO₃and extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (190 mg, LC/MS: 68%). The crude product was purified by preparative HPLC method H1 to afford N-((2-methyl-8-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)acetamide (Cpd. No. 46) as an off-white solid (73 mg, LC/MS: 98.8%). (LC/MS; m/z 363.1 [M+H]⁺).

Example 19: Synthesis of N-((5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 48)

[Image Omitted]

Step-1: A solution of (6-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (Int-8, prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Int-3) (1.7 g, 5.03 mmol) in DMF (30 mL) was treated with LiCl (1.0 g, 25.14 mmol) and p-TSA (4.7 g, 25.14 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.3, detection: UV). The resulting solution was diluted with cold H₂O (100 mL) and extracted with EtOAc (150 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (1.3 g). The crude product was purified by flash chromatography (silica gel) using 5% MeOH in DCM as eluent to afford 7-(hydroxymethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one as a light brown solid (700 mg, LC/MS: 96%). (LC/MS; m/z 325.2 [M+H]⁺).

Step-2: A solution of 7-(hydroxymethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one (250 mg, 0.77 mmol) in DMF (3 mL) was treated with Cs₂CO₃(501 mg, 1.54 mmol) and methyl iodide (131 mg, 0.92 mmol) at room temperature.

The reaction mixture was stirred at room temperature for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.35, detection: UV). The resulting solution was diluted with cooled H₂O (100 mL) and extracted with EtOAc (150 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (250 mg, LC/MS: 80%). The crude product was purified by flash chromatography (silica gel) using 3% MeOH in DCM as eluent to afford 7-(hydroxymethyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one as an off white solid (100 mg, LC/MS: 98%). (LC/MS; m/z 339.3 [M+H]⁺).

Step-3: A solution of 7-(hydroxymethyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one (100 mg, 0.29 mmol) in DCM (3 mL) was treated with Et₃N (45 mg, 0.44 mmol) and MsCl (40 mg, 0.35 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.43, detection: UV). The resulting solution was diluted with H₂O (50 mL) and extracted with DCM (100 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford (5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (130 mg, LC/MS: 92%). (LC/MS; m/z 417.2 [M+H]⁺).

Step-4: A solution of (5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (130 mg, 0.31 mmol) in DMF (3 mL) and H₂O (0.3 mL) was treated with sodium azide (101 mg, 1.56 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 16 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.6, detection: UV). The resulting solution was diluted with cold H₂O (50 mL) and extracted with EtOAc (80 mL). The organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (130 mg, LC/MS: 26%). The crude product was purified by flash chromatography (silica gel) using 2% MeOH in DCM as eluent to afford 7-(azidomethyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one as a light brown gum (100 mg, LC/MS: 86%). (LC/MS; m/z 364.2 [M+H]⁺).

Step-5: A solution of 7-(azidomethyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one (100 mg, 0.27 mmol) in MeOH (3 mL) was treated with 10% Pd/C (50 mg, 50% wt/wt) at room temperature. The reaction mixture was stirred under H₂atmosphere at room temperature for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.2, detection: UV-active). The resulting solution was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to afford 7-(aminomethyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one (90 mg, LC/MS: 58%). (LC/MS; m/z 338.2 [M+H]⁺).

Step-6: A solution of 7-(aminomethyl)-1-methyl-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2(1H)-one (90 mg, 0.26 mmol) in DCM (3 mL) was treated with Et₃N (81 mg, 0.80 mmol) and a solution of acetyl chloride (21 mg, 0.26 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.4, detection: UV). The resulting solution was diluted with cold H₂O (50 mL) and extracted with DCM (100 mL). The combined organic layer was dried with anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (100 mg, LC/MS: 57%). The crude product was purified by preparative HPLC method H3 to afford N-((5-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 48) as an off white solid (7 mg, LC/MS: 97%). (LC/MS; m/z 380.2 [M+H]⁺).

Example 20: Synthesis of N-((7-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 49) and N-((7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 50)

[Image Omitted]

Step-1: In a glass screw-cap pressure vessel, a solution of Cpd. No. 44 (400 mg, 0.934 mmol) in 1,4-dioxane (4 mL) was treated with tert-butyl carbamate (218.843 mg, 1.868 mmol) and KOtBu (314.422 mg, 2.802 mmol). The reaction mixture was degassed with argon for 10 min, then treated with XPhos-Pd-G2 (36.707 mg, 0.047 mmol) and XPhos (44.460 mg, 0.093 mmol). The reaction mixture was sealed with a Teflon screw cap, stirred at 100° C. for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.48, detection: UV). The reaction mixture was allowed to cool to 26° C., quenched with water (15 mL) and extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (520 mg, LC/MS: 32%). The crude product was purified by flash chromatography (silica gel) using 10-20% MeOH in DCM as eluent to afford tert-butyl (7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate as a brown gum (160 mg, LC/MS: 43%). (LC/MS; m/z 465.4 [M+H]⁺).

Step-2: A solution of tert-butyl (7-(acetamidomethyl)-5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (90 mg, 0.194 mmol) in DCM (2 mL) and 4M HCl in dioxane (0.9 mL) at 0° C. The resulting reaction mixture was allowed to warm to 26° C. and stirred for 1 h under nitrogen atmosphere and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.09, detection: UV). The reaction mixture was concentrated under reduced pressure and diluted with NaHCO₃(5 mL) and extracted with EtOAc (2×10 mL). The combined organic layer was concentrated under reduced pressure to afford a brown gum (90 mg, LC/MS: 92%). The crude product was purified by preparative HPLC method H14 to afford N-((7-amino-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 49) as pale yellow solid (16 mg, LC/MS: 99%). (LC/MS; m/z 365.2 [M+H]⁺).

Step-3: Cpd. No. 49 (200 mg, 0.549 mmol) was dissolved in HF·pyridine (10 mL) at 0° C. and then stirred at 50° C. for 20 min. The resulting solution was cooled to 0° C., treated with NaNO₂(45.441 mg, 0.659 mmol) and stirred for 30 min. The resulting reaction mixture was stirred at 130° C. for 3 h under nitrogen atmosphere and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.48, detection: UV). The reaction mixture was allowed to cool to 26° C., quenched with saturated sodium bicarbonate (20 mL) and extracted with EtOAc (2×15 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a pale yellow solid (200 mg, LC/MS: 65%). The crude product was purified by preparative HPLC method H5 to afford N-((7-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 50) as a pale-yellow solid (55 mg, LC/MS: 97%). (LC/MS; m/z 368.2 [M+H]⁺).

The following compounds were prepared in a manner similar (use of appropriate reagents and purification methods known to the person skilled in the art) to Cpd. No. 50: Cpd. No. 51 (using t-BuONO, CuCl and CuCl2 in ACN in step 3).

Example 21: Synthesis of N-((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 54)

[Image Omitted]

Step-1: A solution of Int-4 (1.5 g, 6.66 mmol) in DMF (15 mL) was treated with Cs₂CO₃(4.3 g, 13.33 mmol) and MeI (1.4 g, 9.99 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.2, detection: UV). The reaction mixture was quenched with cold H₂O (100 mL) and extracted with EtOAc (150 mL). The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (1.5 g, LC/MS: 91%). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in Pet ether as eluent to afford 3-bromo-6-methyl-1,6-naphthyridin-5(6H)-one as an off white solid (800 mg, LC/MS: 97%). (LC/MS; m/z 239.2 [M+H]⁺).

Step-2: A solution of 3-bromo-6-methyl-1,6-naphthyridin-5(6H)-one (400 mg, 1.68 mmol) in t-BuOH (4 mL) and H₂O (4 mL) was treated with potassium [[(tert-butoxycarbonyl)amino] methyl]trifluoroborate (597 mg, 2.52 mmol) and K₃PO₄(1.1 g, 5.04 mmol) and degassed with argon for 5 min. S-Phos (69 mg, 0.16 mmol) and Pd(OAc)₂(38 mg, 0.16 mmol) were added, and the reaction mixture was stirred at 80° C. for 2 h under microwave irradiation and monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.20. detection: UV). The reaction mixture was quenched with H₂O (100 mL) and extracted with EtOAc (150 mL). The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (400 mg, LC/MS: 38%). The crude product was purified by flash chromatography (silica gel) using 60% EtOAc in Pet ether as eluent to afford tert-butyl ((6-methyl-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)methyl)carbamate as an off white solid (140 mg, LC/MS: 96%). (LC/MS; m/z 290.4 [M+H]⁺).

Step-3: A solution of tert-butyl ((6-methyl-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)methyl)carbamate (220 mg, 0.76 mmol) in EtOH (10 mL) was treated with Pd(OH)₂(110 mg, 50% wt/wt). The reaction mixture was stirred at 80° C. for 4 h under H₂(50 psi) in a steel bomb and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.25, 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 afford tert-butyl ((6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)carbamate (200 mg, LC/MS: 89%). (LC/MS; m/z 294.4 [M+H]⁺).

Step-4: A solution of tert-butyl ((6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)carbamate (200 mg, 0.68 mmol) in 1,4-dioxane (5 mL) was treated with Cs₂CO₃(555 mg, 1.70 mmol) and degassed with argon for 5 min. X-Phos (32 mg, 0.06) and Pd₂(dba)₃(31 mg, 0.03 mmol) were added and the reaction mixture was further degassed with argon for 5 min. Then, 1-iodo-4-(trifluoromethyl)benzene (278 mg, 1.02 mmol) was added at room temperature, and the reaction mixture was stirred at 100° C. for 16 h in sealed tube and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.48, detection: UV). The resulting solution was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was washed with H₂O (80 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (200 mg, LC/MS: 44%). The crude product was purified by flash chromatography (silica gel) using 40% EtOAc in pet ether as eluent to afford tert-butyl ((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)carbamate as a light brown gum (150 mg, LC/MS: 88%). (LC/MS; m/z 438.4 [M+H]⁺).

Step-5: A solution of tert-butyl ((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)carbamate (150 mg, 0.34 mmol) in DCM (2 mL) was treated with TFA (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.2, detection: UV). The resulting solution was concentrated under reduced pressure to afford crude 3-(aminomethyl)-6-methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one TFA salt as a light brown gum (150 mg, LC/MS: 90%). (LC/MS; m/z 338.4 [M+H]⁺).

Step-6: A solution of 3-(aminomethyl)-6-methyl-1-(4-(trifluoromethyl)phenyl)-2,3,4,6-tetrahydro-1,6-naphthyridin-5(1H)-one TFA salt (150 mg, 0.33 mmol) in DCM (4 mL) was treated with Et₃N (168 mg, 1.66 mmol) and a solution of acetyl chloride (26 mg, 0.33 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.4, detection: UV). The reaction mixture was quenched with H₂O (50 mL) and extracted with DCM (100 mL). The organic layer was dried over Na₂SO₄and concentrated under reduced pressure to afford the crude product (150 mg, LC/MS: 92%). The crude product was purified by preparative HPLC method H8 to afford N-((6-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 54) as an off white solid (37.47 mg, LC/MS: 99%). (LC/MS; m/z 380.2 [M+H]⁺).

Example 22: Synthesis of N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)acetamide (Cpd. No. 56)

[Image Omitted]

Step-1: A solution of 2,3-dichloropyrazine (15 g, 100.691 mmol) in 1,4-dioxane (30 mL) was treated with Et₃N (21.227 mL, 151.037 mmol) and benzylamine (14.385 mL, 120.830 mmol) at room temperature. The resulting reaction mixture was stirred at 100° C. for 7 h under nitrogen and monitored by TLC (mobile phase: 10% EtOAc in pet ether, Rf: 0.29, detection: UV). The reaction mixture was allowed to cool to 26° C., quenched with water (100 mL) and extracted with EtOAc (2×80 mL). The combined organic layer was washed with brine (200 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a pale yellow liquid (20.3 g, LC/MS: 86%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-60% EtOAc in pet. ether as eluent to afford N-benzyl-3-chloropyrazin-2-amine as a pale-yellow liquid (18 g, LC/MS: 94%). (LC/MS; m/z 220.2 [M+H]⁺).

Step-2: In a glass screw-cap pressure vessel, a solution of N-benzyl-3-chloropyrazin-2-amine (14 g, 63.731 mmol) in Et₃N (140 mL) was treated with methyl acrylate (57.754 mL, 637.314 mmol). The reaction mixture was degassed with argon for 10 min, treated with Pd(OAc)₂(0.357 g, 1.593 mmol) and XPhos (4.557 g, 9.560 mmol) and sealed with a Teflon screw-cap. The reaction mixture was stirred at 100° C. for 48 h and monitored by TLC (mobile phase: 10% EtOAc in pet ether, Rf: 0.07, detection: UV). The reaction mixture was allowed to cool to 26° C., quenched with water (300 mL) and extracted with EtOAc (2×250 mL). The combined organic layer was washed with brine (2×400 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (18 g, LC/MS: 33%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-50% EtOAc in pet-ether as eluent to afford methyl (E)-3-(3-(benzylamino)pyrazin-2-yl)acrylate as a yellow solid (4.5 g, LC/MS: 65%). (LC/MS; m/z 270.1 [M+H]⁺).

Step-3: A solution of methyl (E)-3-(3-(benzylamino)pyrazin-2-yl)acrylate (4.5 g, 16.710 mmol) in MeOH (45 mL) and EtOAc (45 mL) was treated with 10% Pd/C (2.5 g) at room temperature. The reaction mixture was stirred at room temperature for 16 h under H₂(balloon) and monitored by TLC (mobile phase: 20% EtOAc in pet-ether, Rf: 0.25, detection: UV). The reaction mixture was filtered through a pad of Celite and washed with MeOH (600 mL). The filtrate was concentrated under reduced pressure to afford methyl 3-(3-(benzylamino)pyrazin-2-yl)propanoate as a light yellow gum (4.5 g, LC/MS: 63%). (LC/MS; m/z 272.2 [M+H]⁺).

Step-4: A solution of methyl 3-(3-(benzylamino)pyrazin-2-yl)propanoate (4.4 g, 16.217 mmol) in MeOH (88 mL) was treated with potassium carbonate (6.724 g, 48.651 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 1 h under nitrogen and monitored by TLC (mobile phase: 20% EtOAc in pet-ether, Rf: 0.25, detection: UV). The reaction mixture was concentrated and the residue was diluted with water (350 mL) and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine (2×80 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a pale yellow gum (3.8 g, LC/MS: 49%). The crude product was purified by flash chromatography (silica gel) using a gradient of 10-65% EtOAc in pet. ether as eluent to afford 5-benzyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one as light yellow solid (840 mg, LC/MS: 96%). (LC/MS; m/z 240.0 [M+H]⁺).

Step-5: A solution of 5-benzyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (850 mg, 3.552 mmol) in THF (12 mL) was treated with LiHMDS (1.0 M in THF) (10.65 mL, 10.657 mmol) at −78° C. and stirred for 10 min. Ethyl chloroformate (424.052 mg, 3.908 mmol) was added and the reaction mixture was stirred at −78° C. for 1 h and monitored by TLC (mobile phase: 30% EtOAc/Pet-ether, Rf: 0.36, detection: UV). The reaction mixture was diluted with aqueous NH₄Cl (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the crude product (1.2 g, LC/MS: 80%). The crude product was purified flash chromatography using 30% EtOAc/hexane as eluent to afford ethyl 5-benzyl-6-oxo-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate as a pale brown solid (880 mg, LC/MS: 86%). (LC/MS; m/z 312.2 [M+H]⁺).

Step-6: A solution of ethyl 5-benzyl-6-oxo-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (880 mg, 2.826 mmol, 1.0 equiv.) in THF (9 mL) was treated with 2M BH₃-DMS in THF (4.23 mL, 8.479 mmol, 3.0 equiv.) at 0° C. The reaction mixture was stirred at 70° C. for 1 h and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.36, detection: UV). The reaction mixture was quenched with MeOH (20 mL) at 0° C. and refluxed for 3 h. The mixture was then concentrated under reduced pressure to afford a brown gum (800 mg, LC/MS: 77%). The crude product was purified by flash chromatography (silica gel) using 3% MeOH in DCM as eluent to afford (5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methanol as a brown solid (420 mg, LC/MS: 91%). (LC/MS; m/z 256.1 [M+H]⁺).

Step-7: A solution of (5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methanol (420 mg, 1.65 mmol) in DCM (5 mL) was treated with trimethylamine (0.34 mL, 2.46 mmol) and methanesulfonyl chloride (0.153 mL, 1.97 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.32, detection: UV). The reaction mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford 5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl methanesulfonate as a brown gum (480 mg, LC/MS: 82%). (LC/MS; m/z 334.2 [M+H]⁺).

Step-8: A solution of (1-benzyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl methanesulfonate (480 mg, 1.44 mmol) in DMF (5 mL) and H₂O (2 mL) was treated with sodium azide (469.36 mg, 7.22 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 16 h and monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.42, detection: UV). The reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2×70 mL). The combined organic layer was washed with cold water (2×20 mL), brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford 7-(azidomethyl)-5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine as a brown gum (400 mg, LC/MS: 81%). (LC/MS; m/z 281.1 [M+H]⁺).

Step-9: A solution of 7-(azidomethyl)-5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (400 mg, 1.427 mmol) in THF (5 mL) was treated with di-tert-butyl dicarbonate (0.492 mL, 2.140 mmol) followed by 10% Pd/C (151.847 mg, 1.427 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h under H₂(balloon) and monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.19, detection: UV). The reaction mixture was filtered through a pad of Celite and washed with EtOAc (80 mL). The filtrate was concentrated under reduced pressure and dried to afford a brown gum (430 mg, LC/MS: 60%). The crude product was purified by flash chromatography (silica gel) using 4% MeOH in DCM as eluent to afford tert-butyl ((5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)carbamate as a brown gum (270 mg, LC/MS: 76%). (LC/MS; m/z 355.3 [M+H]⁺).

Step-10: A solution of tert-butyl ((5-benzyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)carbamate (270 mg, 0.762 mmol) in MeOH (6 mL) was treated with 10% Pd/C (810 mg) and ammonium formate (1.44 g, 22.85 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 4 days and monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.40, detection: UV). The reaction mixture was filtered through a pad of Celite and washed with MeOH (2×50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl ((5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)carbamate as a brown gum (120 mg, LC/MS: 19%). (LC/MS; m/z 264.9 [M+H]⁺).

Step-11: A solution of tert-butyl ((5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)carbamate (110 mg, 0.416 mmol) in 1,4-dioxane (2.0 mL) was treated with 1-iodo-4-(trifluoromethyl)benzene (135.83 mg, 0.499 mmol), Cs₂CO₃(338.12 mg, 1.04 mmol) and X-phos (19.80 mg, 0.042 mmol). The reaction mixture was degassed with argon for 2 min, treated with Pd₂(dba)₃(19.05 mg, 0.021 mmol) and sealed with a Teflon screw-cap. The reaction mixture was stirred at 90° C. for 16 h in a sealed tube and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.13, detection: UV). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (150 mg, LC/MS: 31%). The crude product was purified by flash chromatography (silica gel) using 20-30% EtOAc in pet ether as eluent to afford tert-butyl ((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)carbamate as a brown solid (70 mg, LC/MS: 60%). (LC/MS; m/z 409.2 [M+H]⁺).

Step-12: A solution of tert-butyl ((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)carbamate (70 mg, 0.171 mmol) in DCM (2.0 mL) was treated with TFA (1.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.07, detection: UV). The reaction mixture was concentrated under reduced pressure to afford (5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methanamine TFA Salt (60 mg, LC/MS: 44%). (LC/MS; m/z 309.2 [M+H]⁺).

Step-13: A solution of (5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methanamine TFA salt 13(60 mg, 0.14 mmol) in DCM (1.0 mL) was treated with Et₃N (0.062 mL, 0.44 mmol) and acetyl chloride (0.013 mL, 0.177 mmol). The reaction mixture was stirred at 0° C. for 30 min and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.45, detection: UV). The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×20 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄and concentrated under reduced pressure to afford a brown gum (100 mg, LC/MS: 60%). The crude product was purified by preparative HPLC method H11 to afford N-((5-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-7-yl)methyl)acetamide (Cpd. No. 56) as an off-white solid (16 mg, LC/MS: 98.8%). (LC/MS; m/z 351.2 [M+H]⁺).

Example 23: Synthesis of N-((6-(difluoromethoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 60)

[Image Omitted]

A solution of N-((6-hydroxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (500 mg, 1.36 mmol) in ACN (3.0 mL) was treated with 2.0 M aqueous KOH (3.0 mL) and diethyl (bromodifluoromethyl)phosphonate (739.09 mg, 2.73 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.63, detection: UV). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×80 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (400 mg, LC/MS: 59%). The crude product was purified by preparative HPLC method H9 to afford N-((6-(difluoromethoxy)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 60) as a green solid (110 mg, LC/MS: 416.2). (LC/MS; m/z 416.2 [M+H]⁺).

Example 24: Synthesis of N-((6-(difluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 61)

[Image Omitted]

Step-1: A solution of Cpd. No. 62 (1.0 g, 2.33 mmol) in 1,4-dioxane (10 mL) and H₂O (1.0 mL) was treated with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (539.45 mg, 3.50 mmol) and K₂CO₃(644.47 mg, 4.67 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 2 min, treated with PdCl₂(dpp)·DCM (95.27 mg, 0.117 mmol), stirred at 100° C. for 16 h in a sealed tube and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.48, detection: UV). The reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (1.3 g, LC/MS: 74%). The crude product was purified by flash chromography (silica gel) using a gradient of 50-80% EtOAc in pet ether as eluent to afford N-((1-(4-(trifluoromethyl)phenyl)-6-vinyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide as a brown gum (500 mg, LC/MS: 94%). (LC/MS; m/z 376.3 [M+H]⁺).

Step-2: A solution of N-((1-(4-(trifluoromethyl)phenyl)-6-vinyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (500 mg, 1.33 mmol) in THF (3.0 ml) and H₂O (1.0 mL) was treated with NalO₄(1.13 g, 5.32 mmol) and OSO₄(33.83 mg, 0.133 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.48, detection: UV). The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford a brown gum (700 mg). The crude product was purified by flash chromatography (silica gel) using 30% EtOAc in pet ether as eluent to afford N-((6-formyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide as a brown solid (300 mg, LC/MS: 76%). (LC/MS; m/z 378.2 [M+H]⁺).

Step-3: A solution of N-((6-formyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (300 mg, 0.795 mmol) in DCM (3.0 mL) was treated with DAST (255.98 mg, 1.59 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.48, detection: UV). The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure to a brown gum (300 mg, LC/MS: 28%). The crude product was purified by flash chromatography (silica gel) using a gradient of 50-80% EtOAc in pet ether as eluent to afford a brown gum (80 mg, LC/MS: 76%). The resulting product was further purified by preparative HPLC method H11 to afford N-((6-(difluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)acetamide (Cpd. No. 61) as an off white solid (25 mg, LC/MS: 98%). (LC/MS; m/z 400.2 [M+H]⁺).

TABLE 2

Analytical data for synthesized compounds of the invention:

Cpd.
[M + H]+
LC/MS
RT
1H NMR

No.
(m/z):
Method
(min.)
(δ ppm)

1
456.4
L1
2.84
(DMSO-d6) δ ppm: 8.32-8.36 (m, 2H), 7.83-7.86 (t,

1H), 7.67-7.69 (d, 2H), 7.34-7.42 (m, 4H), 6.99-

7.03 (d, 1H), 6.73-6.75 (d, 1H), 6.39-6.41 (d, 1H),

3.74-3.78 (dd, 1H), 3.31 (s, 1H), 3.06-3.09 (m, 2H),

2.81-2.87 (dd, 1H), 2.32-2.39 (m, 1H), 2.07-2.10

(m, 1H), 1.97-2.03 (q, 2H), 0.89-0.93 (t, 3H).

2
478.3
L1
2.87
(DMSO-d6) δ ppm: 8.33-8.37 (m, 2H), 7.68-7.70

(d, 2H), 7.35-7.44 (m, 4H), 7.13-7.16 (t, 1H), 7.00-

7.04 (t, 1H), 6.73-6.75 (d, 1H), 6.40-6.42 (d, 1H),

3.83-3.87 (dd, 1H), 3.32 (m, 1H), 2.91-3.03 (m,

3H), 2.84-2.88 (m, 3H), 2.32-2.49 (m, 1H), 2.07-

2.13 (m, 1H).

3
454.4
L1
2.79
(DMSO-d6) δ ppm: 8.33-8.36 (m, 2H), 8.20 (m,

1H), 7.67-7.69 (d, 2H), 7.35-7.42 (m, 4H), 6.99-

7.03 (t, 1H), 6.72-6.74 (d, 1H), 6.38-6.40 (dd, 1H),

6.13-6.20 (dd, 1H), 6.01-6.05 (dd, 1H), 5.53-5.56

(dd, 1H), 3.76-3.80 (dd, 1H), 3.13-3.23 (m, 2H),

2.85-2.90 (dd, 2H), 2.32-2.42 (m, 1H), 2.15-2.16

(m, 1H).

4
501.4
L1
2.59
(DMSO-d6) δ ppm: 11.05-11.07 (m, 2H), 8.49 (s,

1H), 8.23-8.25 (t, 1H), 7.62-7.64 (d, 2H), 7.32-7.34

(d, 2H), 6.95-6.99 (t, 1H), 6.56-6.58 (d, 1H), 6.44-

6.46 (d, 1H), 6.17-6.24 (dd, 1H), 6.03-6.08 (dd,

1H), 5.54-5.56 (m, 2H), 4.80 (s, 2H), 3.74-3.78 (dd,

1H), 3.32-3.13 (m, 3H), 2.89-2.94 (dd, 1H), 2.32-

2.41 (m, 2H), 2.08-2.18 (m, 1H).

5
503.2
L2
2.01
(DMSO-d6) δ ppm: 10.90-11.10 (s, 2H), 8.49 (s,

1H), 7.87-7.90 (t, 1H), 7.62-7.64 (d, 2H), 7.31-7.33

(dd, 2H), 6.95-6.99 (t, 1H), 6.56-6.59 (d, 1H), 6.44-

6.46 (d, 1H), 5.57 (s, 1H), 4.79 (s, 1H), 3.73-3.77

(dd, 1H), 3.23-3.32 (m, 1H), 3.04-3.09 (m, 2H),

2.89-2.92 (m, 1H), 2.32-2.49 (m, 1H), 2.01-2.07 (m,

3H), 0.92-0.96 (t, 3H).

6
484.4
L1
2.72
(DMSO-d6) δ ppm: 11.3-11.7 (s, 1H), 8.23-8.25 (t,

1H), 7.64-7.62 (d, 2H), 7.32-7.37 (m, 3H), 6.92-

6.97 (t, 1H), 6.54-6.56 (d, 1H), 6.48-6.50 (d, 1H),

6.36 (s, 1H), 6.17-6.24 (dd, 2H), 6.03-6.08 (dd,

1H), 5.54-5.57 (dd, 1H), 4.99 (s, 2H), 3.75-3.79 (d,

1H), 3.15-3.32 (m, 3H), 3.04-3.15 (m, 2H), 2.89-

2.95 (dd, 1H), 2.32-2.49 (q, 1H), 2.12-2.14 (m, 1H).

6-
484.3
S3
8.07
(DMSO-d6) δ ppm: 11.4 (s, 1H), 8.24 (t, 1H), 7.62-

En1

7.64 (m, 2H), 7.32-7.37 (m, 3H), 6.94 (t, 1H), 6.55

(d, 1H), 6.49 (d, 1H), 6.36 (s, 1H), 6.17-6.24 (m,

2H), 6.06 (dd, 1H), 5.56 (dd, 1H), 4.99 (s, 2H),

3.76-3.79 (m, 1H), 3.13-3.26 (m, 3H), 2.89-2.96

(m, 1H), 2.36-2.43 (m, 1H), 2.13 (m, 1H).

6-
484.3
S3
10.07
(DMSO-d6) δ ppm: 11.4 (s, 1H), 8.24 (t, 1H), 7.62-

En2

7.64 (m, 2H), 7.32-7.37 (m, 3H), 6.94 (t, 1H), 6.55

(d, 1H), 6.49 (d, 1H), 6.36 (s, 1H), 6.17-6.24 (m,

2H), 6.06 (dd, 1H), 5.56 (dd, 1H), 4.99 (s, 2H),

3.76-3.79 (m, 1H), 3.13-3.26 (m, 3H), 2.89-2.96

(m, 1H), 2.36-2.43 (m, 1H), 2.13 (m, 1H).

7
486.4
L2
2.71
(DMSO-d6) δ ppm: 11.5 (s, 1H), 7.87-7.90 (t, 1H),

7.61-7.63 (d, 2H), 7.36-7.38 (d, 1H), 7.31-7.33 (d,

2H), 6.92-6.97 (t, 1H), 6.49-6.56 (m, 2H), 6.37 (s,

1H), 6.20-6.22 (m, 1H), 4.99 (s, 1H), 3.74-3.77

(dd, 1H), 3.24-3.31 (m, 1H), 3.04-3.15 (m, 2H),

2.87-2.92 (dd, 1H), 2.32-2.40 (q, 1H), 2.02-2.09

(m, 3H), 0.96 (t, 3H).

8
525.4
L1
2.64
(DMSO-d6) δ ppm: 11.05-11.07 (m, 2H), 7.63-7.65

(d, 2H), 7.34-7.36 (d, 2H), 7.14-7.17 (t, 1H), 6.96-

7.00 (t, 1H), 6.57-6.59 (d, 1H), 6.45-6.47 (d, 1H),

5.61 (s, 1H), 4.81 (s, 2H), 3.83-3.87 (dd, 1H), 3.26-

3.31 (m, 1H), 3.02-3.07 (m, 1H), 2.90-2.96 (m, 2H),

2.86 (s, 3H), 2.32-2.49 (m, 1H), 2.07-2.10 (m 1H).

9
508.3
L2
2.09
(DMSO-d6) δ ppm: 11.47 (s, 1H), 7.62-7.65 (d,

2H), 7.34-7.37 (t, 3H), 7.13-7.16 (t, 1H), 7.31-7.33

(d, 2H), 6.93-6.97 (t, 1H), 6.49-6.56 (q, 2H), 6.38

(s, 1H), 6.20-6.22 (d, 1H), 4.99 (s, 2H), 3.83-3.87

(d, 1H), 3.29 (s, 1H), 3.02-3.09 (m, 1H), 2.91-2.97

(m, 2H), 2.86 (s, 3H), 2.38-2.45 (q, 1H), 2.06-2.12

(m, 1H).

10
362.5
L4
1.55
(DMSO-d6) δ ppm: 8.23-8.25 (t, 1H), 7.98-8.00

(dd, 1H), 7.67-7.69 (d, 2H), 7.37-7.39 (d, 2H), 7.23-

7.26 (dd, 1H), 6.99-7.03 (m, 1H), 6.18-6.25 (m,

1H), 6.04-6.09 (dd, 1H), 5.56-5.59 (dd, 1H), 3.78-

3.81 (dd, 1H), 3.32-3.37 (m, 1H), 3.21-3.24 (m,

2H), 2.96-3.02 (dd, 1H), 2.65-2.71 (m, 1H), 2.25-

2.27 (m, 1H).

10-
362.3
S1
5.45
(DMSO-d6) δ ppm: 8.23 (t, 1H), 7.98-8.00 (m, 1H),

En1

7.67-7.69 (m, 2H), 7.37-7.39 (m, 2H), 7.24 (dd,

1H), 7.01 (dd, 1H), 6.22 (dd, 1H), 6.06 (dd, 1H),

5.57 (dd, 1H), 3.80 (dd, 1H), 3.34-3.37 (m, 1H),

3.21-3.26 (m, 2H), 2.99 (dd, 1H), 2.68 (dd, 1H),

2.25-2.27 (m, 1H).

10-
362.3
S1
7.25
(DMSO-d6) δ ppm: 8.23 (t, 1H), 7.98-8.00 (m, 1H),

En2

7.67-7.69 (m, 2H), 7.37-7.39 (m, 2H), 7.24 (dd,

1H), 7.01 (dd, 1H), 6.22 (dd, 1H), 6.06 (dd, 1H),

5.57 (dd, 1H), 3.80 (dd, 1H), 3.34-3.37 (m, 1H),

3.21-3.26 (m, 2H), 2.99 (dd, 1H), 2.68 (dd, 1H),

2.25-2.27 (m, 1H).

11
499.4
L6
5.49
(DMSO-d6): δ ppm: 10.5-11.7 (br. s, 1H), 8.21 (t,

1H), 7.58-7.61 (m, 2H), 7.27-7.29 (m, 2H), 6.93-

6.96 (m, 1H), 6.81-6.83 (m, 1H), 6.76-6.77 (m, 1H),

5.57 (dd, 1H), 3.77-3.81 (m, 1H), 3.16-3.40 (m,

1H), 2.84-2.90 (m, 1H), 2.70-2.75 (m, 2H), 2.62-

2.66 (m, 2H), 2.41-2.45 (m, 1H), 2.10-2.12 (m, 1H).

12
350.3
L5
1.50
(DMSO-d6) δ ppm: 7.98-7.99 (m, 2H), 7.67-7.69

(m, 2H), 7.37-7.39 (m, 2H), 7.24 (d, 1H), 7.00 (dd,

1H), 3.77-3.79 (m, 1H), 3.31 (m, 1H), 3.11-3.13 (m,

2H), 2.94-3.00 (m, 1H), 2.62-2.68 (m, 1H), 2.20-

2.21 (d, 1H), 1.80 (s, 3H).

12-
350.3
S2
9.19
(DMSO-d6) δ ppm: 7.96-7.99 (m, 2H), 7.67-7.69

En1

(m, 2H), 7.37-7.39 (m, 2H), 7.24 (dd, 1H), 7.00 (dd,

1H), 3.78 (dd, 1H), 3.29-3.31 (m, 1H), 3.10-3.13

(m, 2H), 2.97 (dd, 1H), 2.65 (dd, 1H), 2.18-2.21 (m,

1H), 1.80 (s, 3H).

12-
350.3
S2
11.08
(DMSO-d6) δ ppm: 7.96-7.99 (m, 2H), 7.67-7.69

En2

(m, 2H), 7.37-7.39 (m, 2H), 7.24 (dd, 1H), 7.00 (dd,

1H), 3.78 (dd, 1H), 3.29-3.31 (m, 1H), 3.10-3.13

(m, 2H), 2.97 (dd, 1H), 2.65 (dd, 1H), 2.18-2.21 (m,

1H), 1.80 (s, 3H).

13
337.3
L5
1.57
(DMSO-d6) δ ppm: 12.35 (br. s, 1H), 7.99-8.00 (m,

1H), 7.66-7.68 (m, 2H), 7.38-7.45 (m, 2H), 7.25-

7.27 (m, 1H), 7.00-7.03 (m, 1H), 3.81-3.85 (m, 1H),

3.36-3.41 (m, 1H), 3.05 (dd, 1H), 2.68 (dd, 1H),

2.45-2.49 (m, 1H), 2.34-2.36 (m, 2H).

14
515.3
L4
1.97
(DMSO-d6): δ ppm: 10.94 (s, 1H), 8.22 (t, 1H),

7.62-7.65 (m, 2H), 7.33-7.35 (m, 2H), 6.99 (t, 1H),

6.65 (d, 1H), 6.59 (d, 1H), 6.20 (dd, 1H), 6.05 (dd,

1H), 5.73 (s, 1H), 5.55 (dd, 1H), 5.06 (s, 2H), 3.75-

3.78 (m, 1H), 3.13-3.27 (m, 6H), 2.89 (dd, 1H),

2.32-2.45 (m, 1H), 2.13-2.14 (m, 1H).

14-
515.4
S5
4.73
(DMSO-d6): δ ppm: 11.34 (s, 1H), 8.23 (t, 1H),

En1

7.62-7.65 (m, 2H), 7.33-7.35 (m, 2H), 6.99 (t, 1H),

6.65 (d, 1H), 6.59 (d, 1H), 6.20 (dd, 1H), 6.05 (dd,

1H), 5.73 (s, 1H), 5.55 (dd, 1H), 5.06 (s, 2H), 3.75-

3.78 (m, 1H), 3.13-3.27 (m, 6H), 2.89 (dd, 1H),

2.32-2.45 (m, 1H), 2.13-2.14 (m, 1H).

14-
515.4
S5
7.04
(DMSO-d6): δ ppm: 11.34 (s, 1H), 8.23 (t, 1H),

En2

7.62-7.65 (m, 2H), 7.33-7.35 (m, 2H), 6.99 (t, 1H),

6.65 (d, 1H), 6.59 (d, 1H), 6.20 (dd, 1H), 6.05 (dd,

1H), 5.73 (s, 1H), 5.55 (dd, 1H), 5.06 (s, 2H), 3.75-

3.78 (m, 1H), 3.13-3.27 (m, 6H), 2.89 (dd, 1H),

2.32-2.45 (m, 1H), 2.13-2.14 (m, 1H).

15-
366.1
S2
3.75
(DMSO-d6) δ ppm: 7.99 (d, 1H), 7.67-7.69 (m, 2H),

En1

7.37-7.39 (m, 2H), 7.31 (t, 1H), 7.25 (d, 1H), 7.02

(dd, 1H), 3.78 (dd, 1H), 3.50 (s, 3H), 3.31-3.34 (m,

1H), 3.04-3.11 (m, 2H), 2.95-3.02 (m, 1H), 2.62-

2.68 (m, 1H), 2.20-2.22 (m, 1H).

15-
366.1
S2
5.11
(DMSO-d6) δ ppm: 7.99 (d, 1H), 7.67-7.69 (m, 2H),

En2

7.37-7.39 (m, 2H), 7.31 (t, 1H), 7.25 (d, 1H), 7.02

(dd, 1H), 3.78 (dd, 1H), 3.50 (s, 3H), 3.31-3.34 (m,

1H), 3.04-3.11 (m, 2H), 2.95-3.02 (m, 1H), 2.62-

2.68 (m, 1H), 2.20-2.22 (m, 1H).

16
366.2
L5
1.54
(DMSO-d6) δ ppm: 8.01 (t, 1H), 7.83 (d, 1H), 7.73-

7.75 (m, 2H), 7.44-7.46 (m, 2H), 7.02 (dd, 1H),

6.73 (d, 1H), 3.69 (dd, 1H), 3.32-3.36 (m, 1H),

3.02-3.14 (m, 3H), 2.46-2.53 (m, 1H), 2.15-2.20 (m,

1H), 1.79 (s, 3H).

17
364.2
L5
1.45
(DMSO-d6) δ ppm: 7.99 (dd, 1H), 7.89 (t, 1H),

7.67-7.69 (m, 2H), 7.36-7.38 (m, 2H), 7.25 (dd,

1H), 7.01 (dd, 1H), 3.78 (dd, 1H), 3.29-3.35 (m,

1H), 3.10-3.13 (m, 2H), 2.97 (dd, 1H), 2.62-2.68

(m, 1H), 2.19-2.24 (m, 1H), 2.06 (q, 2H), 0.96 (t, 3H).

17-
364.3
S4
2.68
(DMSO-d6) δ ppm: 7.99 (dd, 1H), 7.89 (t, 1H),

En1

7.67-7.69 (m, 2H), 7.36-7.38 (m, 2H), 7.25 (dd,

1H), 7.01 (dd, 1H), 3.78 (dd, 1H), 3.29-3.35 (m,

1H), 3.10-3.13 (m, 2H), 2.97 (dd, 1H), 2.62-2.68

(m, 1H), 2.19-2.24 (m, 1H), 2.06 (q, 2H), 0.96 (t, 3H).

17-
364.3
S4
3.80
(DMSO-d6) δ ppm: 7.99 (dd, 1H), 7.89 (t, 1H),

En2

7.67-7.69 (m, 2H), 7.36-7.38 (m, 2H), 7.25 (dd,

1H), 7.01 (dd, 1H), 3.78 (dd, 1H), 3.29-3.35 (m,

1H), 3.10-3.13 (m, 2H), 2.97 (dd, 1H), 2.62-2.68

(m, 1H), 2.19-2.24 (m, 1H), 2.06 (q, 2H), 0.96 (t, 3H).

18
376.2
L5
1.54
(DMSO-d6) δ ppm: 8.19 (t, 1H), 7.98-7.99 (m, 1H),

7.67-7.69 (m, 2H), 7.37-7.39 (m, 2H), 7.23-7.25 (m,

1H), 6.19-7.02 (m, 1H), 3.79 (dd, 1H), 3.31-3.36

(m, 1H), 3.13-3.16 (m, 2H), 2.99 (dd, 1H), 2.66 (dd,

1H), 2.20-2.23 (m, 1H), 1.50-1.56 (m, 1H), 0.61-

0.62 (m, 4H).

19
401.3
L5
1.51
(DMSO-d6) δ ppm: 7.98-8.00 (m, 1H), 7.68-7.70

(m, 2H), 7.38-7.40 (m, 2H), 7.25 (dd, 1H), 6.99-

7.06 (m, 2H), 6.69-6.73 (m, 1H), 3.87 (dd, 1H),

3.35-3.38 (m, 1H), 3.02 (dd, 1H), 2.81-2.92 (m,

2H), 2.67 (dd, 1H), 2.39 (d, 3H), 2.26-2.27 (m, 1H).

20
349.3
L4
1.50
(DMSO-d6) δ ppm: 12.5 (s, 1H), 8.13 (d, 1H), 7.76-

7.78 (m, 2H), 7.48-7.54 (m, 3H), 7.31-7.35 (m, 1H),

6.88 (dd, 1H), 5.92 (d, 1H), 3.89-3.92 (m, 1H),

3.58-3.66 (m, 1H), 3.21-3.29 (m, 1H), 3.04-3.16

(m, 2H).

21
392.3
L6
5.53
(DMSO-d6) δ ppm: 8.20 (t, 1H), 7.57-7.59 (m, 2H),

7.39 (d, 1H), 7.20-7.22 (m, 2H), 6.55 (d, 1H), 6.21

(dd, 1H), 6.06 (dd, 1H), 5.58 (dd, 1H), 3.85 (dd,

1H), 3.80 (s, 3H), 3.15-3.31 (m, 3H), 2.89 (dd, 1H),

2.54-2.61 (m, 1H), 2.13-2.18 (m, 1H).

22
380.3
L4
1.92
(DMSO-d6) δ ppm: 7.95 (t, 1 H), 7.57-7.59 (m, 2H),

7.39 (d, 1H), 7.19-7.22 (m, 2H), 6.55 (d, 1H), 3.85

(dd, 1H), 3.80 (s, 3H), 3.20-3.25 (m, 1H), 3.06-3.09

(m, 2H), 2.86 (dd, 1H), 2.54-2.58 (m, 1H), 2.07-

2.12 (m, 1H), 1.80 (s, 3H).

22-
380.3
S2
3.78
(DMSO-d6) δ ppm: 7.94 (t, 1H), 7.57-7.59 (m, 2H),

En1

7.39 (d, 1H), 7.19-7.22 (m, 2H), 6.55 (d, 1H), 3.85

(dd, 1H), 3.80 (s, 3H), 3.20-3.25 (m, 1H), 3.06-

3.09 (m, 2H), 2.86 (dd, 1H), 2.54-2.58 (m, 1H),

2.07-2.11 (m, 1H), 1.80 (s, 3H).

22-
380.3
S2
5.84
(DMSO-d6) δ ppm: 7.94 (t, 1H), 7.57-7.59 (m, 2H),

En2

7.39 (d, 1H), 7.19-7.22 (m, 2H), 6.55 (d, 1H), 3.85

(dd, 1H), 3.80 (s, 3H), 3.20-3.25 (m, 1H), 3.06-

3.09 (m, 2H), 2.86 (dd, 1H), 2.54-2.58 (m, 1H),

2.07-2.11 (m, 1H), 1.80 (s, 3H).

23
366.3
L6
4.55
(DMSO-d6) δ ppm: 11.34-11.65 (s, 1H), 7.90 (t,

1H), 7.54-7.56 (m, 2H), 7.19 (d, 1H), 7.06-7.08 (m,

2H), 6.15 (d, 1H), 3.83 (dd, 1H), 3.17-3.31 (m, 1H),

2.92-3.06 (m, 2H), 2.61-2.67 (m, 1H), 2.28-2.35 (m,

1H), 1.93-1.97 (m, 1H), 1.77 (s, 3H).

24
353.3
L4
1.39
(DMSO-d6): δ ppm: 8.01 (dd, 1H), 7.64-7.67 (m,

2H), 7.37-7.39 (m, 2H), 7.28 (dd, 2H), 7.02 (dd,

1H), 4.14-4.16 (m, 1H), 3.80-3.93 (m, 2H), 3.72-

3.78 (m, 1H), 3.16 (dd, 1H), 3.01-2.85 (m, 1H).

25
364.3
L4
1.22
(DMSO-d6) δ ppm: 8.05 (dd, 1H), 7.58-7.60 (m,

2H), 7.26-7.29 (m, 2H), 7.21 (dd, 1H), 6.93 (dd,

1H), 4.76-4.81 (m, 1H), 4.36-4.41 (m, 2H), 3.84-

3.94 (m, 2H), 3.45-3.47 (m, 1H), 3.13-3.18 (m, 1H),

2.55-2.78 (m, 2H), 2.27-2.54 (m, 1H), 2.02-2.25

(m, 1H).

26
364.3
L3
3.90
(DMSO-d6) δ ppm: 7.96 (t, 1H), 7.62-7.65 (m, 2H),

7.30-7.32 (m, 2H), 7.23 (d, 1H), 6.89 (d, 1 H), 3.79

(dd, 1 H), 3.24-3.37 (m, 1 H), 3.08-3.11 (m, 2 H),

2.91 (dd, 1 H), 2.56-2.67 (m, 1 H), 2.35 (s, 3 H),

2.14-2.19 (m, 1 H), 1.80 (s, 3 H).

26-
364.2
S6
1.08
(DMSO-d6) δ ppm: 7.96 (t, 1H), 7.62-7.65 (m, 2H),

En1

7.30-7.32 (m, 2H), 7.23 (d, 1H), 6.89 (d, 1H), 3.79

(dd, 1H), 3.24-3.37 (m, 1H), 3.08-3.11 (m, 2H),

2.91 (dd, 1H), 2.56-2.67 (m, 1H), 2.35 (s, 3H),

2.14-2.19 (m, 1H), 1.80 (s, 3H).

26-
364.2
S6
1.55
(DMSO-d6) δ ppm: 7.96 (t, 1H), 7.62-7.65 (m, 2H),

En2

7.30-7.32 (m, 2H), 7.23 (d, 1H), 6.89 (d, 1H), 3.79

(dd, 1H), 3.24-3.37 (m, 1H), 3.08-3.11 (m, 2H),

2.91 (dd, 1H), 2.56-2.67 (m, 1H), 2.35 (s, 3H),

2.14-2.19 (m, 1H), 1.80 (s, 3H).

27
366.2
L6
4.87
(DMSO-d6) δ ppm 10.82 (s, 1H), 7.95 (t, 1H), 7.73-

7.76 (m, 2H), 7.39-7.41 (m, 2H), 6.97 (d, 1H), 5.59

(d, 1H), 3.65 (d, 1H), 3.27-3.31 (m, 1H), 3.05-3.08

(m, 2H), 2.56-2.63 (m, 1H), 2.01-2.10 (m, 2H), 1.78

(s, 3H).

28
419.3
L4
1.36
(DMSO-d6) ppm: 8.13-8.14 (m, 1H), 8.00 (dd, 1H),

7.80 (d, 1H), 7.67-7.69 (m, 2H), 7.36-7.38 (m, 2H),

7.25 (dd, 1H), 7.00-7.03 (m, 1H), 3.93-3.99 (m,

1H), 3.77-3.80 (m, 1H), 3.29-3.27 (m, 1H), 3.10-

3.20 (m, 2H), 2.71-3.03 (m, 1H), 2.64-2.71 (m, 1H),

2.14-2.23 (m, 2H), 2.04-2.10 (m, 2H), 1.72-1.83 (m, 1H).

29
419.4
L4
1.37
(DMSO-d6) δ ppm: 8.13 (s, 1H), 7.99-8.00 (m, 1H),

7.79-7.80 (d, 1H), 7.67-7.69 (m, 2H), 7.36-7.39 (m,

2H), 7.24-7.26 (m, 1H), 7.00-7.03 (m, 1H), 3.93-

3.99 (m, 1H), 3.77-3.80 (m, 1H), 3.37 (s, 1H), 3.10-

3.20 (m, 2H), 2.95-2.99 (m, 1H), 2.50-2.68 (m, 1H),

2.12-2.32 (m, 2H), 2.03-2.09 (m, 2H), 1.71-1.84 (m, 1H).

30
416.3
L4
1.30
(DMSO-d6) δ ppm: 8.37 (t, 1H), 7.99-8.00 (m, 1H),

7.66-7.71 (m, 3H), 7.54 (s, 1H), 7.37-7.39 (m, 2H),

7.25-7.27 (d, 1H), 7.00-7.03 (m, 1H), 3.77-3.84 (m,

4H), 3.36-3.42 (m, 1H), 3.27-3.31 (m, 2H), 3.02

(dd, 1H), 2.68-2.75 (m, 1H), 2.32-2.36 (m, 1H).

31
376.3
L4
1.48
(DMSO-d6) δ ppm: 7.98 (dd, 1H), 7.67-7.70 (m,

2H), 7.38-7.40 (m, 2H), 7.22 (dd, 1H), 6.99-7.02

(m, 1H), 3.72 (dd, 1H), 3.31-3.36 (m, 3H), 3.23-

3.25 (m, 2H), 2.92-2.97 (m, 1H), 2.61-2.67 (m, 1H),

2.41-2.43 (m, 1H), 2.20-2.24 (m, 2H), 1.87-1.94 (m, 2H).

32
349.3
L4
1.38
(DMSO-d6) ppm: 8.30 (t, 1H), 7.80 (d, 2H), 7.51 (d,

2H), 7.05 (s, 1H), 6.93 (s, 1H), 4.22 (d, 2H), 3.71

(s, 2H), 3.01-3.02 (m, 2H), 2.82-2.83 (m, 2H), 1.84

(s, 3H).

33
361.2
L6
4.19
(DMSO-d6) δ ppm: 8.57 (t, 1H), 7.80 (d, 2H), 7.51

(d, 2H), 7.07 (s, 1H), 6.95 (s, 1H), 6.25 (dd, 1H),

6.10 (dd, 1H), 5.60 (dd, 1H), 4.33 (d, 2H), 3.71 (s,

2H), 3.01-3.04 (m, 2H), 2.80-2.83 (m, 2H).

34
353.3
L6
4.16
(DMSO-d6) δ ppm: 7.96-7.99 (m, 2H), 7.67-7.69

(m, 2H), 7.37-7.39 (m, 2H), 7.24 (dd, 1H), 6.99-

7.02 (m, 1H), 3.78 (dd, 1H), 3.29-3.34 (m, 1H),

3.10-3.13 (m, 2H), 2.97 (dd, 1H), 2.62-2.68 (m,

1H), 2.18-2.21 (m, 1H).

34-
353.1
S2
5.31
(DMSO-d6) δ ppm: 7.98-7.99 (m, 2H), 7.68 (d, 2H),

En1

7.38 (d, 2H), 7.23-7.25 (m, 1H), 6.99-7.02 (m,

1H), 3.78 (dd, 1H), 3.29-3.34 (m, 1H), 3.08-3.16

(m, 2H), 2.94-3.00 (m, 1H), 2.62-2.68 (m, 1H),

2.18-2.21 (m, 1H).

34-
353.1
S2
7.08
(DMSO-d6) δ ppm: 7.98-7.99 (m, 2H), 7.68 (d, 2H),

En2

7.38 (d, 2H), 7.23-7.25 (m, 1H), 6.99-7.02 (m,

1H), 3.78 (dd, 1H), 3.29-3.34 (m, 1H), 3.08-3.16

(m, 2H), 2.94-3.00 (m, 1H), 2.62-2.68 (m, 1H),

2.18-2.21 (m, 1H).

35
426.3
L4
1.64
(DMSO-d6) ppm: 8.20 (t, 1H), 7.99 (d, 1H), 7.66-

7.68 (m, 2H), 7.31-7.33 (m, 2H), 7.18-7.24 (m, 6H),

7.02-6.99 (m, 1H), 3.73-3.75 (m, 1H), 3.39 (s, 2H),

3.26-3.31 (m, 1H), 3.12-3.15 (m, 2H), 2.96 (dd,

1H), 2.61-2.68 (m, 1H), 2.21 (m, 1H).

36
419.2
L6
4.09
(DMSO-d6) δ ppm: 12.8 (br. s, 1H), 8.85 (br. s,

2H), 7.86 (d, 2H), 7.57 (d, 2H), 7.22 (d, 1H), 7.13

(s, 1H), 6.59-6.78 (m, 1H), 6.14-6.22 (m, 1H),

5.70-5.73 (m, 1H), 4.76 (s, 1H), 4.59 (s, 1H), 4.21

(s, 1H), 4.10 (m, 2H), 4.04 (s, 1H), 3.36 (m, 2H),

3.06-3.08 (m, 2H).

37
407.2
L7
2.42
(DMSO-d6) δ ppm: 7.81 (d, 2H), 7.52-7.55 (m,

2H), 7.07 (d, 1H), 6.94 (d, 1H), 4.57 (s, 2H), 4.42

(s, 1H), 3.68-3.86 (m, 4H), 3.06-3.16 (m, 2H),

2.85-2.88 (m, 2H), 1.90-2.04 (m, 3H).

38
418.2
L6
4.50
(DMSO-d6) δ ppm: 8.39 (t, 1H), 7.99-8.00 (m, 1H),

7.67-7.69 (m, 2H), 7.36-7.38 (m, 2H), 7.24 (d, 1H),

7.00-7.03 (m, 1H), 3.79 (dd, 1H), 3.15-3.36 (m,

5H), 2.96-3.02 (dd, 1H), 2.64-2.70 (m, 1H), 2.22-

2.24 (m, 1H).

38-
418.1
S7
7.69
(DMSO-d6) δ ppm: 8.37-8.40 (t, 1H), 7.99-8.00

En1

(dd, 1H), 7.67-7.69 (d, 2H), 7.36-7.38 (d, 2H),

7.23-7.26 (dd, 1H), 7.00-7.03 (m, 1H), 3.77-3.81

(dd, 1H), 3.36 (t, 1H), 3.19-3.34 (dd, 2H), 3.17-

3.18 (m, 2H), 2.97-3.02 (d, 1H), 2.64-2.70 (m, 1H),

2.22-2.33 (m, 1H).

38-
418.2
S7
9.34
(DMSO-d6) δ ppm: 8.37-8.40 (t, 1H), 7.99-8.00

En2

(dd, 1H), 7.67-7.69 (d, 2H), 7.36-7.38 (d, 2H),

7.23-7.26 (dd, 1H), 7.00-7.03 (m, 1H), 3.77-3.81

(dd, 1H), 3.36 (t, 1H), 3.17-3.34 (m, 4H), 2.97-

3.02 (dd, 1H), 2.64-2.70 (m, 1H), 2.22-2.24 (m, 1H).

39
378.2
L4
1.50
(DMSO-d6) ppm: 12.7 (s, 1H), 8.00 (d, 1H), 7.84-

7.87 (m, 1H), 7.66-7.69 (m, 2H), 7.35-7.37 (m, 2H),

7.24-7.27 (m, 1H), 7.00-7.03 (m, 1H), 3.75-3.79 (m,

1H), 3.30-3.35 (m, 1H), 3.07-3.16 (m, 2H), 2.94-

3.00 (m, 1H), 2.62-2.68 (m, 1H), 2.30-2.37 (m, 1H),

2.20-2.22 (m, 1H), 0.96 (t, 6H).

40
412.4
L6
3.58
(DMSO-d6) ppm: 8.60 (t, 1H), 7.99-8.00 (m, 1H),

7.80-7.82 (m, 2H), 7.66-7.68 (m, 2H), 7.51-7.53 (m,

1H), 7.38-7.46 (m, 4H), 7.26 (dd, 1H), 7.00-7.03

(m, 1H), 3.84 (dd, 1H), 3.34-3.44 (m, 3H), 3.03 (dd,

1H), 2.66-2.77 (m, 1H), 2.32-2.33 (m, 1H).

41
416.3
L6
4.86
(DMSO-d6) δ ppm: 7.70 (d, 2H), 7.39 (d, 2H), 7.23

(d, 1H), 7.08-7.12 (m, 1H), 6.93-6.97 (m, 2H), 6.83

(dd, 1H), 6.16 (d, 1H), 5.76 (d, 1H), 4.08-4.48 (m,

3H), 3.68-3.72 (m, 4H), 3.14-3.28 (m, 6H).

42
418.2
L4
2.10
(DMSO-d6) δ ppm: 8.00 (t, 1H), 7.79 (d, 2H), 7.53

(d, 2H), 7.40 (d, 1H), 7.14 (d, 1H), 3.77 (dd, 1H),

3.43-3.46 (m, 1H), 3.13-3.14 (m, 2H), 3.06 (dd,

1H), 2.67-2.78 (m, 1H), 2.28-2.32 (m, 1H), 1.81 (s, 3H).

43
365.2
L4
1.38
(DMSO-d6) ppm: 7.99 (dd, 1H), 7.67-7.69 (d, 2H),

7.37-7.39 (d, 2H), 7.24 (dd, 1H), 6.99-7.02 (m, 1H),

6.08-6.11 (m, 1H), 5.69-5.72 (m, 1H), 3.75-3.78 (m,

1H), 3.27-3.32 (m, 1H), 3.02-3.09 (m, 2H), 2.92-

2.98 (m, 1H), 2.59-2.67 (m, 1H), 2.49-2.52 (m, 3H),

2.15-2.17 (m, 1H).

44
430.1
L4
1.99
(DMSO-d6) δ ppm: 8.02 (d, 1H), 7.98 (t, 1H), 7.75-

7.77 (m, 2H), 7.46-7.48 (m, 2H), 7.21 (d, 1H), 3.73

(dd, 1H), 3.34-3.37 (m, 1H), 3.10-3.14 (m, 2H),

2.92-2.98 (m, 1H), 2.60-2.66 (m, 1H), 2.21-2.23 (m,

1H), 1.80 (s, 3H).

45
365.2
L6
4.20
(DMSO-d6) ppm: 7.92 (t, 1H), 7.51 (d, 2H), 7.09-

7.16 (m, 3H), 6.26 (d, 1H), 5.66 (s, 2H), 3.84 (dd,

1H), 3.01-3.37 (m, 3H), 2.66-2.72 (m, 1H), 2.32-

2.38 (m, 1H), 2.01-2.07 (m, 1H), 1.79 (s, 3H).

46
363.1
L4
1.34
(DMSO-d6) ppm: 8.30 (t, 1H), 7.80 (d, 2H), 7.52 (d,

2H), 7.06 (s, 1H), 6.91-6.92 (d, 1H), 4.22 (d, 2H),

3.29 (s, 2H), 2.89 (t, 2H), 2.62 (t, 2H), 2.26 (s, 3H),

1.84 (s, 3H).

47
364.3
L4
1.48
(DMSO-d6) δ ppm: 7.99 (br. s, 1H), 7.87 (t, 1H),

7.68-7.70 (m, 2H), 7.38-7.40 (m, 2H), 7.22 (d, 1H),

6.99-7.02 (m, 1H), 3.38-3.47 (m, 2H), 3.02-3.14 (m,

2H), 2.84 (d, 1H), 2.58-2.67 (m, 1H), 1.80 (s, 3H),

0.91 (s, 3H).

47-
364.3
S8
3.25
(DMSO-d6) δ ppm: 7.97 (dd, 1H), 7.87 (t, 1H),

En1

7.68-7.70 (m, 2H), 7.38-7.40 (m, 2H), 7.21-7.23 (m,

1H), 6.98-7.01 (m, 1H), 3.38-3.47 (m, 2H), 3.02-

3.14 (m, 2H), 2.84 (d, 1H), 2.58-2.67 (m, 1H), 1.80

(s, 3H), 0.91 (s, 3H).

47-
364.2
S8
4.53
(DMSO-d6) δ ppm: 7.97 (dd, 1H), 7.87 (t, 1H),

En2

7.68-7.70 (m, 2H), 7.38-7.40 (m, 2H), 7.21-7.23 (m,

1H), 6.98-7.01 (m, 1H), 3.38-3.47 (m, 2H), 3.02-

3.14 (m, 2H), 2.84 (d, 1H), 2.58-2.67 (m, 1H), 1.80

(s, 3H), 0.91 (s, 3H).

48
380.2
L7
3.54
(DMSO-d6) δ ppm: 7.93 (t, 1H), 7.56 (d, 2H), 7.16

(d, 1H), 7.07 (d, 2H), 6.29 (d, 1H), 3.88 (dd, 1H),

3.42 (s, 3H), 3.07-3.09 (m, 1H), 3.02-3.05 (m, 2H),

2.84-2.90 (m, 1H), 2.45-2.50 (m, 1H), 1.93-1.94 (m,

1H), 1.79 (s, 3H).

49
365.2
L4
1.35
(DMSO-d6) δ ppm: 7.94 (t, 1H), 7.66-7.68 (m, 2H),

7.42 (d, 1H), 7.35-7.37 (m, 2H), 6.49 (d, 1H), 4.96

(s, 2H), 3.67-3.71 (m, 1H), 3.20-3.25 (m, 1H), 3.05-

3.08 (m, 2H), 2.77-2.82 (m, 1H), 2.42-2.45 (m, 1H),

2.13-2.15 (m, 1H), 1.79 (s, 3H)

50
368.2
L4
1.84
(DMSO-d6) δ ppm: 7.98 (t, 1H), 7.91 (d, 2H), 7.73-

7.76 (m, 2H), 7.46-7.48 (m, 2H), 6.95 (dd, 1H),

3.73 (dd, 1H), 3.35-3.38 (m, 1H), 3.10-3.13 (m,

2H), 2.97 (dd, 1H), 2.61-2.67 (m, 1H), 2.20-2.23

(m, 1H), 1.80 (s, 3H).

51
384.1
L6
5.25
(DMSO-d6) δ ppm: 7.94-7.99 (m, 2H), 7.75-7.77

(m, 2H), 7.46-7.48 (m, 2H), 7.09 (d, 1H), 3.74 (dd,

1H), 3.32-3.38 (m, 1H), 3.08-3.16 (m, 2H), 2.94-

3.00 (m, 1H), 2.62-2.69 (m, 1H), 2.21-2.23 (m, 1H),

1.80 (s, 3H).

52
393.2
L6
4.37
(DMSO-d6) δ ppm: 7.93 (t, 1H), 7.52-7.54 (m, 2H),

7.27 (d, 1H), 7.11-7.14 (m, 2H), 6.46 (d, 1H), 3.86

(dd, 1H), 3.00-3.10 (m, 3H), 3.10-3.32 (m, 6H),

2.78 (dd, 1H), 2.46 (m, 1H), 2.03-2.07 (m, 1H),

1.76 (s, 3H).

53
351.2
L4
1.34
(DMSO-d6) δ ppm: 8.58 (s, 1H), 8.16-8.19 (m, 1H),

8.00 (t, 1H), 7.93 (dd, 1H), 7.82 (dd, 1H), 7.23 (d,

1H), 7.16 (dd, 1H), 4.24 (dd, 1H), 3.35-3.41 (m,

1H), 3.09-3.12 (m, 2H), 2.97 (dd, 1H), 2.63 (dd,

1H), 2.13-2.15 (m, 1H), 1.81 (s, 3H).

54
380.2
L4
1.62
(DMSO-d6) δ ppm: 7.96 (t, 1H), 7.74 (d, 2H), 7.40

(d, 2H), 7.28 (d, 1H), 5.67 (d, 1H), 3.63-3.66 (m,

1H), 3.29 (s, 3H), 3.26-3.30 (m, 1H), 3.05-3.08 (m,

2H), 2.60-2.65 (m, 1H), 2.04-2.14 (m, 2H), 1.78 (s, 3H).

55
378.2
L6
4.35
(DMSO-d6) δ ppm 7.96 (t, 1H), 7.64 (d, 2H), 7.32

(d, 2H), 7.25 (d, 1H), 6.90 (d, 1H), 3.79 (dd, 1H),

3.25-3.28 (m, 1H), 3.08-3.11 (m, 2H), 2.90-2.96 (m,

1H), 2.57-2.66 (m, 3H), 2.15-2.17 (m, 1H), 1.80 (s,

3H), 1.18 (t, 3H).

56
351.2
L6
4.74
(DMSO-d6) ppm: 8.01 (t, 1H), 7.8 (d, 1H), 7.83 (d,

1H), 7.72 (d, 2H), 7.55 (d, 2H), 3.84 (dd, 1H), 3.60

(dd, 1H), 3.10-3.20 (m, 2H), 3.02 (dd, 1H), 2.76 (m,

1H), 2.30 (m, 1H), 1.81 (s, 3H).

57
390.2
L8
10.95
(DMSO-d6) δ ppm 7.95 (t, 1H), 7.62 (d, 2H), 7.29

(d, 2H), 7.22 (d, 1H), 6.91 (d, 1H), 3.79 (dd, 1H),

3.21-3.24 (m, 1H), 3.07-3.10 (m, 2H), 2.86 (dd,

1H), 2.54-2.58 (m, 1H), 2.11-2.14 (m, 1H), 1.94-

1.99 (m, 1H), 1.80 (s, 3H), 0.81-0.88 (m, 4H).

58
375.2
L4
1.87
(DMSO-d6) δ ppm: 8.00 (t, 1H), 7.83 (d, 2H), 7.55

(d, 2H), 7.49 (d, 1H), 6.96 (d, 1H), 3.76 (dd, 1H),

3.43-3.48 (m, 1H), 3.12-3.15 (m, 2H), 3.02 (dd,

1H), 2.67-2.76 (m, 1H), 2.27-2.32 (m, 1H), 1.80 (s, 3H).

59
393.2
L4
1.67
(DMSO-d6) δ ppm: 7.00 (t, 1H), 7.76 (d, 2H), 7.70-

7.71 (m, 1H), 7.63 (d, 1H), 7.48 (d, 2H), 7.32-7.33

(m, 1H), 7.18 (d, 1H), 3.78 (dd, 1H), 3.31-3.44 (m,

1H), 3.11-3.18 (m, 2H), 3.04 (dd, 1H), 2.72 (dd,

1H), 2.26-2.32 (m, 1H), 1.81 (s, 3H).

60
416.2
L4
2.16
(DMSO-d6) δ ppm: 7.96 (t, 1H), 7.65 (d, 2H), 7.56

(t, 1H), 7.47 (d, 1H), 7.32 (d, 2H), 6.76 (d, 1H),

3.79-3.83 (dd, 1H), 3.27 (s, 1H), 3.27-3.31 (m, 1H),

3.08-3.11 (m, 2H), 2.90 (dd, 1H), 2.56-2.67 (m,

1H), 2.15-2.17 (m, 1H), 1.80 (s, 3H).

61
400.2
L4
2.00
(DMSO-d6) δ ppm: 7.99 (t, 1H), 7.76 (d, 2H), 7.48

(d, 2H), 7.27 (d, 1H), 7.22 (d, 1H), 6.79 (t, 1H),

3.76-3.79 (m, 1H), 3.75-3.42 (m, 1H), 3.12-3.15

(m, 2H), 2.99-3.05 (m, 1H), 2.67-2.75 (m, 1H),

2.24-2.27 (m, 1H), 1.79 (s, 3H).

62
428.2
L4
2.07
(DMSO-d6) δ ppm: 7.97 (t, 1H), 7.71 (d, 2H), 7.41

(d, 2H), 7.18 (d, 1H), 7.15 (d, 1H), 3.74-3.78 (m,

1H), 3.34 (m, 1H), 3.09-3.12 (m, 2H), 2.96 (dd,

1H), 2.65 (dd, 1H), 2.19-2.21 (m, 1H), 1.80 (s, 3H).

63
374.2
L4
1.81
(DMSO-d6) δ ppm: 7.99 (t, 1H), 7.75 (d, 2H), 7.45

(d, 2H), 7.08-7.21 (m, 2H), 4.24 (s, 1H), 3.75-3.78

(m, 1H), 3.35-3.41 (m, 1H), 3.09-3.16 (m, 2H),

2.96 (dd, 1H), 2.49-2.70 (m, 1H), 2.22-2.24 (m,

1H), 1.80 (s, 3H).

Part B: Experimental Biology Procedures
Example 25: Activity of Compounds of the Disclosure in a Reporter Gene Assay for Measuring the Inhibition of YAP/TAZ-TEAD Transcription

Hek293T cells were cultured in DMEM supplemented with 10% fetal bovine serum, Sodium pyruvate, Sodium bicarbonate, L-glutamine. The cells were harvested and transiently transfected with TEAD-responsive element luciferase reporter. Transfected cells were plated in 384-well plate containing pre-diluted compounds. After 24 hours incubation at 37° C./5% CO₂, assay plates were cooled to room temperature and levelled to an equal volume per well, prior to the addition of 25 uL luciferase substrate SteadyLite (Perkin Elmer)/well. The plate was shaken for 10 min at 600 rpm, centrifuged for 1 min at 500 rpm and measured with an Envision reader (PerkinElmer). The amount of relative light units produced by the TEAD reporter was used to calculate the percentage of inhibition.

The percent of reporter inhibition was calculated in the presence of a positive control inhibitor (100% inhibition) versus a condition with the presence of the vehicle basal activity of the reporter (0% inhibition). The ability of a test compound to inhibit this activity was determined as: Percentage inhibition=[1-((RLU determined in the presence of vehicle−RLU determined for sample with test compound present) divided by (RLU determined in the presence of vehicle−RLU determined for sample with positive control inhibitor))]*100.

The activities of example compounds tested are depicted in Table 3. The activity ranges A, B and C refer to IC₅₀values in the reporter gene assay as follows: “A”: IC₅₀<1 μM; “B”: 1 μM≤IC₅₀10 μM and “C”: IC₅₀>10 μM; NT=not tested.

TABLE 3

Activities of compounds of the disclosure in the gene reporter

assay for measuring YAP/TAZ-TEAD transcription activity

Cpd. No.
IC₅₀

1
A

2
B

3
A

4
A

5
A

6
A

6-En1
A

6-En2
A

7
A

8
B

9
A

10
A

10-En1
A

10-En2
A

11
A

12
A

12-En1
B

12-En2
A

13
B

14
A

14-En1
A

14-En2
A

15-En1
C

15-En2
B

16
B

17
A

17-En1
B

17-En2
A

18
A

19
A

20
A

21
A

22
A

22-En1
B

22-En2
A

23
C

24
C

25
C

26
A

26-En1
A

26-En2
A

27
C

28
C

29
A

30
C

31
C

32
C

33
A

34
A

34-En1
B

34-En2
A

35
B

36
C

37
C

38
A

38-En1
B

38-En2
A

39
A

40
B

41
A

42
A

43
A

44
A

45
A

46
C

47
A

47-En1
A

47-En2
C

48
C

49
B

50
A

51
A

52
A

53
B

54
A

55
A

56
A

57
A

58
C

59
C

60
A

61
B

62
A

63
A

Example 26: Activity of Compounds of the Disclosure in Mesothelioma Cell Line Proliferation Assays

Mesothelioma cell lines, NCI-H226 and NCI-H2052 (both sourced from the ATCC cell culture collection) were plated in 96-well plates (Corning® 96 Well White Polystyrene Microplate clear flat bottom, white polystyrene (TC-Treated)), at 1500 cells/well in full medium (RPMI 1640 ATCC modification with L-glutamine, HEPES, Phenol Red, Sodium Pyruvate, High glucose, Low sodium bicarbonate and 10% fetal bovine serum). Cells were incubated overnight at 37° C. in an incubator with 5% CO₂. Then compounds, dissolved in DMSO, were added in dose-response. Cells were incubated with compound dilutions for another 6 days at 37° C. in an incubator with 5% CO₂. Cell viability was quantitated using the ATPlite kit (Perkin-Elmer) and the luminescence was read-out using an Envision instrument (Perkin-Elmer). The amount of relative light units produced using the ATPlite kit was used to calculate percent of inhibition.

The activities of some example compounds are depicted in Table 4. The activity ranges A, B and C refer to EC₅₀values in the mesothelioma cell line proliferation assay as described as follows: “A”: EC₅₀<1 μM; “B”: 1 μM≤EC₅₀<10 μM and “C”: EC₅₀>10 μM; NT: not tested.

TABLE 4

Activities of a selection of compounds in the

mesothelioma cell line proliferation assay

EC₅₀

Cpd. No.
H226
H2052

4
A
A

6
A
A

6-En1
A
A

6-En2
A
A

7
A
A

10
A
A

10-En1
A
A

10-En2
A
A

11
A
A

12
A
A

12-En2
A
A

14
A
A

14-En1
A
A

14-En2
A
A

17-En2
A
A

22-En2
A
A

26
A
A

26-En2
A
A

34-En2
A
A

47-En1
A
A