Triazolone inhibitors of nicotinamide n-methyltransferase and their therapeutic uses

Abstract

The disclosure provides potent, selective and orally bioavailable inhibitors of nicotinamide N-methyltransferase (NNMT) which have a triazolone-piperidine scaffold. The NNMT inhibitors are useful for treating tumors and cancers, metabolic disorders and liver disorders.

Description

Triazolone Inhibitors of Nicotinamide 7V-Methyltransferase and Their Therapeutic UsesCross-Reference To Related Applications

[0001] This application claims benefit of priority from U.S. Provisional Application No. 63 / 610,682, filed on December 15, 2023, which is incorporated by reference herein in its entirety.Statement of Government Support

[0002] This invention was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HHSN261200800001E, Agreement No. 16X129T10, and intramural funds to the Early Translational Branch at the National Center of Advancing Translational Sciences. The government has certain rights in the invention.Background of the Disclosure

[0003] Nicotinamide / V-m ethyl transferase (NNMT) catalyzes the methylation of nicotinamide and similar compounds using the universal methyl donor N-adenosyl-L-methionine (SAM) to produce 1 -methylnicotinamide (1-MNA) and N-adenosyl-L-homocysteine (SAH). Methylation of nicotinamide by NNMT and SAM is the major pathway for degradation of nicotinamide, which leads to excretion of 1-MNA in the urine. Nicotinamide is a bioactive form of vitamin B3 and the precursor of oxidized nicotinamide adenine dinucleotide (NAD+), a key molecule involved in fundamental redox processes regulating energy metabolism. Therefore, nicotinamide is an important cofactor that associates cellular redox states with energy metabolism.

[0004] High expression of NNMT is a predictor of poor prognosis in many types of human cancers [Cao et al., Frontiers in Genetics, 13: 1000515 (2022); and Dang et al., Open Medicine, 17:292-303 (2022)]. Elevated NNMT level or activity promotes cancer cell survival, growth, proliferation, migration, invasion and metastasis, and resistance to chemotherapeutic drugs [Li et al., Frontiers in Oncology, 12:894744 (2022); Pozzi et al., Biomolecules, 12:1173 (2022); and Eckert et al., Nature, 569:723-728 (2019)].

[0005] In addition, overexpression of NNMT in adipose tissue in humans correlates with obesity and insulin resistance [Pissios, Trends Endocrinol. Metab., 28(5):340-353 (2017)]. Furthermore, NNMT is upregulated in liver steatosis, hepatitis, liver fibrosis and cirrhosis [Liang et al., Genes & Diseases, 10: 1883-1893 (2023)].Summary of the Disclosure

[0006] The present disclosure describes potent, selective inhibitors of nicotinamide 7V- methyltransferase (NNMT) that are orally bioavailable. The NNMT inhibitors have Formula I, or are tautomers or pharmaceutically acceptable salts thereof:wherein X is optionally substituted aryl or heteroaryl, Y is optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaiyl, and n is 1, 2 or 3.

[0007] An exemplary triazolone NNMT inhibitor reduces the level of 1 -methylnicotinamide generated by NNMT in vivo (data not shown), reduces body weight in a high fat diet-induced mouse model of obesity (data not shown), and reduces tumor burden and metastasis in mouse models of cancer. The triazolone NNMT inhibitors are useful for treating tumors and cancers, metabolic disorders such as obesity and type 2 diabetes, and liver disorders.Brief Description of the Drawings

[0008] A better understanding of features and advantages of the present disclosure will be obtained by reference to the following detailed description, which sets forth illustrative embodiments of the disclosure, and the accompanying drawings.Fig. 1 shows that C57BL / 6 mice were intraperitoneally (i.p.) injected with ID8-luciferase ovarian cancer cells and treated three times weekly by intraperitoneal (i.p.) injections with either the NNMT inhibitor (NNMTi), the less active distomer (NNMTi-D) or vehicle control. Tumor burden was assessed by In Vivo Imaging Systems (IVIS) (5-6 mice per group, one-way ANOVA). Treatment with Compound 144 (NNMTi) significantly reduced tumor burden compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D).

[0009] Fig. 2 shows that C57BL / 6 mice were subcutaneously (s.c.) injected with MC38 colon carcinoma cells (day 0) and 5 days later, once the tumor was palpable, treated by intratumoral injection (i.t.) every 3 days with either the NNMTi, NNMTi-D, or vehicle control. Tumor growth was measured twice per week (6-7 mice per group, two-way ANOVA). Treatment with Compound 144 (NNMTi) significantly reduced tumor volume compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D).

[0010] Figs. 3A and 3B show that NNMT inhibition enhances the treatment response to the immune check point inhibitors PD-1 and CD47. Treatment with both Compound 144 (NNMTi) and a PD-1 inhibitor monoclonal antibody (aPDl, InVivoMAb anti -mouse PD-1, clone RPM1- 14, BioXCell, Cat#BE0146; RRID: AB_10949053) dramatically and synergistically reduced tumor volume in the murine subcutaneous MC38 tumor model. Fig. 3A: C57BL / 6 mice were injected s.c. with MC38 cells and treated by intratumoral (i.t.) injection with either NNMTi or NNMTi-D at indicated time points, starting on day 5. aPD-1 treatment was administered i.p. on day 13, 16 and 21 and is highlighted by arrows (6-7 mice per group, two-way ANOVA). Fig. 3B: C57BL / 6 mice were injected s.c. with MC38 cells and treated by i.t. injection with either Compound 144 (NNMTi) or NNMTi-D at indicated time points, starting on day 5. aCD47 is an antibody blocking the CD47-SIRPa axis, which can increase the amount of phagocytosis by macrophages and lead to antitumor effects. The aCD47 antibody was administered i.p. on day 10, 15, 19 and 25 and is highlighted by arrows (7-8 mice per group, two-way ANOVA).

[0011] Fig. 4 shows that treatment with Compound 144 (NNMTi) significantly reduced tumor volume compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D) in a murine model of low-grade serous ovarian cancer.

[0012] Fig. 5: C57BL / 6 mice were intravenously (i.v.) injected with EO771-LMB breast cancer cells (day 0). Mice were treated daily by oropharyngeal inhalation (o.p.) with either the NNMTi, NNMTi-D or vehicle control, starting two days before cancer cell injection (-2) until 5 days after injection. After 13 days, lungs were formalin-fixed, paraffin-embedded, and the number and size of metastases assessed by H&E staining (5 mice per group, one-way ANOVA). Compound 144 (NNMTi) significantly reduced metastasis size compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D).

[0013] Fig. 6: C57BL / 6 mice were i.v. injected with EO771 -LMB cells (day 0). Mice were treated daily with either the NNMTi or NNMTi-D, starting 2 days before cancer cell injection (- 2) until 5 days after cancer cell injection. aPD-1 was administered intraperitoneally (i.p.) on day 7 and 11 as indicated by arrows. After 15 days, lung metastasis was assessed by H&E staining (6-8 mice per group, one-way ANOVA) (prevention study). Compound 144 (NNMTi) in combination with aPD-1 antibody significantly reduced metastasis size compared to treatment with aPD-1 antibody only.

[0014] Figs. 7A and 7B show that whole-body Nnmt- / -mice show reduced tumor burden. Fig. 7A: Nnmt+ / +(n=6) and Nnmt- / -mice (n=6) were injected into the bursa of the left ovary with the murine HGS-2 ovarian cancer cell line and 42 days later, primary ovarian and omental tumor burden was assessed (Student’s t test). Fig. 7B: Nnmt+ / + (n=6) and Nnmt mice (n=6) were injected into the bursa of the left ovary with the murine HGS-3 ovarian cancer cell line and 42 days later, primary ovarian and omental tumor burden was assessed (Student’s t test).

[0015] Fig. 8 shows that whole-body Nnmt- / -mice show reduced tumor burden. Nnmt-knockout in the tumor microenvironment reduces tumor burden. Nnmt+ / + wild type (n=10) and Nnmt- / - knock out mice (n=l 1) were injected into the mammary fat pad with the murine EO771-LMB breast cancer cell line and tumor growth was monitored twice weekly by caliper measurement (One-way ANOVA).

[0016] Figs. 9A and 9B show that NNMT-inhibition significantly reduces tumor burden and metastases in orthotopic mouse models of ovarian cancer. Fig.9A: C57B16 mice were injected with the ovarian cancer cell line HGS-2 into the bursa of the left ovary and starting 4 days post- cancer cell injection, treated daily with Compound 144 (NNMTi) at 25mg / kg via i.p. injection for 5 weeks (Formulation: 10% NMP, 20% PEG400, 70% Solutol). Fig 9B: C57B16 mice were injected with BPPNM ovarian cancer cells into the bursa of the left ovary and starting 4days post-cancer cell injection, treated daily with Compound 144 (NNMTi) at 25mg / kg via i.p. injection for 12 days (Formulation: 10% NMP, 20% PEG400, 70% Solutol). The BPPNM (Trp53- / -R172HBrcal- / -Pten- / -Nfl- / -MycOE genotype) is HR deficient (S.Iyer Cancer Discovery 2021).

[0017] Fig. 10 shows that NNMT-inhibition significantly reduces tumor burden in an orthotopic mouse models of breast cancer. C57B16 mice were injected into the mammary fat pad with themurineEO771-LMB breast cancer cell line and starting 4 days post cancer cell injection mice were treated daily with the Compound 144 (NNMTi) (25mg / kg) or vehicle control by i.p. injection. (Formulation: 10% NMP, 20% PEG400, 70% Solutol) (One-way ANOVA).

[0018] Fig. 11 shows that NNMT inhibition improves the treatment response to local irradiation. C57BL / 6 mice were injected s.c. with LLC (Lung Lewis Carcinoma) cells and treated daily by i.p. injection with either vehicle or Compound 144 (NNMTi), starting on day 4. On day 13, the tumors were locally irradiated with 20 Gy (10 mice per group, two-way ANOVA).

[0019] Figs. 12A, 12B, and 12C show the effect of NNMT inhibition on CAFs in vivo. Fig. 12A: Effect of NNMT inhibition on CAFs in vivo in breast cancer model. NNMT inhibition reduces the abundance of established CAF subtypes in vivo. Flowcytometry: C57B16 mice were injected into the mammary fat pad with the murine EO771-LMB breast cancer cell line and 4days post-injection mice were treated daily with the Compound 144 (NNMTi) (25mg / kg) or vehicle control by i.p. injection. 18 days post cancer cell injection, tumors were dissociated, and flow cytometry performed. Ly6C+ inflammatory CAFs(iCAFs), a-SMA+ myofibroblastic CAFs (myCAFs), MHCII + antigen-presenting CAFs (apCAFs), and PDGFRa + vascular CAFs (vCAFs). Fig. 12B: Compound 144 (NNMTi) treatment reduces the abundance of Ly6C + iCAFs and MHCII + myCAFs in an orthotopic ovarian cancer model. Flowcytometry (Gating): C57B16 mice were injected into the ovarian bursa with the murine HGS-2 ovarian cancer cell line and 4days post-injection mice were treated daily with the Compound 144 (NNMTi) (25mg / kg) or vehicle control by i.p. injection. 19 days post cancer cell injection, tumors were dissociated, and flow cytometry performed. Fig. 12C: Compound 144 (NNMTi) treatment increases H3K27 trimethylation of CAFs in vivo. Flow cytometry: Absolute quantification of H3K27 melow CD45- EPCAM- CD31- Podoplanin+ CAFs in primary EO771-LMB tumors treated with either Compound 144 (NNMTi) or vehicle control.

[0020] Fig. 13 shows the effect of NNMT inhibition on the abundance of complement factor C3. Compound 144 (NNMTi) treatment reduces complement factor secretion in vivo. Enzyme-linked immunosorbent assay (ELISA): EO771-LMB primary tumors treated with either Compound 144 (NNMTi) or vehicle control were homogenized 18 days after cancer cell injection and complement factor C3 protein was detected (Student’s t-test).

[0021] Figs. 14A, 14B, and 14C show the effect of Compound 144 (NNMTi) treatment on tumor immune cell infiltration. Compound 144 (NNMTi) treatment reduces the abundance of immune suppressive monocytic myeloid-derived suppressor cells (M-MDSCs; Ly6Chigh PD-Llhigh) and increases the CD8+ T cell response. Fig. 14A: C57BL / 6 mice were subcutaneously (s.c.) injected with MC38 colon carcinoma cells (day 0) and 5 days later, once the tumor was palpable, treated by intratumoral injection (i.t.) every 3 days with either the Compound 144 (NNMTi), or NNMTi-D control. 15 days after cancer cell injection, MC38 tumors were dissociated, and 19- color spectral flow cytometry was performed (6-8 mice per group, student’s t-test). Fig. 14B: 15 days after cancer cell injection, MC38 tumors were dissociated, stimulated with PMA / Ionomycin, and effector cytokine production quantified (Student’s t-test). Fig. 14C: C57B16 mice were orthotopically injected with either the ovarian cancer cellsHGS-2 or the breast cancer cells EO771-LMB. 4 days post-cancer cell injection, the mice were treated daily with Compound 144 (NNMTi) at 25 mg / kg via i.p. injection. 18 days after cancer cell injection, the primary tumors were dissociated and flow cytometry performed (Student’s t-test).

[0022] Figs. 15A and 15B show the effect of Compound 144 (NNMTi) treatment on the tumor metabolome. Fig.l5A: Experimental plan. C57BL / 6 mice were injected s.c.with MC38 cells, and 13 days later, they were treated intratumorally with either vehicle, NNMTi-D or Compound 144 (NNMTi). The tumors were then sampled at different time points after the injection. Fig.l5B: Tumors were extracted for liquid chromatography-mass spectrometry analysis. Central metabolites of the methionine and nicotinamide cycles are shown to demonstrate the consequences of NNMT inhibition on the levels of these metabolites (n=5 mice / group. Ordinary one-way ANOVA).

[0023] Fig. 16 shows that NNMT inhibition exerts its tumor-reducing effects by targeting the TME, rather than by altering cancer cell growth. To determine whether NNMT inhibition in cancer cells reduces tumor growth in vivo, we injected whole-body Nnmt- / -mice with MC38 colon carcinoma cells and administered either the vehicle or Compound 144 (NNMTi) . These mice completely lack NNMT, so Compound 144 (NNMTi) treatment should have no specific effect on cells of the TME. Since the cancer cells are Nnmt-wildtype and express NNMT, any impact of NNMT inhibition on cancer cell growth would be detectable. Nonetheless, no tumor reduction was seen in our experiments.Detailed Description of the DisclosureGeneral Disclosure

[0024] While various embodiments of the present disclosure are described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications and changes to, and variations and substitutions of, the embodiments described herein will be apparent to those skilled in the art without departing from the disclosure. It is understood that various alternatives to the embodiments described herein can be employed in practicing the disclosure. It is also understood that every embodiment of the disclosure can optionally be combined with any one or more of the other embodiments described herein which are consistent with that embodiment.

[0025] Where a combination is disclosed, it is understood that each possible subcombination of the elements of that combination is also disclosed. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed.

[0026] Where elements are presented in list format or as alternative members of a group (e.g., a Markush group), it is understood that each possible subgroup of the elements is also disclosed, and any one or more elements can be removed from the list or group.

[0027] Where a range of numerical values is recited, it is understood that the endpoints and each intervening integer value and each fraction thereof, as well as each subrange, between the recited endpoints (upper and lower limits) of that range are specifically disclosed. The endpoints of all ranges are included within the range and are independently combinable. Where a value has an inherent limit, that inherent limit is specifically disclosed. Where a value is explicitly recited, it is understood that values which are about the same as the recited value are specifically disclosed.

[0028] It is also understood that, unless clearly indicated to the contrary, in any method described or claimed herein that includes more than one act or step, the order of the acts or steps of the method is not necessarily limited to the order in which the acts or steps of the method are recited, but the disclosure encompasses embodiments in which the order is so limited.

[0029] It is further understood that, in general, where an embodiment in the description or the claims is referred to as comprising one or more features, the disclosure also encompasses embodiments that consist of, or consist essentially of, such feature(s).

[0030] It is also understood that any embodiment of the disclosure, e.g., any embodiment or compound found within the prior art, can be explicitly excluded from the claims, regardless of whether or not the specific exclusion is recited in the specification.

[0031] In addition, it is understood that any functional language used in any claims shall not be construed as “means-plus-function” language under 35 U.S.C. §112(f), unless specifically expressed as such by use of the term “means for” or “step(s) for” in a claim.

[0032] It is further understood that the present disclosure encompasses analogs, derivatives, prodrugs, metabolites, salts, solvates, hydrates, clathrates and polymorphs of all the compounds / sub stances disclosed herein, as appropriate. The specific recitation of “analogs”, “derivatives”, “prodrugs”, “metabolites”, “salts”, “solvates”, “hydrates”, “clathrates” or “polymorphs” with respect to a compound / sub stance or a group of compounds / sub stances in certain instances of the disclosure shall not be interpreted as an intended omission of any of these forms in other instances of the disclosure where the compound / sub stance or the group of compounds / sub stances is mentioned or shown without recitation of any of these forms, unless stated otherwise or the context clearly indicates otherwise.

[0033] It is also understood that the present disclosure encompasses all possible tautomers, all possible regioisomers, and all possible stereoisomers, including both enantiomers and all possible diastereomers in substantially pure form and mixtures of both enantiomers in any ratio (including a racemic mixture of enantiomers) and mixtures of two or more diastereomers in any ratio, of the compounds / substances described herein as appropriate, and not only the specific tautomers, regioisomers and stereoisomers as indicated by drawn structure or nomenclature Some embodiments of the disclosure relate to the specific tautomers, regioisomers and stereoisomers indicated by drawn structure or nomenclature. The specific recitation of the phrase “or tautomers thereof’, “or regioisomers thereof’, “or stereoisomers thereof’ or the like with respect to a compound / sub stance or a group of compounds / substances in certain instances of the disclosure shall not be interpreted as an intended omission of any of the other possible tautomers, regioisomers and stereoisomers of the compound / sub stance or the group ofcompounds / substances in other instances of the disclosure where the term “compound” or the like is used, or where the compound / sub stance or the group of compounds / sub stances is mentioned or shown, without recitation of the phrase “or tautomers thereof', “or regioisomers thereof’, “or stereoisomers thereof’ or the like, unless stated otherwise or the context clearly indicates otherwise.

[0034] Headings are included herein for reference and to aid in locating certain sections. Headings are not intended to limit the scope of the embodiments and concepts described in the sections under those headings, and those embodiments and concepts may have applicability in other sections throughout the entire disclosure.

[0035] All patent literature and all non-patent literature cited herein are incorporated herein by reference in their entirety to the same extent as if each patent literature or non-patent literature were specifically and individually indicated to be incorporated herein by reference in its entirety.Definitions

[0036] Unless defined otherwise or clearly indicated otherwise by their use herein, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs.

[0037] As used in the specification and the claims, the indefinite articles “a” and “an” and the definite article “the” can include plural referents as well as singular referents unless specifically stated otherwise or the context clearly indicates otherwise.

[0038] The terms “or / and” and “and / or” mean “either ... or .. ., or both . .. and ...” when referring to two elements, and mean “either . .. , ... or . .. , or any combination or all thereof’ when referring to three or more elements. As an example, the phrase “A or / and B” means “either A or B, or both A and B”, and the phrase “A, B or / and C” means “either A, B or C, or any combination or all thereof’.

[0039] As used in the specification and the claims, all transitional terms such as “comprising”, “containing”, “having”, “including”, “possessing”, “holding”, “carrying”, “bearing”, “composed of’, “characterized by” and the like are open-ended and inclusive, that is, mean including but not limited to and do not exclude additional, unrecited element(s) or method step(s). Only the transitional term “consisting of’ is closed, that is, excludes any additional, unrecited element ormethod step, and the transitional term “consisting essentially of’ is semi-closed, that is, only allows inclusion of additional, unrecited element(s) or method step(s) that do not materially affect the basic and novel characteristic(s) of that particular embodiment.

[0040] The term “exemplary” as used herein means “serving as an example, instance or illustration”. Any embodiment or feature characterized herein as “exemplary” should not be construed as preferred or advantageous over other embodiments or features.

[0041] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within one standard deviation. In some embodiments, when no particular margin of error (e.g., a standard deviation to a mean value given in a chart or table of data) is recited, the term "about" or “approximately” means that range which would encompass the recited value and the range which would be included by rounding up or down to the recited value as well, taking into account significant figures. In certain embodiments, the term “about” or “approximately” means within ± 10% or 5% of the specified value. Whenever the term “about” or “approximately” precedes the first numerical value in a series of two or more numerical values or in a series of two or more ranges of numerical values, the term “about” or “approximately” applies to each one of the numerical values in that series of numerical values or in that series of ranges of numerical values.

[0042] In some embodiments, the term “substantially all” means at least about 90%, 95%, 96%, 97%, 98% or 99%. In some embodiments, the term “substantially free” means no more than about 10%, 5%, 4%, 3%, 2% or 1% by weight or molarity, or no more than about 1000 ppm, 500 ppm, 400 ppm, 300 ppm, 200 ppm or 100 ppm.

[0043] In some embodiments, the term “substantially pure” means at least about 90%, 95%, 96%, 97%, 98% or 99% pure. In some embodiments, the term “substantially stereochemically pure” means at least about 80% enantiomeric excess (90% of one enantiomer - 10% of the other enantiomer) or 90% enantiomeric excess (95% of one enantiomer - 5% of the other enantiomer), or at least about 80% diastereomeric excess (90% of one diastereomer - 10% of all the other diastereomers) or at least about 90% diastereomeric excess (95% of one diastereomer - 5% of all the other diastereomers).

[0044] Whenever the term “at least” or “greater than” precedes the first numerical value in a series of two or more numerical values, the term “at least” or “greater than” applies to each one of the numerical values in that series of numerical values.

[0045] Whenever the term “no more than” or “less than” precedes the first numerical value in a series of two or more numerical values, the term “no more than” or “less than” applies to each one of the numerical values in that series of numerical values.

[0046] The term “pharmaceutically acceptable” means that a substance (e.g., an active ingredient or an excipient) is generally safe, non-toxic and suitable for use in contact with the cells, tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and other adverse reaction. A “pharmaceutically acceptable” excipient or carrier of a pharmaceutical composition is also compatible with the other ingredients of the composition.

[0047] The term “therapeutically effective amount” refers to an amount of a compound that, when administered to a subject or used ex vivo, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression of or cause regression of the medical condition being treated, or to alleviate or ameliorate to some extent the medical condition or one or more symptoms or complications of that condition, at least in some fraction of the subjects taking that compound or undergoing ex vivo treatment with that compound. The term “therapeutically effective amount” also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human which is sought by a researcher, veterinarian, medical doctor or clinician.

[0048] The terms “treat”, “treating” and “treatment” include alleviating, ameliorating, reducing the incidence, frequency or severity of, slowing or stopping the progress of, reversing or abrogating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating or eradicating one or more causes of the condition. Reference to “treatment” of a medical condition includes prevention of the condition. The terms “prevent”, “preventing” and “prevention” include precluding, reducing the risk or likelihood of developing, and delaying the onset of a medical condition or one or more symptoms or complications associated with the condition.

[0049] The term “medical conditions” (or “conditions” for brevity) includes diseases and disorders. The terms “diseases” and “disorders” are used interchangeably herein.

[0050] The term “subject” refers to an animal, including but not limited to a mammal, such as a primate (e.g., a human, a chimpanzee or a monkey), a rodent (e.g., a rat, a mouse, a guinea pig, a gerbil or a hamster), a lagomorph (e.g., a rabbit), a bovine (e.g., a cattle), a suid (e.g., a pig), a caprine (e.g., a sheep), an equine (e.g., a horse), a canine (e.g., a dog) or a feline (e.g., a cat). The terms “subject” and “patient” may be used interchangeably herein in reference to a subject / patient (e.g., a mammalian subject / patient such as a human subject / patient) having a medical condition.

[0051] A “modulator” of, e.g., a receptor or enzyme can be an activator or inhibitor of that receptor or enzyme, and can increase or reduce the activity or / and the level of that receptor or enzyme.

[0052] The term “compound” or the like (e.g., “molecule”) encompasses salts, solvates, hydrates, clathrates and polymorphs of that compound or a salt of that compound. A “solvate” of a compound comprises a stoichiometric or non-stoichiometric amount of a solvent molecule (e.g., water, acetone or an alcohol [e.g., ethanol]) bound non-covalently to the compound. A “hydrate” of a compound comprises a stoichiometric or non-stoichiometric amount of water molecule bound non-covalently to the compound. A “clathrate” of a compound contains molecules of a substance (e.g., a solvent) enclosed in a crystal structure of the compound. A “polymorph” of a compound is a crystalline form of the compound. The specific recitation of “salt”, “solvate”, “hydrate”, “clathrate” or “polymorph” with respect to a compound or a group of compounds in certain instances of the disclosure shall not be interpreted as an intended omission of any of these forms in other instances of the disclosure where the term “compound” or the like (e.g., “molecule”) is used, or where the compound or the group of compounds is mentioned or shown, without recitation of any of these forms, unless stated otherwise or the context clearly indicates otherwise.

[0053] The terms “halogen”, “halide” and “halo” refer to fluoride, chloride, bromide and iodide.

[0054] The term “alkyl” refers to a linear or branched, saturated monovalent hydrocarbon radical, wherein the alkyl group can optionally be substituted with one or more substituents as described herein. In certain embodiments, an alkyl group is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or is a branched saturated monovalent hydrocarbon radical that has 3 to 20 (C3-20), 3 to 10 (C3-10), or 3to 6 (C3-6) carbon atoms. As an example, the term “C1-6 alkyl” refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Linear C1-6 and branched C3-6 alkyl groups may also be referred to as “lower alkyl”. Non-limiting examples of alkyl groups include methyl, ethyl, propyl (including / / -propyl and isopropyl), butyl (including all isomeric forms, such as n - butyl, isobutyl, sec-butyl and tert-butyl ), pentyl (including all isomeric forms, such as n -pentyl and isopentyl), and hexyl (including all isomeric forms, such as / / -hexyl).

[0055] The terms “alkylene” and “-alkyl-” refer to a divalent alkyl group, which can optionally be substituted with one or more substituents as described herein.

[0056] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halide atoms. A haloalkyl group can optionally be substituted with one or more additional substituents as described herein. Examples of haloalkyl groups include without limitation fluoroalkyl groups such as -CH2F, -CHF 2 and -(CH2)nCF3, and perfluoroalkyl groups such as -CF3 and -(CF2)nCF3, wherein n is I , 2, 3, 4 or 5.

[0057] The term “heteroalkyl” refers to a linear or branched, saturated monovalent hydrocarbon group containing one or more heteroatoms independently selected from O, N and S. In some embodiments, one or more heteroatoms are in the main chain of the linear or branched hydrocarbon group. The terms “heteroalkylene” and “-heteroalkyl-” refer to a divalent heteroalkyl group. A heteroalkyl group and a -heteroalkyl- group can optionally be substituted with one or more substituents as described herein. Examples of heteroalkyl and -heteroalkyl- groups include without limitation -(CH2WlO or S)-(CH2)nCH3 and -(CH2)m-(0 or S)-(CH2)P-, wherein m is 1, 2 or 3, n is 0, 1 or 2, and p is I, 2 or 3.

[0058] The term “alkoxy” refers to an -O-alkyl group, which can optionally be substituted with one or more substituents as described herein.

[0059] The term “haloalkoxy” refers to an -O-haloalkyl group, which can optionally be substituted with one or more substituents as described herein.

[0060] Examples of -O-heteroalkyl and -O-heteroalkyl- groups include without limitation ethylene glycol groups and polyethylene glycol (PEG) groups, including but not limited to - (OCH2CH2)n OR and -(OCH2CH2)n-O-, wherein R is hydrogen or alkyl and n is 1, 2 or 3. An -O-heteroalkyl group and an -O-heteroalkyl- group can optionally be substituted with one or more substituents as described herein.

[0061] The term “cycloalkyl” refers to a cyclic saturated or partially unsaturated, bridged or non- bridged monovalent hydrocarbon radical, which can optionally be substituted with one or more substituents as described herein. In certain embodiments, a cycloalkyl group has from 3 to 10 (C3-10), or from 3 to 8 (C3-8), or from 3 to 6 (C3-6) carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbomyl, decalinyl and adamantyl. The term “-cycloalkyl-” refers to a divalent cycloalkyl group, which can optionally be substituted with one or more substituents as described herein.

[0062] The terms “heterocyclyl” and “heterocyclic” refer to a monocyclic non-aromatic group or a multicyclic group that contains at least one non-aromatic ring, wherein at least one non- aromatic ring contains one or more heteroatoms independently selected from O, N and S. The non-aromatic ring containing one or more heteroatoms may be attached or fused to one or more saturated, partially unsaturated or aromatic rings that may contain only ring carbon atoms or that may contain one or more ring heteroatoms. In certain embodiments, a heterocyclyl or heterocyclic group has from 3 to 15, or 3 to 12, or 3 to 10, or 3 to 8, or 3 to 6 ring atoms. In some embodiments, a heterocyclyl or heterocyclic group is a monocyclic, bicyclic or tricyclic ring system, which may include a fused or bridged ring system, and in which nitrogen or sulfur atoms can optionally be oxidized, nitrogen atoms can optionally be quaternized, and one or more rings may be fully or partially saturated, or aromatic. A heterocyclyl or heterocyclic group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyl or heterocyclic groups include without limitation azepanyl, azepinyl, azetidinyl, aziridinyl, azocanyl, benzodioxanyl (e.g., 1,4- benzodioxanyl), benzodioxolyl (e.g., 1,3-benzodioxolyl), benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, (3-carbolinyl, chromanyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, indolizinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxepanyl, oxetanyl, oxiranyl, oxocanyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl (oxolanyl), tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl (tetrahydrothiophenyl or thiolanyl), thiamorpholinyl (thiomorpholinyl), thiazolidinyl and 1,3,5- trithianyl. The term “-heterocyclyl-” refers to a divalent heterocyclyl group. A heterocyclyl or heterocyclic group, and a -heterocyclyl- group, can optionally be substituted with one or more substituents as described herein.

[0063] The term “aryl” refers to a monocyclic aromatic hydrocarbon group or a multi cyclic group that contains at least one aromatic hydrocarbon ring. In certain embodiments, an aryl group has from 6 to 15, or 6 to 12, or 6 to 10 ring atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, biphenyl and terphenyl. The aromatic hydrocarbon ring of an aryl group may be attached or fused to one or more saturated, partially unsaturated or aromatic rings that may contain only ring carbon atoms (e.g., biphenyl, dihydronaphthyl, indenyl, indanyl and tetrahydronaphthyl [tetralinyl]) or that may contain one or more ring heteroatoms (e.g., indolinyl, isoindolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, chromanyl and 1,4-benzodioxanyl). The term “-aryl-” refers to a divalent aryl group. An aryl group and an -aryl- group can optionally be substituted with one or more substituents as described herein.

[0064] The term “heteroaryl” refers to a monocyclic aromatic group or a multicyclic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, N and S. The heteroaromatic ring may be attached or fused to one or more saturated, partially unsaturated or aromatic rings that may contain only ring carbon atoms or that may contain one or more ring heteroatoms. A heteroaryl group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, a heteroaryl group has from 5 to 15, or 5 to 12, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include without limitation pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinonyl and triazinyl. Non-limiting examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl (benzofurazanyl),benzothienyl (benzothiophenyl), quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzotriazolyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indazolyl, naphthyridinyl, phthalazinyl, quinazolinyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include without limitation carbazolyl, benzindolyl, dibenzofuranyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and phenothiazinyl. The term “-heteroaryl-” refers to a divalent heteroaryl group. A heteroaryl group and a -heteroaryl- group can optionally be substituted with one or more substituents as described herein.

[0065] The terms “-alkylcycloalkyl”, “-alkylheterocyclyl”, “-alkylaryl” and “-alkylheteroaryl” refer to an alkyl group that is substituted with one or more cycloalkyl groups, one or more heterocyclyl groups, one or more aryl groups, or one or more heteroaryl groups, respectively. An -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl or -alkylheteroaryl group can optionally be substituted with one or more additional substituents as described herein.

[0066] Each group described herein (including without limitation monovalent and divalent alkyl, haloalkyl, monovalent and divalent heteroalkyl, -O-alkyl, -O-haloalkyl, -O-heteroalkyl, monovalent and divalent cycloalkyl, monovalent and divalent heterocyclyl, monovalent and divalent aryl, monovalent and divalent heteroaryl, -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl and -alkylheteroaryl), whether as a primary group or as a substituent group, can optionally be substituted with one or more substituents. In some embodiments, each group described herein can optionally be substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from halide, cyano (-CN), nitro (-NO2), hydroxyl (-OH), sulfhydryl (-SH), amino (-NH2), -OR11, - SR1 1, -NR12R13, -C(=O)R”, -C(=O)OR”, -OC(=O)R11, -C(=O)NR12R13, -NR12C(=O)R11, - OC(=O)ORn, -OC(=O)NR12R13, -NR12C(=O)ORn, -NRnC(=O)NR12R13, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein:R11in each occurrence independently is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl or -alkylheteroaryl; andR12and R13in each occurrence independently are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylcycloalkyl, -alkylheterocyclyl, -alkylaryl or -alkylheteroaryl, or R12and R13and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring.NNMT Inhibitors

[0067] The disclosure provides inhibitors of nicotinamide jV-methyltransferase (NNMT) that have Formula I, or are tautomers, pharmaceutically acceptable salts, solvates, hydrates, clathrates or polymorphs thereof:wherein:X is aryl or heteroaryl, wherein the aryl or heteroaryl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, C1-6 alkyl, -CF3, -OH, -OR1, -NH2, -NR2R3, -(C=O)NR4R5and proteolysis-targeting moieties (e.g., thalidomide-based, proteolysis-targeting moieties), and wherein the C1-6 alkyl can optionally be substituted with - OH, -OR1, -NH2or -NR2R3;Y is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, C1-6 alkyl, -CF3, -OH, -OR1, -NH2, -NR2R3and -(C=O)NR4R5, and wherein the C1-6 alkyl can optionally be substituted with -OH, -OR1, -NH2or -NR2R3;R1is hydrogen, C1-6 alkyl, -CHF2, -CF3 or C3-6 cycloalkyl, wherein the alkyl or cycloalkyl can optionally be substituted with -OH, C1-4 alkoxy, -NH2or -NR2R3;R2and R3independently are hydrogen, C1-6 alkyl or -C(=O)-(C1-6 alkyl), or R2and R3and the nitrogen atom to which they are attached form a 3-6-membered heterocyclic ring or a 5- or 6- membered heteroaryl ring;R4and R5independently are hydrogen or C1-6 alkyl; n is 1, 2 or 3; and the stereocenter marked by an asterisk * can have the (S)-stereochemistry or the (R )- stereochemistry or can be racemic; with the proviso that:X is not unsubstituted phenyl or 4-chlorophenyl; and the compound of Formula I is not:or a tautomer or salt thereof.

[0068] In some embodiments, X is optionally substituted, 5-10 membered, monocyclic or bicyclic, aryl or heteroaryl. In further embodiments, X is selected from 2-CN-phenyl, 3-CN- phenyl, 3-CH3-phenyl, 3-OCH3-phenyl, 3-(C(=O)NH2)-phenyl, 4-Br-phenyl, 4-OCH3-phenyl, 4-OCHF2-phenyl, 4-(morpholin-JV-yl)-phenyl, 3-CN-4-CH3-phenyl, 3-F-4-OCH3-phenyl, 3-F-5- CHs-phenyl, 3,5-dimethyl-phenyl, 1 -naphthyl, / V-CHs-pyrazol -4-yl, 4-CH3-pyridin-2-yl, 5-CN- pyridin-2-yl, 5-CH3-pyridin-2-yl, 5-CF3-pyridin-2-yl, 6-CH3-pyridin-2-yl, 2-CH3-pyridin-3-yl, 4-CH3-pyridin-3-yl, 5-CH3-pyridin-3-yl, 6-CH3-pyridin-3-yl, 2-CH3-pyridin-4-yl,

[0069] In some embodiments, the aryl or heteroaryl X group is substituted with or linked to a proteolysis-targeting moiety. In certain embodiments, the proteolysis-targeting moiety is a thalidomide-based, proteolysis-targeting moiety. Linkage of a triazolone compound to a proteolysis-targeting moiety forms a proteolysis-targeting chimera (PROTAC) that induces selective intracellular proteolysis of NNMT. The proteolysis-targeting moiety (e.g., thalidomide) engages an E3 ubiquitin ligase, and the triazolone compound selectively binds to NNMT. Recruitment of the E3 ligase to NNMT results in ubiquitination and subsequent degradation of NNMT via the proteasome.

[0070] In some embodiments with respect to Y: cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl; heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; aryl is phenyl, naphthyl, phthalanyl, benzodioxolyl, benzodioxanyl, isoindolinyl, 1, 2,3,4- tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl; and heteroaryl is furanyl (furyl), thiophenyl (thienyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl (pyridyl), pyrimidinyl, quinolinyl or isoquinolinyl; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl can optionally be substituted as defined above.

[0071] In further embodiments, Y is selected from cyclohexyl, l,l-diF-cyclohex-4-yl, 2- tetrahydropyranyl, 3 -tetrahydropyranyl, 4-tetrahydropyranyl, piperidin-3-yl, / V-CH3-piperidin-3- yl, A-acetyl-piperi din-3 -yl, piperidin-4-yl, A-CH3-piperidin-4-yl, A-acetyl-piperidin-4-yl, phenyl,2-F-phenyl, 2-Cl-phenyl, 2-CF3-phenyl, 2-OCH3-phenyl, 2-OCH2CH3-phenyl, 2-OCH2CH2CH3- phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH3-phenyl, 3-CF3-phenyl, 3-OCH3-phenyl, 3- (OCH2CH2OH)-phenyl, 3-(piperidin-7V-yl)-phenyl, 3-(morpholin-JV-yl)-phenyl, 3-(imidazol-JV- yl)-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-Br-phenyl, 4-CH3-phenyl, 4-ethyl-phenyl, 4-isopropyl- phenyl, 4-CH2OH-phenyl, 4-CF3-phenyl, 4-OH-phenyl, 4-OCH3-phenyl, 4-OCHF2-phenyl, 4- OCF3-phenyl, 4-(OCH2CH2OCH3)-phenyl, 4-(O-cyclopentyl)-phenyl, 4-N(CH3)2-phenyl, 4-(7V- acetyl)-phenyl, 4-(imidazol-2V-yl)-phenyl, 4-(pyrazol-2V-yl)-phenyl, 2-CH3-3-F-phenyl, 2-OCH3-3-F-phenyl, 2-F-4-Cl-phenyl, 2,4-diCl-phenyl, 2,4-dimethyl-phenyl, 2-F-4-methoxy-phenyl, 2-F-4-ethoxy-phenyl, 2-OH-4-OCH3-phenyl, 3-F-4-Cl-phenyl, 3,4-diCl-phenyl, 3-CH3-4-F-phenyl, 3-CF3-4-CH3-phenyl, 3,5-dimethyl-phenyl, 1-naphthyl, 2-naphthyl, 1, 2,3,4- tetrahydroisoquinolin-8-yl, 4-isoindolinyl, 5-phthalanyl, l,3-benzodioxol-5-yl, 1,4-benzodioxan- 6-yl, TV-CFh-pyrazol-4-yl, A'-CH3-3 -CH3-pyrazol -4-yl, 7V-methyl-imidazol-2-yl, A'-ethyl- imidazol-2-yl, 5-CH3-isoxazol-3-yl, 2-pyridyl, 3-F-pyridin-2-yl, 3-CH3-pyridin-2-yl, 4-C1- pyridin-2-yl, 4-CH3-pyridin-2-yl, 4-OCH3-pyridin-2-yl, 5-Cl-pyridin-2-yl, 6-CH3-pyridin-2-yl, 4,6-dimethyl-pyridin-2-yl, 3-pyridyl, 2-OCH3-pyri din-3 -yl, 6-OCH3-pyridin-3-yl, 4,6-diCl- pyridin-3-yl, 4-CH3-pyrimidin-2-yl, 5-CH3-pyrimidin-2-yl, 2-quinolinyl, and 5-isoquinolinyl.

[0072] In some embodiments, n is 2. In other embodiments, n is 1.

[0073] In some embodiments, the compounds of Formula I are selected from the following compounds, and tautomers, pharmaceutically acceptable salts, solvates, hydrates, clathrates and polymorphs thereof:wherein the stereocenter marked by an asterisk * is racemic or has the (S)-stereochemistry, and compounds having a shown (,S')-stereochemistry can alternatively be racemic at that stereocenter.

[0074] In other embodiments, the compounds of Formula I are selected from the following compounds, and tautomers, pharmaceutically acceptable salts, solvates, hydrates, clathrates and polymorphs thereof:wherein the stereocenter marked by an asterisk * is racemic or has the (5)-stereochemistry, and compounds having a shown (5)-stereochemistry can alternatively be racemic at that stereocenter.

[0075] In some embodiments, the stereocenter marked by an asterisk * has the (fl- stereochemistry.

[0076] The compounds of Formula I are potent, selective inhibitors of NNMT and are orally bioavailable.

[0077] In other embodiments, triazolone NNMT inhibitors are selected from the following compounds, and tautomers, pharmaceutically acceptable salts, solvates, hydrates, clathrates and polymorphs thereof:wherein the stereocenter marked by an asterisk * is racemic or has the (S)-stereochemistry, and compounds having a shown (,S')-stereochemistry can alternatively be racemic at that stereocenter, and wherein Boc denotes te / 7-butyloxycarbonyl.

[0078] The triazolone compounds of Formula I have a 1,3-disubstituted piperidinyl group.Alternatively, the 1,3-disubstituted piperidinyl group can be replaced with a 1,4-disubstituted piperidinyl group, a 1,3-disubstituted pyrrolidinyl group or a 1,3-disubstituted azetidinyl group, and triazolone compounds having any of the three alternative groups are also disclosed herein.Salt Forms of Compounds

[0079] The compounds of Formula I have at least one basic nitrogen atom and can exist as a free base or as salts. They can be used as a free base or as pharmaceutically acceptable salts. A basic nitrogen atom can form an addition salt with an acid, such as a mineral acid (e.g., HC1, HBr, HI, nitric acid, phosphoric acid or sulfuric acid) or an organic acid (e g., a carboxylic acid or a sulfonic acid). Suitable acids for use in the preparation of pharmaceutically acceptable salts include without limitation acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(! S)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (±)-DL- lactic acid, (+)-L-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthal ene-2-sulfonic acid, naphthalene- 1,5- disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, propionic acid, L- pyroglutamic acid, pyruvic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid, (±)-DL-tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0080] If a compound has an acidic group (e.g., a carboxyl group), the acidic group can form an addition salt with a base. Pharmaceutically acceptable base addition salts can be formed with, e.g., metals (e.g., alkali metals or alkaline earth metals) or amines (e.g., organic amines).Examples of metals useful as cations include without limitation alkali metals (e.g., lithium, sodium, potassium and cesium), alkaline earth metals (e.g., magnesium, calcium and barium), aluminum and zinc. Metal cations can be provided by way of, e.g., inorganic bases, such as hydroxides, carbonates and hydrogen carbonates. Non-limiting examples of organic amines useful for forming base addition salts include chloroprocaine, choline, cyclohexyl amine, dibenzylamine, N,N’ -dibenzylethylenediamine, di cyclohexylamine, diethanolamine, ethylenediamine, N-ethylpiperidine, histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, triethylamine, trimethylamine and tromethamine. Pharmaceutically acceptable salts are discussed in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wiley-VCH (2011).

[0081] In some embodiments, the NNMT inhibitors described herein are used in the form of pharmaceutically acceptable salts. In certain embodiments, the compounds are used as a hydrochloride (HC1) salt.Pharmaceutical Compositions

[0082] Additional embodiments of the disclosure relate to pharmaceutical compositions comprising an NNMT inhibitor described herein, or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, and one or more pharmaceutically acceptable excipients or carriers. The compositions can optionally contain an additional therapeutic agent. A pharmaceutical composition contains a therapeutically effective amount, or any appropriate fraction thereof, of an NNMT inhibitor, one or more pharmaceutically acceptable excipients or carriers and optionally a therapeutically effective amount of an additional therapeutic agent, and is formulated for administration to a subject for therapeutic use. For purposes of the content of a pharmaceutical composition, the term “active ingredient”, “active agent”, “therapeutic agent”, “drug” or the like encompasses a prodrug.

[0083] A pharmaceutical composition contains an NNMT inhibitor and optionally an additional therapeutic agent in substantially pure form. In some embodiments, the purity of the NNMT inhibitor and the optional additional therapeutic agent independently is at least about 95%, 96%, 97%, 98% or 99%. In addition, a pharmaceutical composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inactive ingredients. Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act §501(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.

[0084] Pharmaceutical compositions / formulations can be prepared in sterile form. For example, pharmaceutical compositions / formulations for parenteral administration by injection or infusion generally are sterile. Sterile pharmaceutical compositions / formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 1211, and 21 Code of Federal Regulations 211.

[0085] Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials and vehicles. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e g., vegetable oils such as olive oil and sesame oil), aqueous solvents {e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution)}, and organic solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional excipient or carrier is incompatible with the active ingredient, the disclosure encompasses the use of conventional excipients and carriers in formulations containing NNMT inhibitors. See, e.g., Remington: The Science and Practice ofPharmacy, 21 st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004).

[0086] Appropriate formulation can depend on various factors, such as the route of administration chosen. Potential routes of administration of pharmaceutical compositions comprising NNMT inhibitors include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal / epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular / intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]). Topical formulations can be designed to produce a local or systemic therapeutic effect. In some embodiments, the NNMT inhibitors are administered as an oral dosage form such as a tablet, capsule or pill.

[0087] As an example, formulations of NNMT inhibitors suitable for oral administration can be presented in discrete units adapted for instant, controlled or sustained release as, e.g., boluses; capsules (including push-fit capsules and soft capsules), tablets, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or / and a non-aqueous liquid; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0088] Push-fit capsules or two-piece hard gelatin capsules can contain an NNMT inhibitor in admixture with, e.g., a filler or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or / and a preservative. For soft capsules or single-piece gelatin capsules, an NNMT inhibitor can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or moreother liquid excipients or / and semi-solid excipients, such as a stabilizer or / and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol).

[0089] Tablets can contain an NNMT inhibitor in admixture with, e.g., a fdler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate). The tablets can be uncoated or can be coated with, e.g., an enteric coating that protects the active agent from the acidic environment of the stomach, or with a material that delays disintegration and absorption of the active agent in the gastrointestinal (GI) tract and thereby provides a sustained action over a longer time period.

[0090] Compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid or / and a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in- oil liquid emulsions. Dispersible powder or granules of an NNMT inhibitor can be mixed with any suitable combination of an aqueous liquid, an organic solvent or / and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or / and a preservative) to form a solution, suspension or emulsion.

[0091] NNMT inhibitors can also be formulated for parenteral administration by injection or infusion to circumvent gastrointestinal absorption and first-pass metabolism. An exemplary parenteral route is intravenous. Additional advantages of intravenous administration include direct administration of a therapeutic agent into systemic circulation to achieve a rapid systemic effect, and the ability to administer the agent continuously or / and in a large volume if desired. Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or / and stabilizing agents. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain an NNMT inhibitor along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject. Aqueous or non-aqueous sterile suspensions can contain an NNMT inhibitor along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the NNMT inhibitor to allow for thepreparation of a more concentrated solution or suspension. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneously or intravenously) can contain an NNMT inhibitor, an isotonic agent (e.g., sodium chloride), a buffering agent (e.g., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or / and an acid (e.g., HC1) to adjust pH.

[0092] Topical formulations for application to the skin or mucosa can be useful for transdermal or transmucosal administration of a therapeutic agent to the local target site of action, or into the blood for systemic distribution. Advantages of topical administration can include circumvention of the GI tract (including enzymes and acid in the GI tract and absorption through it) and first- pass metabolism; delivery of a therapeutic agent with a short half-life, a small therapeutic index or / and low oral bioavailability; controlled, continuous and sustained release of the therapeutic agent; a more uniform plasma level or delivery profile of the therapeutic agent; lower dose and less frequent dosing of the therapeutic agent; reduction of systemic side effects (e.g., side effects caused by a temporary overdose or an overly high peak plasma drug concentration); minimal or no invasiveness; ease of self-administration; and increased patient compliance.

[0093] Compositions suitable for topical administration include without limitation liquid or semi-liquid preparations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops). See Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania

[2005] ). Various excipients can be included in a topical formulation. For example, solvents, including a suitable amount of an alcohol, can be used to solubilize the active agent. Other optional excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, stabilizers, buffers, antioxidants, preservatives, cooling agents (e.g. menthol), opacifiers, fragrances and colorants. For an active agent having a low rate of permeation through the skin or mucosal tissue, a topical formulation can contain a chemical permeation enhancer (e.g., a fatty acid ester [e.g., isopropyl myristate or isopropyl palmitate], a fatty acid [e.g., palmitic acid, oleic acid or palmitoleic acid], or / and an alcohol [e.g., propylene glycol or a fatty alcohol such as geraniol or farnesol]) to increase the permeation of the active agent through the skin or mucosal tissue. A topical formulation can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the active agent, the chemical permeation enhancer orany other component of the formulation. In some embodiments, a topical composition comprises a therapeutic agent dissolved, dispersed or suspended in a carrier. The carrier can be in the form of, e.g., a solution, a suspension, an emulsion, an ointment or a gel base, and can contain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethylene glycol or polypropylene glycol, a diluent (e.g., water or / and an alcohol [e.g., ethanol or propylene glycol]), a gel, an emulsifier, a thickening agent, a stabilizer or a preservative, or any combination thereof. A topical formulation can be administered by means of, e.g., a transdermal or transmucosal delivery device, such as a transdermal patch, a microneedle patch or an iontophoresis device. A topical composition can deliver a drug transdermally or transmucosally via a concentration gradient (with or without the use of a chemical permeation enhancer) or an active mechanism (e.g., iontophoresis or microneedles).

[0094] For topical administration, an NNMT inhibitor can be formulated as, e.g., a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of gastrointestinal absorption and first-pass metabolism, and rapid absorption into systemic circulation. A buccal or sublingual tablet or pill can be designed to provide faster release of the NNMT inhibitor for more rapid uptake of it into systemic circulation. In addition to a therapeutically effective amount of an NNMT inhibitor, the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium steaiyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

[0095] For topical administration, NNMT inhibitors can also be formulated for intranasal administration. The nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability. Moreover, intranasal administration avoids first-pass metabolism and can introduce a significant concentration of the NNMT inhibitor to the central nervous system (CNS). An intranasal formulation can comprise an NNMT inhibitor along with excipients, such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g.,hydroxyethylcellulose) or / and a penetration enhancer. An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or a spray using, e.g., a metering atomizing spray pump. Table 1 shows exemplary excipients of nasal-spray formulations.

[0096] An additional mode of topical administration of NNMT inhibitors is pulmonary, including by oral inhalation and nasal inhalation. A pulmonarily administered drug can treat a lung disease or / and a systemic disease, as the lungs serve as a portal to the systemic circulation. Advantages of pulmonary drug delivery include, for example: 1) avoidance of first-pass metabolism; 2) fast drug action; 3) large surface area of the alveolar region for absorption, high permeability of the lungs (thin air-blood barrier), and profuse vasculature of the airways;4) reduced extracellular enzyme levels compared to the GI tract due to the large alveolar surface area; and 5) smaller doses to achieve equivalent therapeutic effect compared to other oral routes, and hence reduced systemic side effects. Oral inhalation can also enable more rapid action of a drug in the CNS. An advantage of oral inhalation over nasal inhalation includes deeper penetration / deposition of the drug into the lungs, although nasal inhalation can deliver the drug into systemic circulation transmucosally in the nasal cavity as well as in the lungs. Oral or nasal inhalation can be achieved by means of, e.g., a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a nebulizer, as is known in the art. In certain embodiments, a sterile aqueous solution for oral inhalation contains an NNMT inhibitor, sodium chloride, a buffering agent (e.g., sodium citrate), optionally a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or / and an acid (e.g., HC1) to adjust pH. Table 1 shows other exemplary excipients of oral-inhalation formulations.

[0097] Table 1. Exemplary excipients and carriers of pulmonary and nasal formulationsinhalation polysorbate 80, edetate disodium, sodium chloride, pH buffering agents (e.g., (nebulizer) citric acid / sodium citrate), and water nasal microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, water, and spray optionally a pH adjuster (e.g., HC1) nasal microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, spray polysorbate 80, disodium edetate, potassium sorbate, a pH adjuster (e.g., HC1), water, and optionally an alcohol (e.g., ethanol) nasal microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, spray polysorbate 80, benzalkonium chloride, phenylethyl alcohol, water, and optionally an alcohol (e.g., ethanol) nasal hypromellose, benzalkonium chloride, NaCl, EDTA, citric acid, sodium spray phosphate dibasic, water, and optionally an alcohol (e.g., ethanol)

[0098] In some embodiments, an NNMT inhibitor is administered transdermally. In some embodiments, the topical composition or the transdermal delivery system comprises a chemical permeation enhancer (e.g., a surfactant [e.g., sodium laureth sulfate], optionally in combination with an aromatic compound [e.g., phenylpiperazine]) that facilitates the transport of the NNMT inhibitor across the skin. In further embodiments, the NNMT inhibitor is administered via a transdermal patch. In some embodiments, the transdermal patch is a reservoir-type patch comprising an impermeable backing layer / film, a liquid- or gel-based drug reservoir, a semi- permeable membrane that serves as a rate-limiting or rate-controlling diffusion barrier, and a skin-contacting adhesive layer. The semi-permeable membrane can be composed of, e.g., a suitable polymeric material such as cellulose nitrate or acetate, poly isobutene, polypropylene, polyvinyl acetate or a polycarbonate. In other embodiments, the transdermal patch is a drug-in- adhesive patch comprising an impermeable backing layer / film and a skin-contacting adhesive layer incorporating the drug in a polymeric or viscous adhesive. The adhesive of the drug- loaded, skin-contacting adhesive layer can be, e.g., a pressure-sensitive adhesive (PSA), such as a PSA composed of an acrylic polymer (e.g., polyacrylate), a polyalkylene (e.g., polyisobutylene) or a silicone-based polymer (e.g., silicone-2675 or silicone-2920). Transdermal drug-delivery systems, including patches, can be designed to provide controlled and prolonged release of a drug over a period of about 1 week, 2 weeks, 3 weeks, 1 month or longer.

[0099] In some embodiments, an NNMT inhibitor is delivered from a sustained-release composition. As used herein, the term “sustained-release composition” encompasses sustained-release, prolonged-release, extended-release, delayed-release, slow-release and control! ed-rel ease compositions, systems and devices. Advantages of a sustained-release composition include without limitation a more uniform blood level of the drug (e.g., avoidance of wide peak-to- trough fluctuations), delivery of a therapeutically effective amount of the drug over a prolonged time period, reduced frequency of administration, and reduced side effects (e.g., avoidance of a drug overdose). In some embodiments, the sustained-release composition delivers the NNMT inhibitor over a period of at least about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer.

[0100] In some embodiments, the sustained-release composition is a drug-encapsulation system, such as nanoparticles, microparticles or a capsule made of, e g., a biodegradable polymer or / and a hydrogel. In certain embodiments, the sustained-release composition comprises a hydrogel. Non-limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium poly acrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or / and carboxylate groups). In other embodiments, the sustained-release drug-encapsulation system comprises a membrane-enclosed reservoir, wherein the reservoir contains a drug and the membrane is permeable to the drug. Such a drug-delivery system can be in the form of, e.g., a transdermal patch.

[0101] In some embodiments, the sustained-release composition is formulated as polymeric nanoparticles or microparticles, wherein the polymeric particles can be delivered, e.g., by injection or from an implant. In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of a biodegradable polymer. In certain embodiments, the biodegradable polymer comprises lactic acid or / and glycolic acid [e.g., an L- lactic acid-based copolymer, such as poly(L-lactide-co-glycolide) or poly(L-lactic acid-co-D,L- 2-hydroxyoctanoic acid)]. For example, biodegradable polymeric microspheres composed of polylactic acid or / and polyglycolic acid can serve as sustained-release pulmonary drug-delivery systems. The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer’s degradation, like the polymer, are biocompatible.

[0102] In further embodiments, the sustained-release composition comprises a dendrimer. In certain embodiments, the dendrimer is a water-soluble dendrimer, such as a poly(amidoamine) (PAMAM) dendrimer. In some embodiments, a dendrimer encapsulates a drug through the formation of a dendrimer-drug supramol ecu I ar assembly. In other embodiments, the sustained- release composition comprises a water-soluble polymer [e.g., poly(DL-lactide)] or a liposome encapsulating a drug complexed with a dendrimer.

[0103] In other embodiments, the sustained-release composition is an oral dosage form, such as a tablet or capsule. For example, a drug can be embedded in an insoluble porous matrix such that the dissolving drug must make its way out of the matrix before it can be absorbed through the GI tract. Alternatively, a drug can be embedded in a matrix that swells to form a gel through which the drug exits. Sustained release can also be achieved by way of a single-layer or multi- layer osmotic controlled-release oral delivery system (OROS). An OROS is a tablet with a semi- permeable outer membrane and one or more small laser-drilled holes in it. As the tablet passes through the body, water is absorbed through the semi-permeable membrane via osmosis, and the resulting osmotic pressure pushes the drug out through the hole(s) in the tablet and into the Gl tract where it can be absorbed.

[0104] For a delayed or sustained release of an NNMT inhibitor, a composition can also be formulated as, e.g., a depot that can be implanted in or injected into a subject, e.g., intramuscularly, intracutaneously or subcutaneously. A depot formulation can be designed to deliver an NNMT inhibitor over an extended period of time, e.g., over a period of at least about 1 week, 2 weeks, 3 weeks, 1 month, 6 weeks, 2 months, 3 months or longer. For example, an NNMT inhibitor can be formulated with a polymeric material (e.g., polyethylene glycol [PEG], polylactic acid [PLA] or polyglycolic acid [PGA], or a copolymer thereof [e.g., PLGA or PLA- PEG]), with a hydrophobic material (e.g., as an emulsion in an oil) and / or an ion-exchange resin, as a more lipophilic derivative (e.g., as an ester of or a salt with a fatty acid such as a C8-C20 fatty acid [e.g., decanoic acid]), or as a sparingly soluble derivative (e.g., a sparingly soluble salt). As an illustrative example, an NNMT inhibitor can be incorporated or embedded in sustained- release microparticles composed of PLGA and formulated as a monthly depot.

[0105] An NNMT inhibitor can also be contained or dispersed in a matrix material. The matrix material can comprise a polymer (e.g., ethylene-vinyl acetate) and controls the release of thedrug by controlling dissolution and / or diffusion of the drug from, e.g, a reservoir, and can enhance the stability of the drug while contained in the reservoir. Such a release system can be designed as a sustained-release system, can be configured as, e.g., a transdermal or transmucosal patch, and can contain an excipient that can accelerate the drug’s release, such as a water- swellable material (e.g., a hydrogel) that aids in expelling the drug out of the reservoir. US Pat. Nos. 4,144,317 and 5,797,898 describe examples of such a release system.

[0106] The release system can provide a temporally modulated release profile (e.g., pulsatile release) when time variation in plasma levels is desired, or a more continuous or consistent release profile when a constant plasma level is desired. Pulsatile release can be achieved from an individual reservoir or from a plurality of reservoirs. For example, where each reservoir provides a single pulse, multiple pulses (“pulsatile” release) are achieved by temporally staggering the single pulse release from each of multiple reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of a drug through it over an extended time period. In addition, continuous release can be approximated by releasing several pulses of a drug in rapid succession (“digital” release). An active release system can be used alone or in conjunction with a passive release system, as described in US Pat. 5,797,898.

[0107] In addition, pharmaceutical compositions comprising an NNMT inhibitor can be formulated as, e.g., liposomes, micelles (e g., those composed of biodegradable natural or / and synthetic polymers, such as lactosomes), nanoparticles (e.g., lipid nanoparticles such as solid lipid nanoparticles), microparticles or microspheres, whether or not designed for sustained release. For example, liposomes can be used as sustained-release pulmonary drug-delivery systems that deliver drugs to the alveolar surface for treatment of lung diseases and systemic diseases. As another example, lipid nanoparticles containing a lipophilic drug can be delivered into the lungs by oral inhalation for treatment of a lung disorder or a systemic disorder.

[0108] In some embodiments, liposomes or micelles are composed of one or more phospholipids. Phospholipids include without limitation phosphatidic acids (e.g., DEPA, DLPA, DMPA, DOPA, DPPA and DSPA), phosphatidylcholines (e.g, DDPC, DEPC, DLPC, DLOPC, DMPC, DOPC, DPPC, DSPC, MPPC, MSPC, PLPC, PMPC, POPC, PSPC, SMPC, SOPC andSPPC), phosphatidylethanolamines (e.g., DEPE, DLPE, DMPE, DOPE, DPPE, DSPE and POPE), phosphatidylglycerols (e.g., DEPG, DLPG, DMPG, DOPG, DPPG, DSPG and POPG), phosphatidylserines (e.g., DLPS, DMPS, DOPS, DPPS and DSPS), and salts (e.g., sodium and ammonium salts) thereof. In certain embodiments, liposomes or micelles are composed of one or more phosphatidylcholines. Liposomes have a hydrophilic core, so liposomes are particularly suited for delivery of more hydrophilic drugs, whereas micelles have a hydrophobic core, so micelles are particularly suited for delivery of more hydrophobic drugs. Liposomes and micelles can permeate across biological membranes. Moreover, liposomes and micelles composed of a fusogenic lipid (e.g., DPPG) can fuse with the plasma membrane of cells and thereby deliver a drug into those cells. Liposomes and micelles can provide sustained release of a drug based in part on the rate of degradation of the liposomes and micelles.

[0109] The pharmaceutical compositions can be manufactured in any suitable manner known in the art, such as by means of conventional mixing, dissolving, suspending, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or compressing processes, or any combination thereof.

[0110] The compositions can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. A unit dosage form generally contains a therapeutically effective dose of the drug, but can contain an appropriate fraction thereof so that taking multiple unit dosage forms achieves the therapeutically effective dose. Examples of a unit dosage form include a tablet, capsule, or pill for oral uptake; a solution in a pre-fdled syringe of a single-use pen or a pen with a dose counter for parenteral (e.g., intravenous, subcutaneous or intramuscular) injection; a capsule, cartridge or blister pre-loaded in or manually loaded into an inhaler; and a reservoir-type transdermal patch or a drug-in-adhesive patch.

[0111] Alternatively, the compositions can be presented as a kit in which the active ingredient, excipient(s) and carrier(s) [e.g., solvent(s)] are provided in two or more separate containers (e.g., ampules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected parenterally).

[0112] A kit can contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers, and can contain instructions for administering or using the pharmaceutical composition to treat a medical condition. A kit can further contain a device for delivering the composition, such as a needle and a syringe, an injection pen, an inhaler or a transdermal patch.

[0113] In some embodiments, a kit contains an NNMT inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, or a pharmaceutical composition comprising the same, and instructions for administering or using the NNMT inhibitor or the composition to treat a medical condition (e.g., a tumor or cancer, a metabolic disorder or a liver disorder). In some embodiments, the kit further contains a device for delivering the NNMT inhibitor or the composition, such as an injection pen, an inhaler or a transdermal patch.Therapeutic Uses of NNMT Inhibitors

[0114] High expression of nicotinamide A'-methy I transferase (NNMT) is a predictor of poor prognosis in many types of human cancers [Cao et al., Frontiers in Genetics, 13:1000515 (2022); and Dang et al., Open Medicine, 17:292-303 (2022)]. Elevated NNMT level or activity promotes cancer cell survival, growth, proliferation, migration, invasion and metastasis, and resistance to chemotherapeutic drugs [Li et al., Frontiers in Oncology, 12:894744 (2022); Pozzi et al., Biomolecules, 12: 1173 (2022); and Eckert et al., Nature, 569:723-728 (2019)].

[0115] In some embodiments, the NNMT inhibitors disclosed herein are used to treat a tumor or cancer. In some embodiments, the tumor or cancer is selected from solid tumors, head and neck tumors and cancers (e.g., oral squamous cell carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and papillary thyroid cancer), tumors and cancers of the CNS (e.g., glioblastoma, glioma and neuroblastoma), lung cancer (e.g., non-small cell lung cancer), gynecological cancers (e.g., breast cancer, ovarian cancer [e.g., high-grade serous carcinoma], and uterine cancer [e.g., cervical cancer and endometrial cancer]), cancers of the gastrointestinal tract (e.g., stomach cancer [e.g., gastric carcinoma] and colorectal cancer), liver cancer (e.g., hepatocellular carcinoma and intrahepatic cholangiocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), urological cancers (e g., kidney cancer [e.g., renal clear cell carcinoma and renal papillary cell carcinoma], bladder cancer and prostate cancer), skin cancer(e.g., melanoma), sarcomas, and hematological and lymphoid cancers (e g., leukemias and lymphomas [e.g., non-Hodgkin lymphomas such as diffuse large B-cell lymphoma]). In some embodiments, the tumor or cancer is characterized by intra-abdominal, peritoneal or / and omental metastasis, such as ovarian cancer (e.g., ovarian carcinoma), endometrial cancer, gastrointestinal cancer (e.g., gastric cancer or colorectal cancer), or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).

[0116] In addition, overexpression of NNMT in adipose tissue in humans correlates with obesity and insulin resistance [Pissios, Trends Endocrinol. Metab., 28(5):340-353 (2017)]. Accordingly, in further embodiments, the NNMT inhibitors disclosed herein are used to treat a metabolic disorder. In some embodiments, the metabolic disorder is selected from obesity, obesity-associated disorders (e.g., cardiovascular disorders and hypertension), hyperlipidemia (e.g., hypercholesterolemia and hypertriglyceridemia), metabolic syndrome, hyperglycemia, impaired glucose tolerance, insulin resistance, type 2 diabetes, polycystic ovary syndrome (PCOS), and aging-related disorders (e.g., sarcopenia). In certain embodiments, the metabolic disorder is obesity, an obesity-associated disorder, or type 2 diabetes.

[0117] Obesity is a major risk factor for a wide variety of disorders. Obesity-associated disorders include without limitation insulin resistance, type 2 diabetes, cardiovascular disorders (e g., coronary heart / artery disease, atherosclerosis, peripheral vascular disease, hyperlipidemia and hypertension), cerebrovascular disorders (e.g., stroke), inflammatory disorders (e.g., arthritis such as osteoarthritis), fatty liver disorders (e.g., NAFLD and NASH), obesity-linked cancers (e.g., breast, colorectal, kidney and prostate cancers), PCOS and sleep apnea.

[0118] Aging-related disorders and conditions include without limitation aging / senescence, hypertension, eye disorders (e.g., age-related macular degeneration [AMD], cataracts and keratoconjunctivitis sicca [dry eye syndrome]), hearing loss, bone disorders (e.g., osteoporosis), muscle disorders (e.g., muscle atrophy and sarcopenia), neurodegenerative disorders (e.g., dementias [e.g., Alzheimer’s disease] and Parkinson’s disease), metabolic disorders (e.g., metabolic decline, metabolic syndrome, diabetes [including types 1 and 2 diabetes], and obesity), cardiovascular disorders (e.g., arteriosclerosis), inflammatory disorders (e.g., chronic inflammation, arthritis and chronic obstructive pulmonary disease [COPD]), fibrotic disorders(e.g., idiopathic pulmonary fibrosis [IPF]), DNA-repair syndromes (e.g., Cockayne syndrome), and tumors and cancers.

[0119] Moreover, NNMT is upregulated in liver steatosis, hepatitis, liver fibrosis and cirrhosis [Liang etal., Genes & Diseases, 10: 1883-1893 (2023)]. Accordingly, in additional embodiments, the NNMT inhibitors disclosed herein are used to treat a liver disorder. In some embodiments, the liver disorder is selected from liver steatosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), hepatitis, alcoholic steatohepatitis (ASH), non- alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis. In certain embodiments, the liver disorder is ALD, NAFLD, ASH or NASH.

[0120] The therapeutically effective amount and frequency of administration of an NNMT inhibitor may depend on various factors, including the medical condition being treated, the severity of the condition, the potency of the compound, the route of administration, the age, body weight, general health, gender and diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician. In some embodiments, the effective dose (e.g., maintenance dose) of an NNMT inhibitor per day is about 1-200 mg, 1-50 mg, 50-100 mg, 100-150 mg or 150-200 mg, or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses (e.g., 2, 3 or 4 times daily). In certain embodiments, the effective dose (e g., maintenance dose) of an NNMT inhibitor per day is about 1-25 mg or 25-50 mg. The dosing frequency may depend on, e.g., the route of administration chosen. For example, dosing by pulmonary administration (e.g., by oral inhalation) may occur more frequently (e.g., 2, 3 or 4 times daily). To more quickly establish a therapeutic level of the NNMT inhibitor, a loading dose of the inhibitor that is greater (e.g., about 2- or 3-fold greater) than the maintenance dose can be administered at the beginning (e.g., in the first three days) of treatment followed by administration of the maintenance dose.

[0121] An NNMT inhibitor can be administered via any suitable route, which may depend on, e.g., the medical condition being treated and its location and the pharmacokinetics of the inhibitor. Potential routes of administration of an NNMT inhibitor include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal / epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasalspray or drop], ocular / intraocular [e g., by eye drop], pulmonary [e g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]).

[0122] In some embodiments, an NNMT inhibitor is administered orally. In other embodiments, an NNMT inhibitor is administered parenterally, such as intravenously, subcutaneously or intramuscularly. In further embodiments, an NNMT inhibitor is administered intratumorally to treat a tumor or cancer.

[0123] The length of treatment with an NNMT inhibitor can be determined by the treating physician to achieve the desired outcome. In some embodiments, an NNMT inhibitor is administered for at least about 1 week, 2 weeks, 3 weeks or 4 weeks (1 month). In other embodiments, an NNMT inhibitor is administered for at least about 6 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years or longer.

[0124] In some embodiments, disclosed is a method of modulating metabolites in the NAD+, methionine and S-adenosyl-L-methionine (SAM) / / S-adenosyl-L-homocysteine (SAH) pathway with NNMT inhibitors having Formula I, or tautomers or pharmaceutically acceptable salts thereof.

[0125] In some embodiments, disclosed is a method of modulating gene expression or the epigenome with a NNMT inhibitors having Formula I, or tautomers or pharmaceutically acceptable salts thereof.Combination Therapies

[0126] The NNMT inhibitors disclosed herein can optionally be used in combination with one or more additional therapeutic agents to treat a medical condition. In some embodiments, an NNMT inhibitor is used in combination with one or more additional antitumor / anticancer agents to treat a tumor or cancer.

[0127] Antitumor / anticancer agents include without limitation:1) cytotoxic agents, including without limitation: i) alkylating agents, such as aziridines (e.g., diaziquone, mytomycin and thiotepa), nitrogen mustards (e.g., mannomustine, mustine [mechlorethamine or chlormethine], aniline mustard, bendamustine, benzoic acid mustard, chlorambucil, C6-galactose mustard, melphalan,ossichlorin [nitromin], prednimustine, uramustine, nitrogen mustard carbamates [e.g., estramustine], and oxazaphosphorines [e.g., cyclophosphamide, ifosfamide, mafosfamide, and trofosfamide]), nitrosoureas (e.g., carmustine, fotemustine, lomustine, nimustine, A-nitroso-A- methylurea, ranimustine, semustine and streptozotocin), platinum-containing compounds (e.g., cisplatin, carboplatin and oxaliplatin), alkyl sulfonates (e.g., busulfan, mannosulfan and treosulfan), hydrazines (e.g., dacarbazine and procarbazine), imidazotetrazines (e.g., mitozolomide and temozolomide), and triazines (e.g., hexamethylmelamine [altretamine]); ii) cytotoxic antibiotics, such as anthracyclines (e.g., aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin and valrubicin), actinomycins (e.g., actinomycin D), bleomycins (e.g., bleomycins A2 and B2), mitomycins (e.g., mitomycin C), and plicamycins; iii) anti-metabolites, such as anti-folates (e.g., aminopterin, methotrexate, pemetrexed and pralatrexate), deoxynucleoside analogs (e.g., 5-azacytidine [azacitidine], 5-aza-2’-deoxycytidine [decitabine], cladribine, clofarabine, cytarabine, decitabine, fludarabine, gemcitabine, nelarabine and pentostatin), fluoropyrimidines (e.g., 5 -fluorouracil, l-hexylcarbamoyl-5-fluorouracil [carmofur], capecitabine, 5-fluoro-5'-deoxyuridine [doxifluridine] and trifluridine), and thiopurines (e.g., thioguanine, azathioprine and 6-mercaptopurine); iv) anti-microtubule agents, such as dolastatins (e.g., dolastatin 15), epothilones (e.g., epothilones A-F), halichondrins (e.g., halichondrin B) and analogs thereof (e g., eribulin), maytansine, maytansinoids (e.g., ansamitocin, emtansine, mertansine, ravtansine and soravtansine), taxanes (e.g., paclitaxel, docetaxel and cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinflunine and vinorelbine), colchicine, nocodazole, podophyllotoxin and rhizoxin; v) histone deacetylase inhibitors, such as trichostatins (e.g., trichostatin A), romidepsin, panobinostat and vorinostat; vi) kinase inhibitors, such as bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib, curcumin, cyclocreatine, deguelin, fostriecin, hispidin, staurosporine and derivatives thereof (e.g., midostaurin), and tyrphostins (e.g., tyrphostins AG 34 and AG 879); vii) topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan;viii) topoisomerase Il-targeting agents, such as topoisomerase II poisons (e.g., etoposide, tafluposide, teniposide, doxorubicin and mitoxantrone) and topoisomerase II inhibitors (e.g., novobiocin, merbarone and aclarubicin); ix) DNA or RNA synthesis inhibitors, such as 3-amino-l,2,4-benzotriazine 1,4-dioxide, cytosine P-D-arabinofuranoside, 5,6-dichlorobenzimidazole 1-P-D-ribofuranoside, ganciclovir and hydroxyurea; x) protein synthesis inhibitors, such as homoharringtonine; xi) cell growth and differentiation regulators, such as retinoids (e.g., all-trans retinol [vitamin A], 11-cis retinol, al \-trans retinal [vitamin A aldehyde], 1 l-c / .s retinal, all- / ra / / .s retinoic acid [tretinoin], 9-cz.s-retinoic acid [alitretinoin], 1 1 -c / .s retinoic acid, 13-cA-retinoic acid [isotretinoin], all-trans retinyl esters, etretinate, acitretin, adapalene, bexarotene and tazarotene); xii) cell proliferation inhibitors, such as mTOR inhibitors (e.g., everolimus, novolimus, ridaforolimus, sirolimus [rapamycin], temsirolimus, umirolimus [biolimus A9] and zotarolimus), apigenin, cholecalciferol (vitamin D3) and sex hormone-binding globulin; xiii) apoptosis inducers, such as 17-allylamino-17-demethoxygeldanamycin, melatonin, mevinolin, psoralen, thapsigargin, troglitazone, inhibitors of histone deacetylases (e.g., romidepsin), and agonists of retinoid X receptors (RXRs) (e.g., retinoids such as bexarotene); and analogs, derivatives and salts thereof;2) agents that stimulate the immune system, including without limitation: i) agonists / activators of tumor necrosis factor receptor superfamily member 4 (TNFRSF4, 0X40 or CD134), such as OX40-targeting antibodies (e.g., MEDI-6469 and 9B12) and ligands for 0X40 (e.g., OX40L); ii) agonists / activators of TNFRSF member 5 (TNFRSF5 or CD40), such as CD40- targeting antibodies (e.g., dacetuzumab and CP-870,893) and ligands for CD40 (e.g., CD40L [CD154]); iii) agonists / activators of TNFRSF member 9 (TNFRSF9, 4-1BB or CD137), such as 4- IBB-targeting antibodies (e.g., urelumab [BMS-663513] and PF-05082566) and ligands for 4- 1BB (e.g., 4-1BBL);iv) agonists / activators of TNFRSF member 18 (TNFRSF18, glucocorticoid-induced TNFR-related protein [GITR] or CD357), such as GITR-targeting antibodies (e.g., DTA-1 and TRX518) and ligands for GITR (e.g., GITRL); v) agonists / activators of toll-like receptors (TLRs), such as ligands for TLR9 (e.g., unmethylated CpG oligodeoxynucleotides [CpG ODNs], such as agatolimod); vi) cytokines and hormones that stimulate immune cells, such as interleukin-6 (IL-6) and epinephrine (stimulator of, e.g., natural killer cells); and analogs, derivatives, fragments and salts thereof;3) agents that block immune checkpoints, including without limitation: i) inhibitors of programmed cell death 1 (PD-1) receptor or ligands thereof (e.g., PD-L1 and PD-L2), such as anti -PD-1 antibodies (e.g., cemiplimab [REGN-2810], nivolumab [BMS- 936558, MDX-1106 or ONO-4538], pembrolizumab [lambrolizumab or MK-3475], pidilizumab [CT-011] and MEDI-0680 [AMP-514]), anti-PD-1 fusion proteins (e.g., AMP -224 [containing an FcAb domain and PD-L2]), anti-PD-Ll antibodies (e.g., avelumab [MSB0010718C], atezolizumab [MPDL3280A or RG7446], durvalumab [MEDL4736], BMS-936559 [MDX- 1105], LY3300054 and YW243.55.S70), and small-molecule inhibitors of PD-L1 (e.g., BMS- 1001 and BMS-1166); ii) inhibitors of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor or ligands thereof, such as anti-CTLA-4 antibodies (e.g., ipilimumab and tremelimumab); iii) inhibitors of killer cell immunoglobulin-like receptors (KIRs) or ligands thereof, such as anti-KIR antibodies (e.g., lirilumab [IPH2102 or BMS-986015]); iv) inhibitors of lymphocyte activation gene 3 (LAG-3) receptor or ligands thereof, such as anti-LAG-3 antibodies (e.g., relatlimab [BMS-986016] and GSK2831781); v) inhibitors of T-cell immunoglobulin and mucin domain-containing 3 (TIM-3, also called hepatitis A virus cellular receptor 2 [HAVCR2]), such as anti-TIM3 antibodies (e.g., LY3321367, MBG453 and TSR-022); vi) inhibitors of indoleamine 2,3 -dioxygenase (IDO or IDO1), such as indoximod (1- methyl-D-tryptophan or NLG-8189), navoximod (GDC-0919), a-methyl-tryptophan, P-carboline (9H-pyrido[3,4-b]indole or norharmane), epacadostat (INCB024360), BMS-986205, NLG-919, and cyclooxygenase 2 (COX-2) inhibitors (e.g., coxibs [such as apricoxib, celecoxib, etoricoxib,lumiracoxib, parecoxib, rofecoxib and valdecoxib], which down-regulate the expression of IDO); and analogs, derivatives, fragments and salts thereof;4) angiogenesis inhibitors, including without limitation inhibitors of vascular endothelial growth factors (VEGFs) (e.g., squalamine and anti-VEGF antibodies such as bevacizumab) or receptors therefor (VEGFRs) (e.g., axitinib, fruquintinib, pazopanib, regorafenib, sorafenib and sunitinib), inhibitors of platelet-derived growth factors (PDGFs) (e.g., squalamine) or receptors therefor (PDGFRs) (e.g., axitinib, imatinib, nilotinib, pazopanib, sorafenib and sunitinib), inhibitors of fibroblast growth factors (FGFs) (e.g., squalamine) or receptors therefor (FGFRs) (e.g., erdafitinib, pazopanib and anti-FGFR antibodies and fragments thereof), inhibitors of angiopoi etins (e.g., anti-angiopoietin antibodies such as nesvacumab and AMG 780) or receptors therefor, inhibitors of integrins (e.g., ALG-1001 and JSM-6427), anecortave (anecortave acetate), angiostatin (e.g., angiostatin Kl-3), av03 inhibitors (e.g., etaracizumab), berberine, bleomycins, borrelidin, carboxyamidotriazole, cartilage-derived angiogenesis inhibitors (e.g., chondromodulin I and troponin I), castanospermine, CM101, cyclopropene fatty acids (e.g., sterculic acid), a-difluoromethylornithine, endostatin, everolimus, fumagillin, genistein, interferon-a, interleukin- 12, itraconazole, linomide, matrix metalloproteinase (MMP) inhibitors (e.g., batimastat, cipemastat, ilomastat, marimastat, prinomastat, rebimastat, retinoid X receptor agonists (e.g., retinoids such as bexarotene), tanomastat, and tetracyclines [e.g., doxycycline, incyclinide and minocycline]), 2- methoxyestradiol, pigment epithelium-derived factor (PEDF), platelet factor-4, PPAR-y agonists (e.g., thiazolidinediones, such as ciglitazone, lobeglitazone, netoglitazone, pioglitazone, rivoglitazone, rosiglitazone and troglitazone), prolactin, sphingosine- 1- phosphate inhibitors (e g., sonepcizumab), squalene, staurosporine, angiostatic steroids (e.g., tetrahydrocortisol) plus heparin, stilbenoids, suramin, SU5416, tasquinimod, tecogalan, tetrathiomolybdate, thalidomide and derivatives thereof (e.g., lenalidomide and pomalidomide), thiabendazole, thrombospondins (e.g., thrombospondin 1), TNP-470, tranilast, Withaferin A, and analogs, derivatives, fragments and salts thereof; and5) other kinds of antitumor / anticancer agents, including without limitation: i) inhibitors of class IA phosphoinositide 3-kinase pl 10a (PI3K-a), such as alpelisib, buparlisib (pan-PI3K), copanlisib (PI3K-a / 8), pictilisib (pan-PI3K), taselisib, voxtalisib (pan- PI3K), GNE-477, INK-1117, PWT-33597, SF-1126 (pan-PI3K) and ZSTK-474; ii) drug-efflux pump inhibitors, such as P-glycoprotein inhibitors (e.g., mifepristone and verapamil); iii) cell adhesion inhibitors, such as cimetidine; iv) Golgi apparatus disruptors, such as brefeldins (e.g., brefeldin A); v) ionizing radiation, such as X-ray; vi) radiopharmaceuticals, such as 1131-iodide, I131-MIBG (m-iodobenzylguanidine), Ra223 -di chloride, Sml53-EDTMP (ethylenediaminotetramethylenephosphoric acid), and Sr89- chloride; vii) radiation sensitizers of tumor / cancer cells, such as poly(ADP -ribose) polymerase (PARP) inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, 4-amino-l,8- naphthalimide, BGB290, CEP9722 and E7016), berberine and indomethacin; viii) enhancers of cell survival after treatment with cytotoxic drugs or radiation, such as pifithrin-a; ix) vaccines, such as those that stimulate the immune system to recognize proteins produced by tumor / cancer cells and thereby to attack tumor / cancer cells; and analogs, derivatives and salts thereof.

[0128] In other embodiments, an NNMT inhibitor is used in combination with one or more anti- obesity agents, or / and one or more antidiabetics, to treat a metabolic disorder.

[0129] Anti-obesity agents include, but are not limited to: appetite suppressants (anorectics), including amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine (with or without topiramate) and lorcaserin; pro-satiety agents, including ciliary neurotrophic factor (e.g., axokine) and longer-acting analogs of amylin, calcitonin, cholecystokinin (CCK), glucagon (GCG), GLP-1, gastric inhibitory peptide (GIP, also called glucose-dependent insulinotropic polypeptide), leptin, oxyntomodulin (OXM), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY);lipase inhibitors, including caulerpenyne, cetilistat, ebelactone A and B, esterastin, lipstatin, orlistat, percyquinin, panclicin A-E, valilactone and vibralactone; melanocortin 4 (MC4) receptor agonists, including selective MC4R agonists (e.g., AZD- 2820, LY-2112688, MK-0493, PF-00446687, PG-931, PL-6983, Ro 27-3225 and THIQ [drug name]) and non-selective MC4R agonists (e.g., afamelanotide, bremelanotide, melanotan II, modimelanotide and setmelanotide); agents that increase energy expenditure or / and fat burning, including longer-acting glucagon analogs, glucagon receptor agonists (e.g., NN9030) and dual GLP-1 receptor / glucagon receptor agonists (infra)', triiodothyronine (Tj) and thyroid hormone receptor-beta (THR-p) agonists (e.g., MB07344, MB07811, MGL-3196, MGL-3745, VK0214 and VK2809); fibroblast growth factor 21 (FGF21) and analogs and derivatives thereof (e.g., BMS-986036 [PEGylated FGF21] and BMS-986171); and mitochondrial uncouplers (e.g., those providing mild uncoupling, such as nitazoxanide, tizoxanide, BAM15, 2,4-dinitrophenol [DNP], and A'-(4- cyanobicyclo[2.2.2]octan-l-yl)-4-fluoro-2-[(3,3,3-trifluoropropyl)sulfonamido]benzamide [GS- 3752]); antihyperlipidemic agents (infra),- other agents that reduce body weight or / and fat mass, including GLP-1 receptor agonists (infra), dual GLP-1R / GIPR agonists (infra), and triple GLP-1 R / GIPR / GCGR agonists (infra),- and analogs, derivatives and salts thereof.

[0130] Antihyperlipidemic agents include without limitation:HMG-CoA reductase inhibitors, including statins {e.g., atorvastatin, cerivastatin, fluvastatin, mevastatin, monacolins (e.g., monacolin K [lovastatin]), pitavastatin, pravastatin, rosuvastatin and simvastatin} and flavanones (e.g., naringenin); squalene synthase inhibitors, including lapaquistat, zaragozic acid and RPR-107393; fatty acid synthase inhibitors, including TVB-2640; acetyl-CoA carboxylase (ACC) inhibitors, including anthocyanins, avenaciolides, chloroacetylated biotin, cyclodim, diclofop, firsocostat (GS-0976, NDI-010976 or ND-630), gemcabene, haloxyfop, soraphens (e.g., soraphen Aia), 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), CP-640186, DRM-01, PF-05175157, PF-05221304, QLT-091382; 7-(4-propyloxy- phenylethynyl)-3,3-dimethyl-3,4 dihydro-2H-benzo[b][l,4]di ox epine; N-ethyl-N’-(3-{[4-(3,3-dimethyl-l -oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-l -yl]-carbonyl}-l -benzothien-2-yl)urea; 5-(3-acetamidobut-l-ynyl)-2-(4-propyloxyphenoxy)thiazole; and l-(3-{[4-(3,3-dimethyl-l-oxo- 2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-l-yl]-carbonyl }-5-(pyridin-2-yl)-2-thienyl)-3-ethylurea;ATP citrate lyase (ACL) inhibitors, including bempedoic acid (ETC-1002), 2-furoic acid, (-)-hydroxycitric acid, BMS-303141, MEDICA-16 and SB-204990;PPAR-a agonists, including fibrates (e.g., bezafibrate, ciprofibrate, clinofibrate, clofibric acid, clofibrate, aluminum clofibrate [alfibrate], clofibride, etofibrate, fenofibric acid, fenofibrate, gemfibrozil, ronifibrate and simfibrate), isoflavones (e.g., daidzein and genistein), and perfluoroalkanoic acids (e.g., perfluorooctanoic acid and perfluorononanoic acid);PPAR-5 agonists, including elafibranor (dual PPAR-a / 8 agonist), lanifibranor (triple PPAR-a / 8 / y agonist), GFT505 (dual PPAR-a / 8 agonist), GW0742, GW501516 (dual PPAR-0 / 8 agonist), sodelglitazar (GW677954), seladelpar (MBX-8025), and isoflavones (e.g., daidzein and genistein);PPAR-y agonists, including thiazolidinediones (infra), saroglitazar (dual PPAR-a / y agonist), IVA-337 (triple PPAR-a / 8 / y agonist), 4-oxo-2-thioxothiazolines (e.g., rhodanine), berberine, honokiol, perfluorononanoic acid, cyclopentenone prostaglandins (e.g., cyclopentenone 15-deoxy-A-prostaglandin J2 [ISd-PGL]), and isoflavones (e.g., daidzein and genistein); liver X receptor (LXR) agonists, including endogenous ligands (e.g., oxysterols such as 22(R )-hydroxy cholesterol, 24(5)-hydroxychol esterol, 27-hydroxycholesterol and cholestenoic acid) and synthetic agonists (e.g., acetyl-podocarpic dimer, hypocholamide, V,7V-dimethyl-3P- hydroxy-cholenamide [DMHCA], BMS-852927, GW3965 and T0901317); retinoid X receptor (RXR) agonists, including endogenous ligands (e.g., 9-cis-retinoic acid) and synthetic agonists (e.g.., bexarotene, AGN 191659, AGN 191701, AGN 192849, BMS649, LG100268, LG100754 and LGD346);G protein-coupled bile acid receptor 1 (TGR5) agonists, including RDX-009, INT-777 and INT-767 (dual TGR5 / FXR agonist); triiodothyronine and thyroid hormone receptor-beta agonists (supra); ketohexokinase inhibitors (infra);inhibitors of acyl-CoA cholesterol acyltransferase (ACAT, also called sterol O- acyltransferase [SOAT], including ACAT1 [SOAT1] and ACAT2 [SOAT2]), including avasimibe, pactimibe, pellitorine, terpendole C and flavanones (e.g., naringenin); inhibitors of stearoyl-CoA desaturase- 1 (SCD-1, also called stearoyl-CoA delta-9 desaturase) activity or expression, including aramchol, CAY-10566, CVT-11127, SAR-224, SAR-707, XEN-103; 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2- yl]benzamide and 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2- yl]benzamide; T-{6-[5-(pyridin-3-ylmethyl)-l,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5- (trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine]; 5-fluoro-T-{6-[5-(pyridin-3- ylmethyl)-l,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine]; 6- [5-(cyclopropylmethyl)-4,5-dihydro-TH,3H-spiro[l,5-benzoxazepine-2,4'-piperidin]-T-yl]-JV-(2- hydroxy -2-pyridin-3-ylethyl)pyridazine-3-carboxamide; 6-[4-(2-methylbenzoyl)piperidin-l- yl]pyridazine-3 -carboxylic acid (2 -hydroxy -2 -pyri din-3 -ylethyl)amide; 4-(2-chlorophenoxy)- / V- [3-(methyl carbamoyl)phenyl]piperidine-l -carboxamide; the cis-9,trans-l 1 isomer and the trans- 10,cis-12 isomer of conjugated linoleic acid, substituted heteroaromatic compounds disclosed in WO 2009 / 129625 Al, anti-sense polynucleotides and peptide-nucleic acids (PNAs) that target mRNA for SCD-1, and SCD-1 -targeting siRNAs; cholesterylester transfer protein (CETP) inhibitors, including anacetrapib, dalcetrapib, evacetrapib, torcetrapib and AMG 899 (TA-8995); inhibitors of microsomal triglyceride transfer protein (MTTP) activity or expression, including implitapide, lomitapide, dirlotapide, mitratapide, CP-346086, JTT-130, SLx-4090, anti-sense polynucleotides and PNAs that target mRNA for MTTP, MTTP-targeting microRNAs (e.g., miRNA-30c), and MTTP-targeting siRNAs;GLP-1 receptor agonists (infra), glucagon receptor agonists (e.g., NN9030), and dual GLP-1 receptor / glucagon receptor agonists (infra}, inhibitors of pro-protein convertase subtilisin / kexin type 9 (PCSK9) activity or expression, including berberine (reduces PCSK9 level), annexin A2 (inhibits PCSK9 activity), anti-PCSK9 antibodies (e.g., alirocumab, bococizumab, evolocumab, LGT-209, LY3015014 and RG7652), peptides that mimic the epidermal growth factor-A (EGF-A) domain of the LDL receptor which binds to PCSK9, PCSK9-binding adnectins (e.g., BMS-962476), anti-sensepolynucleotides and PNAs that target mRNA for PCSK9, and PCSK9-targeting siRNAs (e.g., inclisiran [ALN-PCS] and ALN-PCS02);FGF21 and analogs and derivatives thereof (supra)-, apolipoprotein mimetic peptides, including apoA-I mimetics (e.g., 2F, 3F, 3F-1, 3F-2, 3F-14, 4F, 4F-P-4F, 4F-IHS-4F, 4F2, 5F, 6F, 7F, 18F, 5A, 5A-C1, 5A-CH1, 5A-CH2, 5A-H1, 18A, 37pA [18A-P-18A], ELK [name], ELK-1A, ELK-1F, ELK-1K1A1E, ELK-1L1K, ELK- 1W, ELK-2A, ELK-2A2K2E, ELK-2E2K, ELK-2F, ELK-3E3EK, ELK-3E3K3A, ELK-3E3LK, ELK-PA, ELK-P2A, ELKA [name], ELKA-CH2, ATI-5261, CS-6253, ETC-642, FAMP [name], FREL [name] and KRES [name]) and apoE mimetics (e.g., Ac-hE18A-NH2 [AEM-28], Ac-[R]hE18A-NH2, AEM-28-14, EpK, hEp, mR18L, COG-112, COG-133 and COG-1410); omega-3 fatty acids, including docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EP A), a-linolenic acid (ALA), fish oils (which contain, e g., DHA and EP A), and esters (e.g., glyceryl and ethyl esters) thereof; and analogs, derivatives and salts thereof.

[0131] Antidiabetic agents include without limitation:AMP-activated protein kinase (AMPK) agonists, including biguanides (e.g., buformin, metformin and phenformin) and allosteric AMPK activators (e.g., MK-8722 and PF-793); peroxisome proliferator-activated receptor gamma (PPAR-y) agonists, including thiazolidinediones (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, lobeglitazone, netoglitazone, pioglitazone, deuterated (7?)-pioglitazone [e.g., DRX-065], rivoglitazone, rosiglitazone and troglitazone), saroglitazar (dual PPAR-a / y agonist) and IVA-337 (triple PPAR- a / 5 / y agonist); glucagon-like peptide-1 (GLP-1) receptor agonists, including exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, tirzepatide, AC-3174, CNTO736, CNTO3649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZY0G1; dual GLP-1 receptor (GLP-lR) / glucagon receptor (GCGR) agonists, including pemvidutide and longer-acting oxyntomodulin analogs {e.g., lipid-conjugated OXM analogs (e.g., DualAG disclosed in A. Pocai et al., Diabetes, 58:2258-2266

[2009] ), PEGylated OXM analogs, cross-linked OXM analogs disclosed in A. Muppidi et al., ACS Chem. Biol., 11 :324-328 (2016) and OX-SR disclosed in R. Scott et al., Peptides, 104:70-77 (2018)}, HM12525A, JNJ-54728518, LY2944876 (TT-401), MEDI0382, MK-8521, MOD-6031 , NN9277, SAR425899, SP-1373 and ZP2929; dual GLP-lR / gastric inhibitory peptide receptor (GIPR) agonists, including Cpd86, LY3298176, NN9709 (MAR709), SAR438335, ZP-DI-70 and ZP-I-98; triple GLP-1R / GIPR / GCGR agonists, including HM15211 and MAR423; dipeptidyl peptidase 4 (DPP-4) inhibitors, including alogliptin, anagliptin, dutogliptin, evogliptin, gemigliptin, gosogliptin, linagliptin, omarigliptin, saxagliptin, septagliptin, sitagliptin, des-fluoro-sitagliptin, teneligliptin, trelagliptin and vildagliptin; glucokinase activators, including piragliatin, ARRY-403, HMS-5552, TMG-123 and TTP-399; inhibitors of a-glucosidases, including acarbose, miglitol and voglibose; ketohexokinase (KHK) inhibitors, including PF-06835919; sodium-glucose transport protein 2 (SGLT2) inhibitors, including bexagliflozin, canagliflozin (also inhibits SGLT1), dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin etabonate, sotagliflozin (also inhibits SGLT1) and tofogliflozin; blockers of ATP-dependent K+(KATP) channels on pancreatic beta cells, including meglitinides (e.g., mitiglinide, nateglinide and repaglinide) and sulfonylureas {including first generation (e.g., acetohexamide, carbutamide, chlorpropamide, glycyclamide [tolhexamide], metahexamide, tolazamide and tolbutamide) and second generation (e.g., glibenclamide [glyburide], glibomuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide and glyclopyramide)}; insulin and analogs thereof, including fast-acting insulin (e.g., insulin aspart, insulin glulisine and insulin lispro), intermediate-acting insulin (e.g , NPH insulin), and long-acting insulin (e.g , insulin degludec, insulin detemir and insulin glargine); amylin and analogs thereof, including pramlintide; and analogs, derivatives and salts thereof.Examples

[0132] The following examples are intended only to illustrate the disclosure. Other synthetic processes, assays, studies, protocols, procedures, methodologies, techniques, reagents and conditions may alternatively be used as appropriate.Synthesis of CompoundsGeneral methods for synthesis

[0133] All air- or moisture-sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware. Anhydrous solvents such as dichloromethane (DCM), N,N- dimethylformamide (DMF), acetonitrile, methanol and triethylamine were purchased from Sigma-Aldrich. Preparative purification was performed on a Waters semi-preparative HPLC system. The column used was a Phenomenex Luna™ C18 column (5 microns, 30 x 75 mm) at a flow rate of 45 mL / min. Purification was performed using Method Acidic Standard Gradient (10:90 MeCN with 0.1% trifluoroacetic acid (TFA) / deionized water with 0.1% TFA ramped to 100% deionized water with 0.1% TFA) or Method Basic Standard Gradient (10:90 MeCN with 0.1% NH4OH / deionized water with 0.1% NH4OH ramped to 100% deionized water with 0.1% NH4OH) over 8 minutes unless otherwise noted. Fraction collection was triggered by UV detection (220 nM). Analytical analysis was performed on an Agilent LC / MS (Agilent Technologies, Santa Clara, Cal.). Purity analysis was determined using a 7 minute gradient of 4% to 100% acetonitrile (containing 0.025% TFA) in water (containing 0.05% TFA) with an 8 minute run time at a flow rate of 1 mL / min. A Phenomenex Luna™ Cl 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C using an Agilent Diode Array Detector.

[0134] Chiral separation was performed with an Agilent 1200 series system. The column used was Chiralpak® IG (20 pM, 5 x 50 cm) at a flow rate of 35 mL / min. The mobile phase consisted of hexane, ethanol and diethylamine (50 / 50 / 0.05).

[0135] Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization (ESI) in the positive mode.1H NMR spectra were recorded using Varian 400 MHz spectrometers. Chemical shifts are reported in ppm with non -deuterated solvent (DMSO-ds peak at 2.50 ppm) as internal standard for DMSO-de solutions. All the compounds tested in the biological assays have a purity greater than 95% based on LCMS analysis. High resolution mass spectrometry was recorded using an Agilent 6210 Time-of-Flight LC / MS system. Confirmation of molecular formulae was accomplished using electrospray ionization in the positive mode with the Agilent Masshunter software (version B.02).Example 1

[0136] The process below describes the synthesis of an exemplary compound.

[0137] Step 1: To a solution of (5)-l-(7er / -butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 43.6 mmol) in DCM (210 ml) were added 1 -hydroxy benzotri azole (HOBt) (8.25 g, 61.1 mmol), EDC (10.03 g, 52.3 mmol), DIPEA (19.04 ml, 109 mmol) and (4-methoxyphenyl)hydrazine hydrochloride (9.14 g, 52.3 mmol). The reaction mixture was stirred at r.t. for 1.5 hr. The mixture was quenched with 200 ml water. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by ISCO (30-80%, EtOAc / hexane) to obtain tert- butyl (S)-3-(2-(4-methoxyphenyl)hydrazine-l-carbonyl)piperidine-l -carboxylate (13.5 g, 89 % yield). MS m / z' (M+H+) 350.2.

[0138] Step 2: To a solution of / cvz-butyl (5)-3-(2-(4-methoxyphenyl)hydrazine-l- carbonyl)piperidine-l -carboxylate (1 g, 2.86 mmol) in DCM (30 ml) at 0 °C was added 2,2,2- trichloroacetyl isocyanate (0.477 ml, 4.01 mmol). The reaction mixture was stirred at 0 °C for 10 min. The solvent was evaporated. The residue was treated with MeOH (30.0 ml) and potassium carbonate (1.582 g, 11.45 mmol). The reaction mixture was stirred at r.t. for 2 hrs, and then the reaction mixture was stirred at 65 °C for 3 days. The reaction was quenched with water, and was extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated. The crude product was purified by ISCO (0-50%, EtOAc / DCM) to obtain / c / 7-butyl (S)-3-(l-(4- methoxyphenyl)-5-oxo-2,5-dihydro-lH-l, 2, 4-triazol-3-yl)piperidine-l -carboxylate. MS m / z (M+H+) 375.1

[0139] Step 3: To a solution of tert-butyl (S)-3-(l-(4-methoxyphenyl)-5-oxo-2,5-dihydro-lH-1.2.4-triazol-3-yl)piperi dine- 1 -carboxylate (0.11 g, 0.294 mmol) in DCM (2 ml) was added TFA (0.226 ml, 2.94 mmol). The mixture was stirred at r.t. for 4 hr. The solvent was evaporated. The crude (5)-2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one was used in next reaction without purification. MS m / z (M+H+) 275.1.

[0140] Step 4: To a solution of (5)-2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4-dihydro-3H-1.2.4-triazol-3-one (0.08 g, 0.292 mmol) in 1,2-Dichloroethane (2 ml) were added DIPEA (0.102 ml, 0.583 mmol), acetic acid (0.025 ml, 0.437 mmol) and 3 -formylbenzamide (0.043 g, 0.292 mmol). The mixture was stirred at r.t. for 30 min, and then sodium triacetoxyborohydride (0.124 g, 0.583 mmol) was added. The reaction mixture was stirred at r.t. for 3 hr. The reaction was quenched with water, and extracted with EtOAc (3x). The combined organic layer was dried and concentrated. The crude product was purified by ISCO ( 0-10%, MeOH / DCM) to obtain (5)-3- ((3 -( 1 -(4-methoxyphenyl)-5 -oxo-4, 5 -dihydro- 1 H- 1 , 2,4-triazol -3 -y l)piperidin- 1 - yl)methyl)benzamide (Compound 18). MS m / z (M+H+) 408.1, 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.73 (dt, J= 7.6, 1.6 Hz, 1H), 7.69 (d, J= 9.1 Hz, 2H), 7.44 (dd, J= 7.6, 1.5 Hz, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.30 (s, 1H), 6.95 (d, J= 9.2 Hz, 2H), 3.73 (s, 3H), 3.53 (s, 2H), 2.96 (dd, J = 11.3, 3.6 Hz, 1H), 2.80 - 2.68 (m, 2H), 2.14 (t, J= 10.7 Hz, 1H), 1.96 (ddt, J= 16.6, 12.7, 6.5 Hz, 2H), 1.73 - 1.64 (m, 1H), 1.61 - 1.37 (m, 2H).Synthesis of tert-butyl 3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidine-l-carboxylate (Cpd 1):

[0141] The title compound was prepared according to Example 1 using tert-butyl 3-(2-(4- methoxyphenyl)hydrazine-l-carbonyl)piperidine-l -carboxylate in Step 2 as starting material.MS m / z (M+H-) 375.2. 1H NMR (400 MHz, chloroform-d ) δ 7.92 - 7.72 (m, 2H), 7.00 - 6.89 (m, 2H), 4.18 (m, 1H), 3.90 (m, 1H), 3.83 (s, 3H), 3.19 (ddd, J = 11.4, 9.6, 1.8 Hz, 1H), 3.01 (d, J = 12.7 Hz, 1H), 2.83 (d, J= 10.6 Hz, 1H), 2.20 - 2.05 (m, 1H), 1.81 (m, 2H), 1.70 - 1.49 (m, 1H), 1.47 (s, 9H).Synthesis of 2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l ,2,4-triazol-3-one (Cpd 2):Compound 2

[0142] The title compound was prepared according to Example 1 using tert-butyl 3-(l-(4- methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate in Step 3 as starting material. MS m z (M+H+) 275.2.Synthesis of 5-(l-benzylpiperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 3):Compound 3

[0143] The title compound was prepared according to Example 1 using benzaldehyde in Step 4 as the starting material. MS m / z (M+H+) 365.2.1H NMR (400 MHz, chloroform-d ) δ 7.83 - 7.74 (m, 2H), 7.39 - 7.28 (m, 6H), 6.97 - 6.90 (m, 2H), 3.82 (s, 3H), 3.60 (d, J= 12.8 Hz, 1H), 3.49 (d, J= 12.8 Hz, 1H), 3.01 (q, J= 4.3 Hz, 1H), 2.80 (s, 1H), 2.54 (d, J= 11.5 Hz, 1H), 2.32 (t, J = 11.5 Hz, 1H), 1.91 - 1.51 (m, 4H).Synthesis of 2-(4-methoxyphenyl)-5-(l-(pyridin-2-ylmethyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 6):Compound 6

[0144] The title compound was prepared according to Example 1 using picolinaldehyde in Step4 as starting material. MS m / z (M+H+) 366.4.Synthesis of 2-(4-methoxyphenyl)-5-(l -(pyridin-4-ylmethyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 7):Compound 7

[0145] The title compound was prepared according to Example 1 using isonicotinaldehyde in Step 4 as starting material. MS m / z (M+H+) 366.2.1H NMR (400 MHz, methanol-d4) δ 8.48 (d, J = 4.9 Hz, 2H), 7.69 (d, J= 8.5 Hz, 2H), 7.46 (d, J= 5.0 Hz, 2H), 7.01 - 6.94 (m, 2H), 3.81 (d, J = 1.9 Hz, 3H), 3.64 (s, 2H), 3.03 (m, 1H), 2.91 (m, 1H), 2.90 - 2.79 (m, 1H), 2.34 (t, J= 10.7 Hz, 1H), 2.20 (t, J= 11.0 Hz, 1H), 2.04 (d, J= 12.9 Hz, 1H), 1.84 (d, J= 11.8 Hz, 1H), 1.72 (d, J = 12.2 Hz, 1H), 1.63 (t, J= 11.8 Hz, 1H).Synthesis of 2-(4-methoxyphenyl)-5-(l-(pyridin-3-ylmethyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 8):Compound 8

[0146] The title compound was prepared according to Example 1 using nicotinaldehyde in Step 4 as starting material. MS m / z (M+H+) 366.2. 1H NMR (400 MHz, methanol-d 4) δ 8.52 (s, 1H), 8.45 (d, J = 4.8 Hz, 1H), 7.86 (d, J= 7.9 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.43 (t, J= 6.5 Hz, 1H), 7.02 - 6.91 (m, 2H), 3.81 (s, 3H), 3.64 (s, 2H), 3.06 (d, J= 10.7 Hz, 1H), 2.87 (d, 8.8 Hz,2H), 2.32 (t, J = 10.8 Hz, 1H), 2.18 (t, J= 11.1 Hz, 1H), 2.04 (d, J = 12.7 Hz, 1H), 1.83 (d, J = 13.2 Hz, 1H), 1.74 - 1.54 (m, 2H).Synthesis of tert-butyl 3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)azetidine-l-carboxylate (Cpd 10):Compound 10

[0147] The title compound was prepared according to Example 1 using tert-butyl 3-(2-(4- methoxyphenyl)hydrazine-l-carbonyl)azetidine-l -carboxylate in Step 2 as starting material.MS m / z (2M+Na+) 715.3. 1H NMR (400 MHz, chloroform-d) δ 7.90 - 7.70 (m, 2H), 6.97 (dd, J = 9.1, 2.0 Hz, 2H), 4.40 - 4.14 (m, 4H), 3.84 (s, 3H), 3.73 (ddd, J= 8.5, 6.1, 2.4 Hz, 1H), 1.46 (d, J= 1.9 Hz, 9H).Synthesis of 5-(azetidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one(Cpd 11):Compound 11

[0148] The title compound was prepared according to Example 1 using tert-butyl 3-(l-(4- methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)azetidine-l-carboxylate in Step 3 as starting material. MS m / z (M+H1) 247.1. 1H NMR (400 MHz, methanol -d4) δ 7.81 — 7.72 (m, 2H), 7.04 - 6.96 (m, 2H), 4.41 (d, J= 8.2 Hz, 4H), 4.16 - 4.03 (m, 1H), 3.82 (s, 3H).Synthesis of 2-(4-methoxyphenyl)-5-(l-(cyclohexylmethyl)70zetidine-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 12):

[0149] The title compound was prepared from 5-(azetidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one according to Example 1 using cyclohexanecarbaldehyde in Step 4 as starting material. MS m / z' (M+H1) 343.2. (400 M1HHz N,M mRethanol -d4 ) δ 7.80 - 7.72 (m, 2H), 7.04 - 6.96 (m, 2H), 4.47 (m, 4H), 4.06 (m, 1H), 3.82 (s, 3H), 3.17 (d, J= 6.9 Hz, 2H), 1.78 - 1.62 (m, 7H), 1.43 - 1.18 (m, 2H), 1.08 (m, 1H), 1.04 (m, 1H).Synthesis of tert-butyl 3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)pyrrolidine-l-carboxylate (Cpd 13):Compound 13

[0150] The title compound was prepared according to Example 1 using tert-butyl 3-(2-(4- methoxyphenyl)hydrazine-l-carbonyl)pyrrolidine-l -carboxylate in Step 2 as starting material. MS m / z (M+H ) 361.2. 1H NMR (400 MHz, chloroform-d ) δ 7.78 (d, J= 8.9 Hz, 2H), 7.02 - 6.87 (m, 2H), 3.83 (s, 3H), 3.80 - 3.29 (m, 4H), 2.37 - 2.09 (m, 3H), 1.47 (s, 9H).Synthesis of 2-(4-methoxyphenyl)-5-(pyrrolidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one(Cpd 14):Compound 14

[0151] The title compound was prepared according to Example 1 using tert-butyl 3-(l-(4- methoxyphenyl)-5-oxo-2,5-dihydro-lH-l,2,4-triazol-3-yl)pyrrolidine-l-carboxylate in Step 3 as starting material. MS m z (M+H+) 261.1. 1H NMR (400 MHz, methanol-d4) δ 7.78 - 7.69 (m, 2H), 7.03 - 6.94 (m, 2H), 3.82 (s, 3H), 3.79 - 3.68 (m, 1H), 3.71 - 3.58 (m, 2H), 3.49 - 3.41 (m, 2H), 2.52 - 2.40 (m, 1H), 2.40 - 2.28 (m, 1H).Synthesis of 5-(l -(cyclohexylmethyl)pyrrolidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 15):Compound 15

[0152] The title compound was prepared from tert-butyl 3-(l-(4-methoxyphenyl)-5-oxo-4,5- dihydro-lH-1, 2, 4-triazol-3-yl)pyrrolidine-l -carboxylate according to Example 1 using cyclohexanecarbaldehyde in Step 4 as starting material. MS m / Z (M+H+) 357.2. 1H NMR (400 MHz, methanol-d4) δ 7.78 - 7.68 (m, 2H), 7.02 - 6.95 (m, 2H), 4.07 (m, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.22 - 3.09 (m, 2H), 2.53 (m, 3H), 1.92 - 1.67 (m, 8H), 1.47 - 1.18 (m, 3H), 1.15 - 1.00 (m, 2H).Synthesis of 2-(4-methoxyphenyl)-5-((35)-l-((tetrahydro-2H-pyran-3-yl)methyl)piperidin- 3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 17):Compound 17

[0153] The title compound was prepared from (S)-2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one according to Example 1 using tetrahydro-2H-pyran-3- carbaldehyde in Step 4 as starting material. MS m / z (M+H+) 373.2. 1H NMR (400 MHz, methanol-d4) δ77.72 (d, J= 8.2 Hz, 2H), 6.99 (d, J= 8.7 Hz, 2H), 4.10 (m, 1H), 3.89 (m, 2H), 3.82 (s, 3H), 3.75 - 3.60 (m, 1H), 3.57 - 3.38 (m, 1H), 3.23 - 2.90 (m, 7H), 2.21 (m, 3H), 1.95 (m, 2H), 1.70 (m, 2H), 1.53 - 1.34 (m, 1H).Synthesis of 2-(4-methoxyphenyl)-5-((35)-l-((tetrahydro-2H-pyran-2-yl)methyl)piperidin- 3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 23):Compound 23

[0154] The title compound was prepared from (5)-2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one according to Example 1 using tetrahydro-2H-pyran-2- carbaldehyde in Step 4 as starting material. MS m / z (M+H+) 373.1.Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(pyridin-2-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (Cpd 24):Compound 24

[0155] The title compound was prepared according to Example 1 using 2-hydrazinylpyridine in Step 1 as starting material and cyclohexanecarbaldehyde in Step 4 as starting material, respectively. MS m / z (M+H+) 342.3. 1H NMR (400 MHz, rnethanol-d4 ) δ 8.55 - 8.46 (m, 1H), 8.18 - 8.08 (m, 1H), 8.05 - 7.91 (m, 1H), 7.40 - 7.29 (m, 1H), 3.99 (m, 1H), 3.74 - 3.40 (m, 2H), 3.26 - 3.18 (m, 1H), 3.05 (m, 2H), 2.23 - 2.04 (m, 2H), 2.02 - 1.85 (m, 4H), 1.85 - 1.59 (m, 5H), 1.47 - 1.19 (m, 3H), 1.09 (m, 2H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(pyridin-3-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (Cpd 25):Compound 25

[0156] The title compound was prepared according to Example 1 using 3-hydrazinylpyridine in Step 1 as starting material and cyclohexanecarbaldehyde in Step 4 as starting material, respectively. MS m / z (M+H+) 342.2.Synthesis of 5-(piperidin-3-yl)-2-(pyridin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 26):Compound 26

[0157] The title compound was prepared according to Example 1 using tert-butyl 3-(5-oxo-l- (pyridin-3-yl)-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate in Step 3 as starting material. MS m / z (M+H+) 246.1. 1H NMR (400 MHz, methanol-d4) δ 8.52 (t, J= 8.4 Hz, 2H), 7.71 (broad s, 2H), 3.64 (m, 1H), 3.50 - 3.32 (m, 3H), 3.25 - 3.02 (m, 1H), 2.25 (m, 1H), 2.08 - 1.97 (m, 1H), 1.89 (m, 2H).Synthesis of (5)-5-(l-(3-cyclohexylpropyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (Compound 92

[0158] The title compound was prepared according to Example 1 using 3-cyclohexylpropanal (0.051 g, 0.365 mmol) in Step 4 as starting material. MS m / z (M+H+) 399.3, 1H NMR (400 MHz, chloroform-d ) δ 7.79 (d, J= 9.1 Hz, 2H), 6.94 (d, J= 9.1 Hz, 2H), 3.82(s, 3H), 3.13 (s, 1H), 2.80 (s, 2H), 2.70 (s, 2H), 2.42 (s, 3H), 1.92 - 1.86 (m, 1H), 1.78 (s, 3H), 1.74 - 1.50 (m, 4H), 1.30 - 1.10 (m, 8H), 0.95 - 0.80 (m, 3H).Synthesis of (S)-2-(4-methoxyphenyl)-5-(l-((5-methylpyrimidin-2-yl)methyl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 100):

[0159] The title compound was prepared according to Example 1 using 5-methylpyrimidine-2- carbaldehyde in Step 4 as starting material. MS m / z (M+H+) 381.2, 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.78 (d, J= 0.9 Hz, 2H), 7.70 (d, J= 8.6 Hz, 2H), 7.03 - 6.95 (m, 2H), 4.64 (s, 2H), 3.74 (s, 3H), 3.65 - 3.15 (m, 4H), 3.17 - 2.99 (m, 1H), 2.32 (s, 3H), 2.17 - 2.07 (m, 1H), 1.95 - 1.86 (m, 2H), 1.63 - 1.53 (m, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(pyrimidin-2-ylmethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 101):Compound 101

[0160] The title compound was prepared according to Example 1 using pyrimidine-2- carbaldehyde in Step 4 as starting material. MS m / z (M+H+) 367.2, (400 MHz,1H DM NMSOR- d6) δ 10.36 (s, 1H), 8.93 (d, J= 5.0 Hz, 2H), 7.76 - 7.67 (m, 2H), 7.60 (t, J= 5.0 Hz, 1H), 6.98 (d, J= 8.7 Hz, 2H), 4.70 (s, 2H), 3.74 (s, 3H), 3.51 - 3.18 (m, 4H), 3.14 - 3.05 (m, 1H), 2.16 - 2.10 (m, 1H), 1.96 - 1.85 (m, 2H), 1.58 (dd, J= 11.8, 5.8 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-((4-methylpyrimidin-2-yl)methyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 102):Compound 102

[0161] The title compound was prepared according to Example 1 using 4-methylpyrimidine-2- carbaldehyde in Step 4 as starting material. MS m z (M+H+) 381.2, 1H NMR (400 MHz, DMSO- d6 ) δ 10.27 (s, 1H), 8.76 (d, J= 5.2 Hz, 1H), 7.71 (d, J= 8.6 Hz, 2H), 7.47 (d, J= 5.2 Hz, 1H), 7.03 - 6.93 (m, 2H), 4.71 - 4.57 (m, 2H), 3.74 (s, 3H), 3.63 - 3.16 (m, 4H), 3.19 - 2.94 (m, 1H), 2.52 (s, 3H), 2.16 - 2.07 (m, 1H), 1.93 (q, J= 13.6, 10.8 Hz, 2H), 1.65 - 1.54 (m, 1H).Synthesis of methyl (5)-2-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)isonicotinate, TFA (Cpd 104):Compound 104

[0162] The title compound was prepared according to Example 1 using methyl 2- (bromomethyl)isonicotinate in Step 4 as starting material. MS m / z (M+H+) 424.2, (400 1H NMR MHz, DMSO-d6) δ 10.24 (s, 1H), 8.90 (d, .7 = 5.1 Hz, 1H), 8.06 (s, 1H), 7.93 (dd, J= 5.2, 1.6 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.02 - 6.93 (m, 2H), 4.61 (s, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 3.32 - 2.93 (m, 4H), 2.10 - 2.02 (m, 1H), 1.98 - 1.74 (m, 3H), 1.67 - 1.56 (m, 1H).Synthesis of tert-butyl (5)-3-(l-(isoquinoIin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidine-l-carboxylate (Cpd 128):Compound 128

[0163] The title compound was prepared according to Example 1 using 5-hydrazinylisoquinoline in Step 1 as starting material. MS m'z (M+H+) 396.2, 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 9.39 (d, J= 0.9 Hz, 1H), 8.52 (d, J= 6.0 Hz, 1H), 8.17 (dd, J= 8.1, 1.3 Hz, 1H), 7.84 (dd, J= 7.5, 1.2 Hz, 1H), 7.80 - 7.71 (m, 2H), 4.10 - 3.91 (m, 1H), 3.78 - 3.56 (m, 1H), 3.02 - 2.95 (m, 2H), 2.76 - 2.67 (m, 1H), 2.09 - 2.01 (m, 1H), 1.74 (s, 2H), 1.41 (t, .7= 7.3 Hz, 1H), 1.36 (s, 9H).Synthesis of (5)-2-(isoquinolin-5-yl)-5-(l-(2-(naphthalen-2-yl)ethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 134):

[0164] The title compound was prepared according to Example 1 using 5-hydrazinylisoquinoline in Step 1 and 2-(naphthalen-2-yl)acetaldehyde in Step 4 as starting materials. MS m / z (M+H+) 450.2, 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 9.74 (s, 1H), 9.47 (d, J= 0.9 Hz, 1H), 8.56 (d, J = 6.0 Hz, 1H), 8.24 (d, J= 8.1 Hz, 1H), 7.93 - 7.85 (m, 3H), 7.85 - 7.77 (m, 3H), 7.49 (ddd, J= 6.7, 4.1, 1.8 Hz, 2H), 7.44 (dd, J= 8.4, 1.8 Hz, 1H), 3.95 (d, J= 9.9 Hz, 1H), 3.67 (d, J= 12.0 Hz, 1H), 3.53 - 3.43 (m, 2H), 3.22 (dd, J= 13.9, 7.0 Hz, 4H), 3.01 (q, J= 11.2 Hz, 1H), 2.22 (d, J= 12.7 Hz, 1H), 2.04 (d, J= 14.2 Hz, 1H), 1.83 (q, J= 13.5 Hz, 1H), 1.67 (dt, J= 13.2, 10.2 Hz, 1H).Synthesis of (5)-2-(isoquinolin-5-yl)-5-(l-(2-(naphthalen-l-yl)ethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TEA (Cpd 136):Compound 136

[0165] The title compound was prepared according to Example 1 using 5-hydrazinylisoquinoline in Step 1 and 2-(naphthalen-l-yl)acetaldehyde in Step 4 as starting materials. MS m / z (M+H+) 450.3, 1H NMR (400 MHz, DMSO-d6 ) δ 12.22 (s, 1H), 9.80 (s, 1H), 9.46 (s, 1H), 8.56 (d, J= 6.0 Hz, 1H), 8.24 (d, J= 8.1 Hz, 1H), 8.13 (d, J= 8.3 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.91 - 7.74 (m, 3H), 7.64 - 7.51 (m, 2H), 7.51 - 7.40 (m, 2H), 4.03 (d, J= 10.4 Hz, 1H), 3.73 (s, 1H), 3.57 - 3.44 (m, 4H), 3.33 - 3.15 (m, 2H), 3.05 (q, J= 11.2, 10.5 Hz, 1H), 2.23 (d, J= 12.9 Hz, 1H), 2.06 (d, J= 14.2 Hz, 1H), 1.86 (q, J= 13.7 Hz, 1H), 1.76 - 1.62 (m, 1H).Example la

[0166] The process below describes the synthesis of an exemplary compound.

[0167] Step 1 : Tert-butyl ((1R ,4S)-4-(2-((5)-3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-3-yl)piperidin-l-yl)ethyl)cyclohexyl)carbamate was prepared according to Example 1 using tert-butyl ((15,45)-4-(2-oxoethyl)cyclohexyl)carbamate in Step 4 as starting material. MS m / z (M+H+) 500.3.

[0168] Step 2: To a solution of tert-butyl ((lA,45)-4-(2-((S)-3-(l-(4-methoxyphenyl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)ethyl)cyclohexyl)carbamate (0.18 g, 0.360 mmol) in DCM (1 ml) was added TFA (0.2 ml, 2.60 mmol). The mixture was stirred at r.t. for Time. The solvent was removed. The crude product was submitted for purification to afford 5-((S)-l-(2- ((15,4R )-4-aminocyclohexyl)ethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4- triazol-3-one, 2 TFA (Compound 94). MS m / z (M+H+) 400.3,1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.78 (s, 2H), 7.74 - 7.66 (m, 2H), 7.03 - 6.94 (m, 2H), 3.75 (s, 3H), 3.52 (d, J = 12.6 Hz, 2H), 3.22 - 3.01 (m, 4H), 2.95 - 2.82 (m, 1H), 2.12 (d, J= 11.5 Hz, 1H), 1.96 (d, J = 14.2 Hz, 1H), 1.78 (t, J= 13.8 Hz, 1H), 1.61 (tt, J = 9.6, 5.9, 4.8 Hz, 7H), 1.54 - 1.46 (m, 4H), 1.44 - 1.37 (m, 2H).Synthesis of tert-butyl 3-(((5)-3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)piperidine-l-carboxylate (Cpd 88):Compound 88

[0169] The title compound was prepared according to Example la using Zc / 7-butyl 3- formylpiperidine-1 -carboxylate in Step 1 as starting material. MS m / z (M+H~) 472.3. 1H NMR (400 MHz, methanol-d4 ) δ 7.70 (dd, J= 9.0, 2.1 Hz, 2H), 7.09 - 6.83 (m, 2H), 4.04 (d, J= 13.3 Hz, 1H), 3.88 (d, J= 13.2 Hz, 1H), 3.81 (s, 3H), 3.19 - 2.73 (m, 4H), 2.56 (s, 1H), 2.21 (dt, J = 25.5, 9.8 Hz, 3H), 2.02 (d, J= 10.9 Hz, 2H), 1.69 (ddd, J= 58.3, 34.4, 12.3 Hz, 3H), 1.43 (d, J = 3.1 Hz, 10H), 1.19 (s, 1H).Synthesis of 3-(((A)-3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)piperidine (Cpd 90):Compound 90

[0170] The title compound was prepared according to Example la using zc / v-butyl 3-(((5)-3-(l- (4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)methyl)piperidine-l- carboxylate in Step 2 as starting material. MS m / z (M+H+) 372.3. (400 MHz1H, m NeMthRanol- d4) δ 7.78 - 7.59 (m, 2H), 6.99 (dd, J= 8.9, 1.7 Hz, 2H), 3.82 (s, 3H), 3.59 - 3.46 (m, 1H), 3.39 (m, 1H), 3.17 - 3.04 (m, 2H), 2.99 - 2.87 (m, 1H), 2.80 (td, J= 12.1, 4.5 Hz, 1H), 2.39 (broad s, 2H), 2.20 (broad s, 2H), 2.11 - 1.89 (m, 4H), 1.80 (m, 3H), 1.39 (m, 2H) (one proton missing).Synthesis of 5-((S)-l-(2-((1R, 4S)-4-aminocyclohexyl)ethyl)piperidin-3-yl)-2-(4- methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one, 2 TFA (Cpd 93):Compound 93

[0171] The title compound was prepared according to Example la using / m-butyl ((1R ,4R )-4- (2-oxoethyl)cyclohexyl)carbamate in Step 1 as starting material. MS m / z (M+H+) 400.3, 1H NMR (400 MHz, DMSO-D6) δ 9.70 (s, 1H), 7.79 (d, J= 5.1 Hz, 2H), 7.74 - 7.66 (m, 2H), 7.03 - 6.94 (m, 2H), 3.75 (s, 3H), 3.50 (d, J= 12.2 Hz, 2H), 3.17 - 3.02 (m, 5H), 2.98 - 2.73 (m, 2H), 2.11 (d, J= 12.8 Hz, 1H), 1.99 - 1.85 (m, 3H), 1.80 - 1.71 (m, 4H), 1.63 - 1.49 (m, 3H), 1.33 - 1.18 (m, 2H), 0.99 (q, .7= 14.2, 12.5 Hz, 1H).Example lb

[0172] The process below describes the synthesis of an exemplary compound.

[0173] To a solution of tert-butyl (5)-3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl)piperidine-l -carboxylate (130 mg, 0.347 mmol) in CH2CI2 (1 mL) was added trifluoroacetic acid (267 μl, 3.47 mmol). The reaction was stirred at rt for 1.5 h. The solvent was removed, and the residue was dried under high vacuum for 2 h. The residue was dissolved in DMF (1 mL), and was treated with potassium carbonate (240 mg, 1.736 mmol), a suspension of (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (81 mg, 0.417 mmol) in DMF (0.5 mL). The reaction mixture was stirred at rt for 3 h, and then was heated at 50 °C for 3 d. The reaction was quenched with water, and extracted with 10% iPrOH / CFLCL. The combined organic layers were washed with water, brine, and concentrated. The residue was purified by flash chromatography to provide (5)-2-(4-methoxyphenyl)-5-(l-((tetrahydro-2H-pyran-4- yl)methyl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 16). MS m / z (M+FL) 373.5. 1H NMR (400 MHz, methanol-d4) δ 7.74 - 7.67 (m, 2H), 6.99 (d, J= 8.6 Hz, 2H), 4.20 (m, 1H), 4.04 - 3.84 (m, 3H), 3.82 (s, 3H), 3.69 (d, J= 12.6 Hz, 1H), 3.53 - 3.43 (m, 2H), 3.22 (s, 1H), 3.13 (m, 2H), 3.01 (s, 1H), 2.31 - 2.24 (m, 1H), 2.11 (p, J= 15.2 Hz, 1H), 2.00 - 1.81 (m, 1H), 1.70 (m, 3H), 1.48 - 1.25 (m, 3H).Example 1c

[0174] The process below describes the synthesis of an exemplary compound.

[0175] Step 1 : To a mixture of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (5.0 g, 21.62 mmol) and 1 -hydroxybenzotriazole hydrate (HOBt, 4.09 g, 30.3 mmol) in DMF (15 ml) was added EDC HC1 (4.97 g, 25.9 mmol), triethylamine (7.53 ml, 54.1 mmol), and (4- methoxyphenyl)hydrazine hydrochloride (4.53 g, 25.9 mmol). The reaction mixture was stirred at rt for 24 h. The reaction mixture was filtered through a fritted funnel. The filtrated solution was diluted with H2O (150 mL), and extracted with EtOAc (3X200 mL). The combined organic layers were washed with water, brine, and concentrated. The residue was purified by flash chromatography. The fractions eluted at 80% EtOAc / hexanes were pooled and concentrated to provide tert-butyl 2-(2-(4-methoxyphenyl)hydrazine-l-carbonyl)morpholine-4-carboxylate (4.988 g, 14.19 mmol, 65.6 % yield) as a white powder.

[0176] Step 2: To a solution of tert-butyl 2-(2-(4-methoxyphenyl)hydrazine-l- carbonyl)morpholine-4-carboxylate (1.64 g, 4.67 mmol) in CH2CI2 (30 mL) at 0 °C was added2.2.2-trichloroacetyl isocyanate (0.779 ml, 6.53 mmol). The reaction was stirred at 0 °C for 30 min. The solvent was evaporated. The residue was treated with MeOH (20 mL) and potassium carbonate (2.58 g, 18.67 mmol). The reaction was stirred at rt for 3.5 h, then at 65 °C for 3 d. The solvent was removed, and the residue was purified by flash chromatography. The fractions eluted at EtOAc were pooled and concentrated to provide terZ-butyl 2-(l-(4-methoxyphenyl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-3-yl)morpholine-4-carboxylate (Compound 131). MS m / z (M+H+) 377.2. 1H NMR (400 MHz, DMSO-d6 ) δ 12.17 (s, 1H), 7.79 - 7.69 (m, 2H), 7.04 - 6.96 (m, 2H), 4.45 (dd, J = 9.1, 3.0 Hz, 1H), 4.05 - 3.93 (m, 1H), 3.89 (dt, J = 11.5, 3.0 Hz, 1H), 3.76 (s, 3H), 3.70 (dq, J= 13.2, 2.5 Hz, 1H), 3.57 (m, 1H), 3.23 (broad s, 1H), 3.05 (t, J= 12.1 Hz, 1H), 1.42 (s, 9H).

[0177] Step 3: To a solution of tert-butyl 2-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl)morpholine-4-carboxylate (250 mg, 0.664 mmol) in CH2CI2 (1 mL) was added trifluoroacetic acid (614 μl, 7.97 mmol). The reaction was stirred for 2.5 d. The solvent was removed, and the residue was dried under high vacuum overnight. The residue was redissolved in1.2-dichloroethane / THF (2 mL:l mL). Hunig's base (347 μl, 1.992 mmol) was added, followed by 2-cyclohexylacetaldehyde (168 μl, 1.328 mmol). Then sodium triacetoxyhydroborate (282 mg, 1.328 mmol) was added. The reaction mixture was stirred for 1 h. The reaction was quenched with IN NaOH solution (0.5 mL). The solvent was removed, and the resulting residue was purified by flash chromatography to provide 5-(4-(2-cyclohexylethyl)morpholin-2-yl)-2-(4-methoxyphenyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 137). MS m / z (M+H+) 387.2. 1H NMR (400 MHz,DMSO-d6,) δ 12.36 (s, 1H), 7.72 (d, J= 8.7 Hz, 2H), 7.11 - 6.91 (m, 2H), 4.76 (d, J= 9.9 Hz, 1H), 4.17 (d, J= 12.7 Hz, 1H), 3.84 (d, J= 12.4 Hz, 1H), 3.69 - 2.87 (m, 7H), 1.82 - 1.50 (m, 6H), 1.42 - 1.03 (m, 4H), 1.01 - 0.77 (m, 2H).Example Id

[0178] The process below describes the synthesis of exemplary compounds.

[0179] Step 1: To a mixture of l,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.0 g, 3.03 mmol) and 1 -hydroxybenzotriazole hydrate (0.573 g, 4.24 mmol) in DMF (20 ml) was added EDC HC1 (0.696 g, 3.63 mmol), Hunig's base (1.322 ml, 7.57 mmol), and (4- methoxyphenyl)hydrazine hydrochloride (0.634 g, 3.63 mmol). The reaction mixture was stirred at rt for 20 h. The reaction mixture was quenched with water. The mixture was filtered through a filtration funnel. The filtrate was collected and purified by flash chromatography. The fractions collected at 60% EtOAc / hexanes were pooled and concentrated to provide di-Ze / V-butyl 2-(2-(4- methoxyphenyl)hydrazine-l-carbonyl)piperazine-l,4-dicarboxylate (540 mg, 1.199 mmol, 39.6 % yield) as a pale yellow powder.

[0180] Step 2: To a solution of di-tert-butyl 2-(2-(4-methoxyphenyl)hydrazine-l- carbonyl)piperazine-l,4-dicarboxylate (540 mg, 1.199 mmol) in CH2CI2 (20 mL) at 0 °C was added 2,2,2-trichloroacetyl isocyanate (200 μl, 1.678 mmol). The reaction was stirred at 0 °C for 1 h. The solvent was evaporated. The remaining crude material was dissolved in MeOH (15 mL) and was treated with potassium carbonate (663 mg, 4.79 mmol). The reaction was stirred at rt for 20 h, then the reaction mixture was heated at 60 °C for 6 d. The reaction mixture was concentrated and purified by flash chromatography. The fractions eluted around 80%EtOAc / hexanes were collected and pooled to provide di- / c / 7-butyl 2-(l-(4-methoxyphenyl)-5- oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperazine-l,4-dicarboxylate (40 mg, 0.084 mmol, 7.02 % yield) as a pale yellow oil.

[0181] Step 3: To a solution of di-tert-butyl 2-(l-(4-methoxyphenyl)55-oxo-4,5-dihydro-lH- l,2,4-triazol-3-yl)piperazine-l,4-dicarboxylate (25 mg, 0.053 mmol) in CH2CI2 (1 mL) was added TFA (405 μl, 5.26 mmol). The reaction was stirred at rt for 30 min. The solvent was evaporated and the residue was dissolved in THF (1 mL). Hunig's base (23.42 μl, 0.134 mmol), 2-cyclohexylacetaldehyde (8.85 μl, 0.064 mmol), and sodium triacetoxyhydroborate (17.05 mg, 0.080 mmol) were added. The reaction mixture as a slurry was stirred for 40 min. The reaction was quenched with a few drops of IN NaOH solution. The solvent was removed, and the crude product was purified by flash chromatography to provide two products: 5-(4-(2- cyclohexylethyl)piperazin-2-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 292), MS m / z (M+FF) 386.3, and 5-(l-(2-cyclohexylethyl)piperazin-2-yl)-2-(4- methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 293), MS m / z (M+FF) 386.3.Example 2

[0182] The process below describes the synthesis of an exemplary compound.

[0183] To a solution of (S)-2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (50 mg, 0.182 mmol) (from Example 1, Step 3) in DMF (2 ml) were added potassium carbonate (126 mg, 0.911 mmol) and 4-(bromomethyl)benzamide (46.8 mg, 0.219 mmol). The reaction mixture was stirred at r.t. for 30 min. The crude product was purified byISCO 0-20%, MeOH / DCM) to afford (S)-4-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-1.2.4-triazol-3-yl)piperidin-l-yl)methyl)benzamide (Compound 19). MS m / z (M+H+) 408.1, 'H NMR (400 MHz, methanol-d4) δ 7.84 (d, J= 8.3 Hz, 2H), 7.67 (d, J= 9.1 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.96 (d, J= 9.1 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 2H), 3.06 (dd, J= 11.2, 3.6 Hz, 1H), 2.88 (ddt, J= 14.8, 11.7, 4.0 Hz, 2H), 2.33 (t, J= 10.7 Hz, 1H), 2.20 (td, J= 11.0, 3.0 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.82 (dt, J= 12.9, 3.7 Hz, 1H), 1.77 - 1.52 (m, 2H).Synthesis of 5-(l-(cyclopropylmethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-1.2.4-triazol-3-one (Cpd 9):Compound 9

[0184] The title compound was prepared according to Example 2 using (bromomethyl)cyclopropane as starting material. MS m / z (M+H+) 329.4.Synthesis of ($)-. / V-(3-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)phenyl)acetamide (Cpd 20):Compound 20

[0185] The title compound was prepared according to Example 2 using N-(3- (bromomethyl)phenyl)acetamide as starting material. MS m / z (M+H+) 422.1, 1H NMR (400 MHz, chloroform-d ) δ 8.09 (s, 1H), 7.75 (d, J= 9.1 Hz, 2H), 7.64 (d, J= 8.2 Hz, 1H), 7.38 (s, 1H), 7.30 - 7.21 (m, 1H), 6.98 (d, J= 7.6 Hz, 1H), 6.92 (d, J= 9.1 Hz, 2H), 3.80 (d, J= 1.9 Hz, 3H), 3.64 (d, J= 13.0 Hz, 1H), 3.46 (d, J= 13.7 Hz, 1H), 3.04 (s, 1H), 2.69 (d, J= 8.6 Hz, 3H), 2.47 (s, 1H), 2.14 (s, 3H), 1.88 - 1.80 (m, 2H), 1.81 - 1.70 (m, 3H).Synthesis of (A)-2-(4-methoxyphenyl)-5-(l -phenethylpiperidin-3-yl)-2,4-dihydro-3H-l ,2,4- triazol-3-one (Cpd 21):Compound 21

[0186] The title compound was prepared according to Example 2 using (2-bromoethyl)benzene as starting material. MS m / z (M+H+) 379.1, 1H NMR (400 MHz, chloroforms-d) δ 7.78 (d, J= 9.0 Hz, 2H), 7.31 (dd, J= 8.0, 6.7 Hz, 2H), 7.24 (d, J= 7.6 Hz, 1H), 7.19 (d, J= 7.1 Hz, 2H), 6.90 (d, J= 9.1 Hz, 2H), 3.79 (d, J= 1.1 Hz, 3H), 3.06 (s, 1H), 2.91 - 2.82 (m, 2H), 2.81 - 2.76 (m, 2H), 2.68 (t, J = 8.0 Hz, 3H), 2.49 (s, 1H), 1.89 (s, 1H), 1.77 (d, J= 18.6 Hz, 4H).Synthesis of (A)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 22

[0187] The title compound was prepared according to Example 2 using (2- bromoethyl)cyclohexane as starting material. MS m / z (M+H+) 385.2, (400 MHz,1H NMR chloroforms-d) δ 7.84 - 7.75 (m, 2H), 6.97 - 6.88 (m, 2H), 3.81 (d, J= 1.0 Hz, 3H), 3.06 (s, 1H), 2.84 - 2.62 (m, 6H), 2.42 (t, J= 7.8 Hz, 2H), 1.92 - 1.59 (m, 7H), 1.49 - 1.36 (m, 2H), 1.31 - 1.06 (m, 5H), 0.91 (dt, J= 15.0, 11.4 Hz, 2H).Synthesis of (S )-2-(4-methoxyphenyl)-5-(l-((6-methylpyridin-2-yl)methyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 30):

[0188] The title compound was prepared according to Example 2 using 2-(bromomethyl)-6- methylpyridine as starting material. MS m / z (M+H+) 380.3, 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.81 (t, J= 7.7 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.34 (dd, J= 7.8, 3.0 Hz, 2H), 7.02 - 6.94 (m, 2H), 4.44 (s, 2H), 3.74 (s, 3H), 3.67 - 3.57 (m, 1H), 3.43 - 3.27 (m, 2H), 3.26 - 3.14 (m, 1H), 3.11 - 3.02 (m, 1H), 2.52 (s, 3H), 2.10 - 2.02 (m, 1H), 1.97 - 1.77 (m, 2H), 1.67 (t, J = 11.0 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(4-(trifluoromethoxy)benzyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TEA (Cpd 31):Compound 31

[0189] The title compound was prepared according to Example 2 using l-(bromomethyl)-4- (trifluoromethoxy)benzene as starting material. MS m / z (M+H+) 449.2, (400 MHz,1H NMR DMSOd6 ) δ 10.01 (s, 1H), 7.75 - 7.60 (m, 4H), 7.51 (dd, J= 26.2, 8.1 Hz, 2H), 7.04 - 6.94 (m, 2H), 4.48 - 4.33 (m, 2H), 3.74 (s, 3H), 3.69 - 3.34 (m, 2H), 3.19 - 2.79 (m, 3H), 2.12 - 2.04 (m, 1H), 1.97 - 1.86 (m, 1H), 1.78 - 1.66 (m, 1H), 1.55 (q, J= 12.4 Hz, 1H).Synthesis of (S)-5-(l-(3-methoxybenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one, TEA (Cpd 32):

[0190] The title compound was prepared according to Example 2 using l-(bromomethyl)-3- methoxybenzene as starting material. MS m / z (M+H+) 395.3, 1H NMR (400 MHz, DMSO-d6) 8 9.76 (s, 1H), 7.68 (dd, J= 9.2, 2.4 Hz, 2H), 7.42 (dt, J= 20.3, 7.9 Hz, 1H), 7.19 - 7.01 (m, 3H), 6.98 (dd, J= 9.7, 2.8 Hz, 2H), 4.33 (d, J= 4.9 Hz, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.63 (d, J = 10.2 Hz, 1H), 3.18 - 3.01 (m, 3H), 2.95 - 2.84 (m, 1H), 2.09 (d, J= 13.6 Hz, 1H), 1.95 (d, J = 15.4 Hz, 1H), 1.75 (q, J= 13.5 Hz, 1H), 1.55 (q, J = 12.1 Hz, 1H).Synthesis of (S)-5-( 1 -(3-fluorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 33):Compound 33

[0191] The title compound was prepared according to Example 2 using l-(bromomethyl)-3- fluorobenzene as starting material. MS m / z (M+H+) 383.2,NMR (400 MHz, DMSO-d6 ) δ 9.84 (s, 1H), 7.69 (d, J= 9.0 Hz, 2H), 7.61 - 7.26 (m, 4H), 6.98 (d, J= 9.1 Hz, 2H), 4.38 (s, 2H), 3.74 (s, 3H), 3.66 - 3.29 (m, 2H), 3.12 - 3.02 (m, 2H), 2.92 (d, J = 11.6 Hz, 1H), 2.09 (d, J = 13.0 Hz, 1H), 1.92 (t, J = 16.9 Hz, 1H), 1.82 - 1.62 (m, 1H), 1.56 (q, J= 13.7, 13.0 Hz, 1H).Synthesis of (5)-5-(l-(3-chlorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 34):Compound 34

[0192] The title compound was prepared according to Example 2 using l-(bromomethyl)-3- chlorobenzene as starting material. MS m z (M+H+) 399.2, 'HNMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.69 (d, J= 9.1 Hz, 2H), 7.66 - 7.43 (m, 4H), 6.98 (d, J= 9.2 Hz, 2H), 4.37 (s, 2H), 3.74 (s, 3H), 3.71 - 3.23 (m, 2H), 3.20 - 3.01 (m, 2H), 3.00 - 2.84 (m, 1H), 2.09 (d, J = 13.1 Hz, 1H), 1.93 (t, J= 18.2 Hz, 1H), 1.82 - 1.63 (m, 1H), 1.63 - 1.47 (m, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(4-(trifluoromethyl)benzyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 35):

[0193] The title compound was prepared according to Example 2 using l-(bromomethyl)-4- (trifluoromethyl)benzene as starting material. MS m / z (M+H+) 433.3, (400 MHz1,H NMR DMSO-d6 ) δ 9.98 (s, 1H), 8.03 - 7.51 (m, 6H), 7.08 - 6.90 (m, 2H), 4.47 (s, 2H), 3.74 (s, 3H), 3.70 - 3.48 (m, 1H), 3.36 (d, J= 38.2 Hz, 1H), 3.21 - 2.99 (m, 2H), 2.94 (s, 1H), 2.07 (s, 1H), 1.91 (d, J= 13.7 Hz, 1H), 1.74 (d, J= 13.9 Hz, 1H), 1.57 (t, J= 12.6 Hz, 1H).Synthesis of (S)-2-(4-methoxyphenyl)-5-(l-(3-methylbenzyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 36):Compound 36

[0194] The title compound was prepared according to Example 2 using l-(bromomethyl)-3- methylbenzene as starting material. MS m / z (M+H+) 379.3, 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.73 - 7.64 (m, 2H), 7.39 - 7.28 (m, 4H), 6.99 (dd, J= 9.3, 7.4 Hz, 2H), 4.31 (d, J = 4.9 Hz, 2H), 3.74 (s, 3H), 3.67 - 3.39 (m, 2H), 3.18 - 3.00 (m, 2H), 2.91 (q, J= 11.5 Hz, 1H), 2.33 (s, 3H), 2.09 (d, J= 13.5 Hz, 1H), 1.94 (d, J= 15.3 Hz, 1H), 1.72 (p, J= 14.0 Hz, 1H), 1.62- 1.48 (m, 1H).Synthesis of (5)-5-(l-(4-isopropylbenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one,Compound 37

[0195] The title compound was prepared according to Example 2 using 1 -(bromomethyl)-4- isopropylbenzene as starting material. MS m / z (M+Hl) 407.3, (400 M1HHz N, M DMRSO-d6 ) δ 9.63 (s, 1H), 7.68 (dd, J= 8.9, 6.4 Hz, 2H), 7.52 - 7.30 (m, 4H), 7.00 (dd, J= 12.1, 9.1 Hz, 2H), 4.32 (d, J= 4.7 Hz, 2H), 3.74 (s, 3H), 3.63 (d, J= 11.2 Hz, 1H), 3.18 - 2.99 (m, 2H), 2.92 (dd, J= 14.0, 7.2 Hz, 2H), 2.12 - 2.03 (m, 1H), 1.92 (t, J= 16.5 Hz, 1H), 1.77 - 1.65 (m, 1H), 1.55 (q, J= 12.0 Hz, 1H), 1.20 (dd, J= 6.9, 4.3 Hz, 7H).Synthesis of (1S)-2-(4-methoxyphenyl)-5-(l-(4-((trifluoromethyl)thio)benzyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 38):Compound 38

[0196] The title compound was prepared according to Example 2 using (4-(bromomethyl)phenyl)(trifluoromethyl)sulfide as starting material. MS m z (M+H~) 465.2,1H NMR (400 MHz, DMSO-d6) δ 9.87 (d, J= 13.0 Hz, 1H), 7.86 (dd, J= 17.6, 7.8 Hz, 3H), 7.77 -7.62 (m, 3H), 6.99 (dd, J= 13.7, 9.2 Hz, 2H), 4.44 (s, 2H), 3.74 (s, 3H), 3.69 - 3.47 (m, 2H),3.24 - 2.88 (m, 3H), 2.18 - 2.01 (m, 1H), 1.91 (d, J=1H), 1.74 (d, J= 14.6 Hz, 1H),1.63 - 1.49 (m, 1H).Synthesis of (S)-5-(l-(4-bromobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 39):Compound 39

[0197] The title compound was prepared according to Example 2 using 4-bromo-l- (bromomethyl)benzene as starting material. MS m / z (M+H+) 443.2 / 445.2, 1H NMR (400 MHz, DMSO-d6,) δ99.85 (s, 1H), 7.78 - 7.60 (m, 3H), 7.50 (dd, J= 27.4, 8.1 Hz, 3H), 7.05 - 6.94 (m, 2H), 4.35 (s, 2H), 3.74 (s, 3H), 3.57 (dd, J= 29.1, 13.2 Hz, 1H), 3.39 (s, 1H), 3.07 (td, J= 11.3, 7.4 Hz, 2H), 2.90 (d, J= 11.5 Hz, 1H), 2.08 (d, J= 12.8 Hz, 1H), 1.92 (t, J= 16.8 Hz, 1H), 1.78 - 1.66 (m, 1H), 1.55 (q, J= 11.7 Hz, 1H).Synthesis of (S )-N-(4-(2-(3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)ethyl)phenyl)acetamide, TFA (Cpd 40):Compound 40

[0198] The title compound was prepared according to Example 2 using 7V-(4-(2- bromoethyl)phenyl)acetamide as starting material. MS m / z (M+H+) 436.3, (400 MHz, 1H NMR DMSO-d6 ) δ 9.91 (s, 1H), 7.75 - 7.66 (m, 2H), 7.56 - 7.50 (m, 2H), 7.20 (dd, J= 7.8, 5.8 Hz, 2H), 7.04 - 6.94 (m, 2H), 3.88 - 3.77 (m, 2H), 3.74 (s, 3H), 3.66 - 3.53 (m, 2H), 3.46 - 3.27 (m, 2H), 3.21 - 3.01 (m, 1H), 3.01 - 2.87 (m, 3H), 2.12 (d, J= 12.8 Hz, 1H), 2.00 (s, 4H), 1.75 (t, J = 13.7 Hz, 1H), 1.64 - 1.50 (m, 1H).Synthesis of (5)-5-(l-([l,l'-biphenyl]-4-ylmethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 41):Compound 41

[0199] The title compound was prepared according to Example 2 using 4-(bromomethyl)-l,T- biphenyl as starting material. MS m / z (M+H+) 441.3, 1H NMR (400 MHz, DMSO-d6 ) δ 9.78 (s, 1H), 7.87 - 7.57 (m, 8H), 7.53 - 7.43 (m, 2H), 7.43 - 7.34 (m, 1H), 6.96 (dd, J= 16.2, 9.1 Hz, 2H), 4.41 (d, J= 4.6 Hz, 2H), 3.74 (s, 3H), 3.69 - 3.46 (m, 2H), 3.22 - 3.03 (m, 2H), 2.95 (d, J= 11.7 Hz, 1H), 2.14 - 2.05 (m, 1H), 2.00 - 1.88 (m, 1H), 1.80 - 1.69 (m, 1H), 1.57 (q, J= 12.2 Hz, 1H).Synthesis of (A)-5-(l-(2,6-dichlorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one, TFA (Cpd 42):Compound 42

[0200] The title compound was prepared according to Example 2 using 2-(bromomethyl)-l,3- dichlorobenzene as starting material. MS m / z (M+H1) 433.1, (400 M1HHz N, DMMRSO-d6) δ 9.67 (s, 1H), 7.71 (d, J= 8.7 Hz, 2H), 7.62 (s, 2H), 7.53 (s, 1H), 7.03 - 6.94 (m, 2H), 4.68 - 4.53 (m, 2H), 3.74 (s, 3H), 3.58 - 3.23 (m, 3H), 3.14 (s, 1H), 2.11 - 2.01 (m, 1H), 1.91 - 1.80 (m, 3H), 1.64 - 1.53 (m, 1H).Synthesis of (S)-5-(l-(3,4-difluorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one, TEA (Cpd 43):Compound 43

[0201] The title compound was prepared according to Example 2 using 4-(bromom ethyl)- 1,2- difluorobenzene as starting material. MS m / z (M+H+) 401.3, 1H NMR (400 MHz, DMSO-d6 ) δ 9.95 (s, 1H), 7.73 - 7.50 (m, 4H), 7.40 - 7.31 (m, 1H), 7.02 - 6.94 (m, 2H), 4.36 (s, 2H), 3.74(s, 3H), 3.69 - 3.49 (m, 2H), 3.09 - 3.02 (m, 2H), 2.92 - 2.85 (m, 1H), 2.12 - 2.04 (m, 1H), 1 .96- 1.86 (m, 1H), 1.77 - 1.68 (m, 1H), 1.57 (t, J= 11.9 Hz, 1H).Synthesis of (S)-JV-(3-(2-(3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)ethyl)phenyl)acetamide, TFA (Cpd 44):Compound 44

[0202] The title compound was prepared according to Example 2 using N -(3-(2- bromoethyl)phenyl)acetamide as starting material. MSm / z (M+H+) 436.3, (400 MHz, 1H NMR DMSO-d6,) δ 9.93 (s, 1H), 7.75 - 7.67 (m, 2H), 7.63 (s, 1H), 7.31 (td, J= 6.5, 6.0, 3.2 Hz, 1H), 7.25 (t, J= 7.8 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.95 (dd, J= 7.2, 5.6 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.74 (s, 3H), 3.68 - 3.38 (m, 2H), 3.50 - 3.25 (m, 2H), 3.22 - 3.04 (m, 1H), 3.05 - 2.89 (m, 2H),2.12 (d, J= 12.9 Hz, 1H), 2.02 (s, 3H), 2.01 - 1.92 (m, 1H), 1.76 (d, J= 13.9 Hz, 1H), 1.64 - 1.51 (m, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(3-(trifluoromethyl)benzyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 45):Compound 45

[0203] The title compound was prepared according to Example 2 using l-(bromomethyl)-3- (trifluoromethyl)benzene as starting material. MS m / z (M+H+) 433.2, (400 MHz1,H NMR DMSO-d6 ) δ 9.98 (s, 1H), 7.99 - 7.88 (m, 1H), 7.85 (dd, J= 20.5, 10.9 Hz, 2H), 7.79 - 7.60 (m, 3H), 7.02 - 6.93 (m, 2H), 4.47 (s, 2H), 3.74 (s, 3H), 3.67 - 3.48 (m, 2H), 3.22 - 3.04 (m, 2H), 2.98 - 2.92 (m, 1H), 2.09 (d, J= 13.4 Hz, 1H), 1.93 (s, 1H), 1.78 - 1.67 (m, 1H), 1.56 (q, J = 12.0 Hz, 1H).Synthesis of (S)-5-(l-(3,4-dichlorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one, TFA (Cpd 46):Compound 46

[0204] The title compound was prepared according to Example 2 using 4-(bromom ethyl)- 1,2- dichlorobenzene as starting material. MS m / z (M+H+) 433.1, 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.82 (d, J= 7.4 Hz, 1H), 7.77 (d, J= 7.8 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.03 - 6.94 (m, 2H), 4.41 - 4.31 (m, 2H), 3.74 (s, 3H), 3.69 - 3.52 (m, 1H), 3.13 - 3.00 (m, 2H), 2.96 - 2.89 (m, 1H), 2.11 - 2.04 (m, 1H), 1.98 - 1.84 (m, 2H), 1.77 - 1.66 (m, 1H), 1.56 (d, J= 12.5 Hz, 1H).Synthesis of (S )-5-(1 -(3-(2H-tetrazol-5-yl)benzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 47):Compound 47

[0205] The title compound was prepared according to Example 2 using 5-(3-(bromomethyl)phenyl)-2H-tetrazole as starting material. MS m z (M+H+) 433.3,NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.70 (s, 4H), 7.00 - 6.94 (m, 2H), 6.80 (s, 1H), 4.45 (s, 2H), 3.74 (s, 3H), 3.70 - 3.44 (m, 1H), 3.25 - 2.84 (m, 3H), 2.12 - 2.04 (m, 1H), 1.99 - 1.88 (m, 2H), 1.80 - 1.69 (m, 1H), 1.62 - 1.53 (m, 1H)..Synthesis of (5)-5-(l-(3-chloro-4-(trifluoromethyl)benzyl)piperidin-3-yl)-2-(4- methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 48):Compound 48

[0206] The title compound was prepared according to Example 2 using 4-(bromomethyl)-2- chloro-l-(trifluoromethyl)benzene as starting material. MS m z (M+H+) 467.2, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.00 (d, J= 10.6 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.73 - 7.61 (m, 3H), 6.98 (d, J= 9.1 Hz, 2H), 4.58 - 4.36 (m, 2H), 3.74 (s, 3H), 3.69 - 3.51 (m, 3H), 3.19 - 2.84 (m, 2H), 2.10 - 2.02 (m, 1H), 1.91 (dd, J= 12.3, 7.7 Hz, 1H), 1.83 - 1.46 (m, 2H).Synthesis of (S')-5-( l-(2-fluorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 49):

[0207] The title compound was prepared according to Example 2 using l-(bromomethyl)-2- fluorobenzene as starting material. MS m / z (M+H+) 383.3,1H NMR (400 MHz, DMSO-d6 ) δ 9.83 (s, 1H), 7.75 - 7.67 (m, 2H), 7.68 - 7.52 (m, 2H), 7.38 (dd, J= 29.4, 8.5 Hz, 2H), 7.04 - 6.94 (m, 2H), 4.46 - 4.39 (m, 2H), 3.74 (s, 3H), 3.72 - 3.54 (m, 2H), 3.28 - 3.13 (m, 2H), 3.08 (qd, J= 7.3, 4.7 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.92 (dd, J= 23.8, 13.3 Hz, 1H), 1.83 - 1.62 (m, 1H), 1.55 (d, J= 13.2 Hz, 1H).Synthesis of (5)-5-(l-(4-chloro-3-fluorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TEA (Cpd 50):Compound 50

[0208] The title compound was prepared according to Example 2 using 4-(bromom ethyl)- 1- chloro-2-fluorobenzene as starting material. MS m / z (M+H+) 417.2, 1H NMR (400 MHz, DMSO-d6 ) δ 9.80 (s, 1H), 7.82 (dt, J= 19.5, 5.7 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.57 - 7.51 (m, 2H), 6.98 (d, J= 9.1 Hz, 2H), 4.42 - 4.30 (m, 2H), 3.74 (s, 3H), 3.69 - 3.47 (m, 2H), 3.05 (d, J =13.7 Hz, 2H), 2.94 - 2.86 (m, 1H), 2.07 (s, 1H), 1.93 (s, 1H), 1.77 - 1.65 (m, 1H), 1.56 (d, J =12.8 Hz, 1H).Synthesis of (S')-5-( l-(4-chlorobenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 51):Compound 51

[0209] The title compound was prepared according to Example 2 using l-(bromomethyl)-4- chlorobenzene as starting material. MS m / z (M+H+) 399.2, (400 MH1Hz N, DM SO-d6,, δ 9.77 (s, 1H), 7.73 - 7.66 (m, 2H), 7.66 - 7.50 (m, 4H), 7.00 - 6.94 (m, 2H), 4.40 - 4.34 (m, 2H), 3.74 (s, 3H), 3.65 - 3.42 (m, 2H), 3.13 - 3.01 (m, 2H), 2.90 (d, J = 11.3 Hz, 1H), 2.08 (d, J = 13.2 Hz, 1H), 1.94 (d, J = 15.9 Hz, 1H), 1.77 - 1.66 (m, 1H), 1.62 - 1.51 (m, 1H).Synthesis of (S)-5-( 1 -( benzo [d | 11.3 |dioxol-5-ylinethyl)piperidin-3-yl)-2-(4-niethoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 52):Compound 52

[0210] The title compound was prepared according to Example 2 using 5- (bromomethyl)benzo[t / ][l,3]dioxole as starting material. MS m / z (M+H+) 409.3,1H NMR (400 MHz, DMSO-d6 ) δ 9.60 (s, 1H), 7.70 (dd, J= 9.0, 6.5 Hz, 2H), 7.21 - 6.93 (m, 5H), 6.06 (s, 2H), 4.32 - 4.22 (m, 2H), 3.74 (s, 3H), 3.64 - 3.47 (m, 1H), 3.15 - 3.01 (m, 3H), 2.85 (dt, J = 24.1, 12.3 Hz, 1H), 2.08 (d, J= 13.3 Hz, 1H), 1.99 - 1.84 (m, 1H), 1.70 (dd, J= 27.0, 13.2 Hz, 1H), 1.58 (dd, J = 22.1, 11.0 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(4-(methylsulfonyl)benzyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 53):Compound 53

[0211] The title compound was prepared according to Example 2 using 4-(bromom ethyl)- 1- (methylsulfonyl)benzene as starting material. MS m / z (M+H+) 443.2, 1H NMR (400 MHz, DMSO-d6 ) δ 9.96 (s, 1H), 8.12 - 7.98 (m, 2H), 7.81 (dd, J= 27.0, 6.6 Hz, 2H), 7.69 (d, J= 9.1 Hz, 2H), 6.98 (d, J= 9.1 Hz, 2H), 4.52 (dd, J= 32.0, 9.5 Hz, 2H), 3.74 (s, 3H), 3.72 - 3.37 (m, 2H), 3.24 (s, 3H), 3.13 - 2.81 (m, 3H), 2.09 - 1.85 (m, 2H), 1.83 - 1.45 (m, 2H).Synthesis of (5)-5-(l-(4-fluoro-3-methylbenzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 54):Compound 54

[0212] The title compound was prepared according to Example 2 using 4-(bromom ethyl)- 1 - fluoro-2-methylbenzene as starting material. MS m / z' (M+H1) 397.2, 1H NMR (400 MHz, DMSO ,) δ 9.90 (s, 1H), 7.73 - 7.63 (m, 2H), 7.49 - 7.39 (m, 1H), 7.40 - 7.28 (m, 2H), 7.30 - 7.15 (m, 1H), 7.08 - 6.94 (m, 2H), 4.36 - 4.27 (m, 2H), 3.74 (s, 3H), 3.62 (d, J= 9.4 Hz, 1H), 3.07 (s, 2H), 2.90 (d, J= 11.8 Hz, 1H), 2.24 (s, 3H), 2.12 - 2.04 (m, 1H), 1.92 (t, J= 16.7 Hz, 1H), 1.78 - 1.66 (m, 1H), 1.55 (q, J = 11.8 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(4-methyl-3-(trifluoromethyl)benzyl)piperidin-3- yl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 55):Compound 55

[0213] The title compound was prepared according to Example 2 using 4-(bromom ethyl)- 1- methyl-2-(trifluoromethyl)benzene as starting material. MS m / z (M+H+) 447.3, (400 1H NMR MHz, DMSO-d6 ) δ 9.82 (s, 1H), 7.89 (d, J= 19.7 Hz, 1H), 7.79 - 7.62 (m, 3H), 7.58 (dd, J = 20.5, 8.3 Hz, 1H), 7.02 - 6.93 (m, 2H), 4.42 (t, J= 5.6 Hz, 2H), 3.74 (s, 3H), 3.65 - 3.25 (m, 2H), 3.19 - 2.82 (m, 3H), 2.52 (s, 3H), 2.07 (t, J= 11.4 Hz, 1H), 1.93 (t, J= 17.3 Hz, 1H), 1.77 - 1.65 (m, 1H), 1.55 (q, J = 12.1, 11.5 Hz, 1H).Synthesis of (5)-3-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)benzoic acid, TFA (Cpd 56):Compound 56

[0214] The title compound was prepared according to Example 2 using 3-(bromomethyl)benzoic acid as starting material. MS m z (M+H+) 409.2, 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.77 (s, 1H), 8.15 (s, 1H), 8.05 (dd, J= 21.1, 7.8 Hz, 1H), 7.78 (dd, .7= 28.8, 7.6 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.65 - 7.54 (m, 1H), 6.97 (dd, J= 9.1, 4.8 Hz, 2H), 4.48 (d, J= 18.4 Hz, 2H), 3.75(d, J= 7.8 Hz, 3H), 3.59 (dd, J= 39.5, 12.2 Hz, 1H), 3.18 - 2.84 (m, 4H), 2.09 (d, J= 12.5 Hz, 1H), 1.92 (t, J = 19.1 Hz, 1H), 1.71 (t, J= 15.8 Hz, 1H), 1.55 (q, J= 11.5, 10.5 Hz, 1H).Synthesis of (S)-5-(l-(4-(2H-tetrazol-5-yl)benzyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 57):Compound 57

[0215] The title compound was prepared according to Example 2 using 5-(4- (bromomethyl)phenyl)-2H-tetrazole as starting material. MS m / z (M+H+) 433.2, 1H NMR (400 MHz, DMSO4) δ 9.92 (s, 1H), 8.79 (s, 1H), 8.14 (d, J= 7.7 Hz, 2H), 7.74 (s, 2H), 7.71 - 7.64 (m, 2H), 7.02 - 6.94 (m, 2H), 4.39 (s, 2H), 3.74 (s, 3H), 3.69 - 3.48 (m, 2H), 3.14 - 2.85 (m, 3H), 2.11 - 2.01 (m, 1H), 1.98 - 1.87 (m, 1H), 1.84 - 1.68 (m, 1H), 1.63 - 1.53 (m, 1H).Synthesis of (5)-5-(l-(3,5-diinethylbenzyl)piperidin-3-yl)-2-(4-inethoxyphenyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one,Compound 58

[0216] The title compound was prepared according to Example 2 using l-(bromomethyl)-3,5- dimethylbenzene as starting material. MS m / z (M+H+) 393.3,1H NMR (400 MHz, DMSO-d6,, δ 10.00 (s, 1H), 7.73 - 7.65 (m, 2H), 7.18 - 7.06 (m, 3H), 7.02 - 6.94 (m, 2H), 4.28 - 4.24 (m, 2H), 3.74 (s, 3H), 3.63 (d, J = 9.6 Hz, 1H), 3.38 (s, 1H), 3.12 - 3.02 (m, 2H), 2.90 (d, J = 11.6 Hz, 1H), 2.28 (s, 6H), 2.09 (d, J= 13.1 Hz, 1H), 1.91 (t, 16.2 Hz, 1H), 1.72 (dd, J= 26.9,13.2 Hz, 1H), 1.56 (td, J= 12.5, 3.6 Hz, 1H).Synthesis of (tV)-4-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)-7V,2V-dimethylbenzenesulfonamide, TFA (Cpd 59):Compound 59

[0217] The title compound was prepared according to Example 2 using 4-(bromomethyl)-N, / V- dimethylbenzenesulfonamide as starting material. MS m / z (M+H+) 472.2, 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.87 (d, J= 13.2 Hz, 2H), 7.80 - 7.74 (m, 2H), 7.73 - 7.65 (m, 2H), 7.00 - 6.94 (m, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.71 - 3.36 (m, 2H), 3.23 - 2.88 (m, 3H), 2.61 (s, 6H), 2.08 (s, 1H), 1.91 (d, J= 16.3 Hz, 1H), 1.78 - 1.67 (m, 1H), 1.56 (q, J= 12.6 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-3- yl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 60):Compound 60

[0218] The title compound was prepared according to Example 2 using 4-(2- bromoethyl)tetrahydro-2H-pyran as starting material. MS m / z (M+H+) 387.3, 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.74 - 7.66 (m, 2H), 7.03 - 6.94 (m, 2H), 3.86 - 3.78 (m, 2H), 3.74 (s, 3H), 3.51 (d, J= 12.1 Hz, 1H), 3.25 (td, J= 11.5, 1.9 Hz, 2H), 3.19 - 3.10 (m, 3H), 3.07 (ddt, J= 12.0, 9.4, 3.6 Hz, 2H), 2.88 (q, J= H.6 Hz, 1H), 2.10 (d, J= 12.9 Hz, 1H), 1.95 (d, J = 14.3 Hz, 1H), 1.74 (d, J= 13.6 Hz, 1H), 1.65 - 1.47 (m, 5H), 1.25 - 1. l l (m, 3H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(2-morpholinoethyl)piperidin-3-yl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (Cpd 61):Compound 61

[0219] The title compound was prepared according to Example 2 using 4-(2- bromoethyl)morpholine, HC1 as starting material. MS m / z (M+H1) 388.3,1H NMR (400 MHz, DMSCM,) 8 11.75 (s, 1H), 7.76 - 7.67 (m, 2H), 7.00 - 6.92 (m, 2H), 3.73 (s, 3H), 3.57 (td, J= 4.7, 2.4 Hz, 4H), 2.88 - 2.78 (m, 1H), 2.78 - 2.71 (m, 1H), 2.70 - 2.57 (m, 1H), 2.44 - 2.31 (m, 9H), 2.16 - 2.08 (m, 1H), 1.88 - 1.81 (m, 1H), 1.67 - 1.59 (m, 1H), 1.51 (q, J= 9.8, 7.9 Hz, 2H).Synthesis of (5)-2V-(4-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)phenyl)acetamide, TEA (Cpd 63):Compound 63

[0220] The title compound was prepared according to Example 2 using A-(4- (bromomethyl)phenyl)acetamide as starting material. MS m / z (M+H+) 422.3, 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.72 - 7.63 (m, 4H), 7.43 (d, J = 8.2 Hz, 2H), 7.02 - 6.95 (m, 2H), 4.30 (s, 2H), 3.76 (s, 3H), 3.61 (d, J= 7.2 Hz, 1H), 3.39 (s, 4H), 2.94 - 2.85 (m, 1H), 2.05 (s, 3H), 1.93 (t, J= 18.3 Hz, 2H), 1.75 (d, J= 13.9 Hz, 1H), 1.56 (d, J= 12.2 Hz, 1H).Synthesis of (5)-5-(l-((5-fluoropyridin-3-yl)methyl)piperidin-3-yl)-2-(4-methoxyphenyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 64):Compound 64

[0221] The title compound was prepared according to Example 2 using 3-(bromomethyl)-5- fluoropyridine as starting material. MS m / z (M+Hl) 384.2, 1H NMR (400 MHz, DMSO-d6 ) δ 9.96 (s, 1H), 8.81 - 8.49 (m, 2H), 8.04 - 7.87 (m, 1H), 7.74 - 7.67 (m, 2H), 7.04 - 6.93 (m, 2H), 4.51 - 4.40 (m, 2H), 3.76 (s, 3H), 3.62 (s, 1H), 3.16 - 2.87 (m, 4H), 2.16 - 1.87 (m, 2H), 1.74 (s, 1H), 1.58 (d, J= 12.8 Hz, 1H).Synthesis of methyl (5)-4-(2-(3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-1,2,4-triazol-3- yl)piperidin-l-yl)ethyl)benzoate, TFA (Cpd 65):Compound 65

[0222] The title compound was prepared according to Example 2 using methyl 4-(2- bromoethyl)benzoate as starting material. MS m / z (M+Hl) 437.2, (400 MH1Hz, D NMMRSO- d6) 6 9.73 (s, 1H), 7.95 (d, J= 8.2 Hz, 2H), 7.76 - 7.68 (m, 2H), 7.47 (d, J= 7.9 Hz, 2H), 7.05 - 6.95 (m, 2H), 3.91 - 3.84 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.62 (d, J= 11.2 Hz, 1H), 3.49 - 3.39 (m, 2H), 3.20 - 3.08 (m, 4H), 2.97 (d, J= 10.8 Hz, 1H), 2.14 (d, J= 12.8 Hz, 1H), 2.01 (d, J = 14.7 Hz, 1H), 1.79 (d, J= 13.7 Hz, 1H), 1.59 (q, J= 12.6 Hz, 1H).Synthesis of (5)-5-(l-(4-methoxyphenethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TEA (Cpd 66):Compound 66

[0223] The title compound was prepared according to Example 2 using l-(2-bromoethyl)-4- methoxybenzene as starting material. MS m / z (M+H+) 409.3, 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.73 (dd, J= 8.9, 2.0 Hz, 2H), 7.26 - 7.18 (m, 2H), 7.05 - 6.96 (m, 2H), 6.95 - 6.88 (m, 2H), 3.89 - 3.81 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.67 - 3.55 (m, 2H), 3.12 (t, J = 10.9 Hz, 1H), 2.95 (dt, J= 22.3, 7.7 Hz, 4H), 2.14 (d, J= 12.7 Hz, 1H), 2.00 (d, J= 14.8 Hz, 1H), 1.79 (d, J= 13.7 Hz, 1H), 1.65 - 1.53 (m, 1H).Synthesis of (1S)-2-(4-methoxyphenyl)-5-(l-((5-methylpyridin-3-yl)methyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 67):

[0224] The title compound was prepared according to Example 2 using 3-(bromomethyl)-5- methylpyridine as starting material. MS m / z (M+H+) 380.2, 1H NMR (400 MHz, DMSO-tA) 8 9.86 (s, 1H), 8.60 - 8.49 (m, 2H), 7.86 - 7.62 (m, 3H), 7.04 - 6.94 (m, 2H), 4.39 (s, 2H), 3.76 (s, 3H), 3.69 - 3.63 (m, 1H), 3.20 - 3.02 (m, 3H), 2.94 (s, 1H), 2.35 (s, 3H), 2.12 - 2.06 (m, 1H), 1.96 - 1.90 (m, 1H), 1.75 - 1.67 (m, 1H), 1.64 - 1.54 (m, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(4-(trifluoromethyl)phenethyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 68):Compound 68

[0225] The title compound was prepared according to Example 2 using l-(2-bromoethyl)-4- (trifluoromethyl)benzene as starting material. MS m / z (M+H+) 447.2, (400 MHz1,H NMR DMSO-d6,) δ 9.70 (s, 1H), 7.83 - 7.66 (m, 4H), 7.55 (d, J= 8.0 Hz, 2H), 7.06 - 6.96 (m, 2H), 3.87 (d, J= 11.6 Hz, 1H), 3.76 (s, 3H), 3.62 (d, J= 1 1.7 Hz, 1H), 3.44 (ddd, J= 12.0, 8.1 , 4.1 Hz, 3H), 3.24 - 3.06 (m, 3H), 2.98 (d, 11.7 Hz, 1H), 2.14 (d, J = 12.7 Hz, 1H), 2.01 (d,14.7 Hz, 1H), 1.80 (d, J= 13.8 Hz, 1H), 1.62 (t, J= 12.0 Hz, 1H).Synthesis of (S')-5-( l-(2,4-dichlorophenethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 69):Compound 69

[0226] The title compound was prepared according to Example 2 using l-(2-bromoethyl)-2,4- dichlorobenzene as starting material. MS m / z (M+H1) 447.2, (400 M1HHz N, DMMRSO-d6,) δ 9.78 (s, 1H), 7.77 - 7.68 (m, 2H), 7.67 (s, 1H), 7.47 (s, 2H), 7.06 - 6.96 (m, 2H), 3.88 (d, J = 11.5 Hz, 1H), 3.76 (s, 3H), 3.69 - 3.60 (m, 1H), 3.13 (dt, J= 15.4, 7.2 Hz, 6H), 3.00 (d, J= 11.8 Hz, 1H), 2.14 (d, J= 12.6 Hz, 1H), 2.01 (d, J = 14.2 Hz, 1H), 1.81 (dd, J= 15.5, 8.7 Hz, 1H), 1.62 (t, J= 11.3 Hz, 1H).Synthesis of (5)-2-(4-bromophenyl)-5-(l-(cyclohexylmethyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 70):Compound 70

[0227] The title compound was prepared according to Example 1 using (4- bromophenyl)hydrazine hydrochloride in Step 1 and according to Example 2 using (bromomethyl)cyclohexane as starting material. MS m / z (M+H+) 419.0 / 421.0, 1H NMR (400 MHz, methanol-d4) δ 7.88 - 7.80 (m, 2H), 7.59 - 7.51 (m, 2H), 3.05 (dd, J= 11.5, 3.7 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.23 (d, J= 7.0 Hz, 3H), 2.15 - 2.05 (m, 1H), 2.01 (dd, J= 12.8, 4.1 Hz, 1H), 1.89 - 1.47 (m, 8H), 1.38 - 1.11 (m, 4H), 1.00 - 0.84 (m, 2H).Synthesis of (S)-2-(4-bromophenyl)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Compound 71

[0228] The title compound was prepared according to Example 1 using (4- bromophenyl)hydrazine hydrochloride in Step 1 and according to Example 2 using (2- bromoethyl)cyclohexane as starting material. MS m / z (M+H+) 433.0 / 435.0, 1HNMR (400 MHz, methanol-d4 ) δ 7.88 - 7.80 (m, 2H), 7.59 - 7.51 (m, 2H), 3.15 (dd, J= 11.3, 3.5 Hz, 1H), 2.94 (d,J= 11.7 Hz, 1H), 2.87 (tt, J= 10.5, 3.7 Hz, 1H), 2.53 - 2.44 (m, 2H), 2.29 (t, J= 11.0 Hz, 1H), 2.18 - 2.08 (m, 1H), 2.08 - 2.00 (m, 1H), 1.84 (dt, J= 13.3, 3.6 Hz, 1H), 1.79 - 1.52 (m, 7H), 1.50 - 1.40 (m, 2H), 1.35 - 1.11 (m, 4H), 1.03 - 0.89 (m, 2H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(2-(pyridin-2-yl)ethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 77):Compound 77

[0229] The title compound was prepared according to Example 2 using 2-(2- bromoethyl)pyridine as starting material. MS m z ' (M+H1) 380.3, 1H NMR (400 MHz, DMSO- 6 / 6) 8 9.87 (s, 1H), 8.52 (ddd, J= 5.0, 1.8, 0.9 Hz, 1H), 7.82 (td, J= 7.7, 1.8 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.40 (dt, J= 7.9, 1.1 Hz, 1H), 7.32 (ddd, J= 7.6, 4.9, 1.2 Hz, 1H), 7.03 - 6.94 (m, 2H), 3.74 (m, 4H), 3.62 - 3.48 (m, 3H), 3.37 - 3.14 (m, 3H), 3.15 (s, 1H), 3.07 (td, J= 10.2, 2.7 Hz, 1H), 2.09 (dd, J= 13.4, 4.0 Hz, 1H), 1.95 (dt, J= 11.9, 3.8 Hz, 1H), 1.81 (tdd, J= 14.3, 9.2, 3.3 Hz, 1H), 1.68 (q, J= 11.4, 10.6 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(2-(pyridin-3-yl)ethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 78):Compound 78

[0230] The title compound was prepared according to Example 2 using 3-(2-bromoethyl)pyridine as starting material. MS m / z (M+H+) 380.3, 1H NMR (400 MHz, DMSO-d6 ) δ 9.74 (s, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.54 (dt, J = 4.6, 2.3 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.49 (dd, J = 7.7, 5.2 Hz, 1H), 7.05 - 6.95 (m, 2H), 3.86 (d, J= 11.8 Hz, 2H), 3.75 (s, 3H), 3.60 (d, J= 12.3 Hz, 1H), 3.49 - 3.37 (m, 3H), 3.20 - 2.88 (m, 3H), 2.13 (d, J= 12.9 Hz, 1H), 2.00 (d, J= 14.4 Hz, 1H), 1.78 (d, J= 14.0 Hz, 1H), 1.61 (dd, J= 13.6, 10.3 Hz, 1H).Synthesis of (A)-2-(4-methoxyphenyl)-5-(l-(2-(pyridin-4-yl)ethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 79):Compound 79

[0231] The title compound was prepared according to Example 2 using 4-(2- bromoethyl)pyridine as starting material. MS m z (M+H+) 380.3, 1H NMR (400 MHz, DMSO- d6 ) δ 9.80 (s, 1H), 8.63 (d, J= 5.3 Hz, 2H), 7.81 - 7.66 (m, 2H), 7.51 (d, J= 5.3 Hz, 2H), 7.05 - 6.95 (m, 2H), 3.84 (d, J= 11.4 Hz, 1H), 3.75 (s, 3H), 3.64 - 3.54 (m, 1H), 3.51 - 3.39 (m, 3H), 3.13 (dt, J= 20.2, 9.6 Hz, 3H), 3.00 - 2.92 (m, 1H), 2.13 (d, J= 12.8 Hz, 1H), 1.99 (d, J= 14.6 Hz, 1H), 1.78 (q, J= 14.0, 13.5 Hz, 1H), 1.59 (q, J= 12.1, 11.7 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-((5-methoxypyridin-3-yl)methyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 81):Compound 81

[0232] The title compound was prepared according to Example 2 using 3-(bromomethyl)-5- methoxypyridine as starting material. MS m z (M+H+) 396.3, 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.47 - 8.13 (m, 2H), 7.82 - 7.45 (m, 3H), 6.98 (dq, J= 8.5, 3.0, 2.3 Hz, 2H), 4.44 - 4.36 (m, 2H), 3.89 - 3.55 (m, 8H), 3.49 - 3.38 (m, 1H), 3.22 - 3.00 (m, 1H), 2.97 - 2.89 (m, 1H), 2.09 (d, J= 12.9 Hz, 1H), 1.94 (t, J= 18.2 Hz, 1H), 1.75 (d, J= 14.8 Hz, 1H), 1.57 (q, J = 11.3 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-((4-methoxypyridin-2-yl)methyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 82):Compound 82

[0233] The title compound was prepared according to Example 2 using 2-(bromomethyl)-4- methoxypyridine as starting material. MS m / z (M+H1) 396.3, 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.51 (d, J= 5.9 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.18 (d, J = 2.5 Hz, 1H), 7.10 (dd, J= 5.9, 2.5 Hz, 1H), 7.02 - 6.94 (m, 2H), 4.41 (d, J= 3.1 Hz, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.59 (d, J= 10.6 Hz, 1H), 3.30 - 3.17 (m, 2H), 3.14 - 2.96 (m, 2H), 2.06 (d, J= 12.3 Hz, 1H), 1.86 (ttd, J= 14.5, 8.1, 7.2, 4.5 Hz, 2H), 1.64 (d, J= 10.8 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(3-phenylpropyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one, TFA (Cpd 83):Compound 83

[0234] The title compound was prepared according to Example 2 using (3-bromopropyl)benzene as starting material. MS m / z (M+H+) 393.3, (401H0 M NMHzR, DMSO-d6) δ 9.43 (s, 1H), 7.73- 7.66 (m, 2H), 7.36 - 7. 16 (m, 5H), 7.03 - 6.96 (m, 2H), 3.74 (s, 3H), 3.52 (d, J= 12. 1 Hz, 1H), 3.38 (s, 2H), 3.08 (dddd, J= 20.9, 18.5, 9.3, 4.9 Hz, 4H), 2.90 (q, J= 11.4 Hz, 1H), 2.63 (t, J = 7.7 Hz, 2H), 2.10 (d, J= 13.1 Hz, 1H), 2.05 - 1.88 (m, 2H), 1.74 (q, J= 14.3, 13.6 Hz, 1H), 1.62- 1.49 (m, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-(2-(pyrimidin-5-yl)ethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 95):Compound 95

[0235] The title compound was prepared according to Example 2 using 5-(2- bromoethyl)pyrimidine as starting material. MS m / z (M+H+) 381.2, 1H NMR (400 MHz, DMSO- d6) δ 9.70 (s, 1H), 9.10 (s, 1H), 8.78 (s, 2H), 7.76 - 7.68 (m, 2H), 7.03 - 6.95 (m, 2H), 3.85 (d, J = 11.5 Hz, 1H), 3.75 (s, 3H), 3.59 (d, J= 11.1 Hz, 1H), 3.13 - 3.05 (m, 6H), 3.00 - 2.93 (m, 1H),2.13 (d, J= 12.8 Hz, 1H), 2.00 (d, J= 14.0 Hz, 1H), 1.78 (d, J= 13.1 Hz, 1H), 1.60 (q, J= 12.2 Hz, 1H).Synthesis of (5)-2-(4-methoxyphenyl)-5-(l-((4-methylpyridin-2-yl)methyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 96):

[0236] The title compound was prepared according to Example 2 using 2-(bromomethyl)-4- methylpyridine as starting material. MS m / z (M+H+) 380.2, 1H NMR (400 MHz, DMSO-fifc) δ 10.05 (s, 1H), 8.54 (d, J= 5.0 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.37 (s, 1H), 7.33 (d, J= 5.1 Hz, 1H), 7.03 - 6.94 (m, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.62 (dd, J= 9.1, 3.6 Hz, 1H), 3.21 (dd, J = 13.4, 4.2 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.36 (s, 3H), 2.07 (d, J= 12.7 Hz, 1H), 1.98 - 1.74 (m, 4H), 1.65 (d, J= 12.1 Hz, 1H).Synthesis of (5)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 97):Compound 97

[0237] The title compound was prepared according to Example 1 using 5- hydrazinylisoquinoline in Step 1 and according to Example 2 using (2-bromoethyl)cyclohexane as starting materials. MS m z (M+H+) 406.3, 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.39 (d, J= 1.1 Hz, 1H), 8.53 (d, .7 = 6.0 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.83 (dd, J= 7.4, 1.3 Hz, 1H), 7.79 - 7.71 (m, 2H), 3.01 (d, J= 11.2 Hz, 1H), 2.75 (dt, J= 16.3, 8.1 Hz, 3H), 2.30 (t, J = 7.5 Hz, 2H), 2.12 (t, J= 10.5 Hz, 1H), 1.95 (tt, J= 8.3, 3.3 Hz, 3H), 1.73 - 1.46 (m, 7H), 1.32 (q, J= 7.2, 6.6 Hz, 2H), 1.28 - 1.05 (m, 3H), 0.93 - 0.80 (m, 2H).Synthesis of (tV)-2-(isoquinolin-5-yl)-5-(l-(2-(pyridin-2-yl)ethyl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one,Compound 133

[0238] The title compound was prepared according to Example 1 using 5- hydrazinylisoquinoline in Step 1 and according to Example 2 using 2-(2-bromoethyl)pyridine as starting materials. MS m / z (M+H+) 401.2, 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.47 (s, 1H), 8.55 (d, J= 6.1 Hz, 1H), 8.48 - 8.42 (m, 1H), 8.25 (d, J= 8.1 Hz, 1H), 7.90 (dd, J= 7.5,I.2 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.76 (td, J= 7.7, 1.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.25 (dd, J= 7.5, 4.9 Hz, 1H), 3.82 (d, J= 11.8 Hz, 1H), 3.55 (tt, J= 8.4, 4.7 Hz, 3H), 3.35 (t, J =I I.5 Hz, 1H), 3.22 (dd, J= 9.8, 5.9 Hz, 3H), 3.14 - 3.04 (m, 1H), 2.19 - 2.11 (m, 1H), 1.98 (d, J = 14.5 Hz, 1H), 1.90 - 1.79 (m, 1H), 1.79 - 1.70 (m, 1H).Synthesis of (A)-5-(l-(2-(4,6-dichloropyridin-3-yl)ethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 135):Compound 135

[0239] The title compound was prepared according to Example 1 using 5- hydrazinylisoquinoline in Step 1 and according to Example 2 using 5-(2-bromoethyl)-2,4- dichloropyridine as starting materials. MS m / z (M+H+) 469.1, (400 MH1Hz N, DMMRSO-d6 )8 12.20 (s, 1H), 9.80 (s, 1H), 9.46 (s, 1H), 8.56 (d, J = 6.1 Hz, 1H), 8.45 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.88 (dd, J= 7.5, 1.2 Hz, 1H), 7.86 - 7.76 (m, 2H), 3.92 (d, J= 10.9 Hz, 1H), 3.64 (d, J = 11.8 Hz, 1H), 3.36 (t, J= 7.3 Hz, 3H), 3.17 (td, J= 7.2, 3.3 Hz, 3H), 3.04 - 2.95 (m, 1H), 2.20 (d, J = 12.9 Hz, 1H), 2.03 (d, J= 14.2 Hz, 1H), 1.81 (q, J = 13.7 Hz, 1H), 1.73 - 1.59 (m, 1H).Synthesis of (tV)-5-(l-(2-(4-chloropyridin-2-yl)ethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 141):Compound 141

[0240] The title compound was prepared according to Example 1 using 5- hydrazinylisoquinoline in Step 1 and according to Example 2 using 2-(2-bromoethyl)-4- chloropyridine as starting materials. MS m / z (M+H+) 435.2.Synthesis of 5-(l-(2-cyclohexylethyl)-5,5-difluoropiperidin-3-yl)-2-(isoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 147):Compound 147

[0241] The title compound was prepared according to Example 1 using 1 -(tert-butoxycarbonyl)- 5,5-difluoropiperidine-3-carboxylic acid and 5-hydrazinylisoquinoline in Step 1 and according to Example 2 using (2-bromoethyl)cyclohexane as starting materials. MS m / z (M+Hl) 442.3,1H NMR (400 MHz, DMSO-r76) 8 9.45 (d, J= 1.0 Hz, 1H), 9.23 (s, 1H), 8.56 (dd, J= 6.1, 2.4 Hz, 1H), 8.25 (dt, J= 8.2, 1.1 Hz, 1H), 7.88 (dd, J= 7.4, 1.3 Hz, 1H), 7.86 - 7.75 (m, 2H), 3.83 - 3.60 (m, 2H), 3.58 (d, J= 12.1 Hz, 1H), 3.41 (t, J= 12.2 Hz, 1H), 3.20 (t, J= 12.2 Hz, 1H), 1.78 (td, J = 14.2, 13.6, 3.4 Hz, 3H), 1.72 - 1.54 (m, 8H), 1.40 - 1.05 (m, 4H), 1.05 - 0.83 (m, 2H).Example 2a

[0242] The process below describes the synthesis of an exemplary compound.

[0243] To a solution of methyl (S)-2-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl)piperidin-l-yl)methyl)isonicotinate (35 mg, 0.083 mmol, prepared according to Example 2 using methyl 2-(bromomethyl)isonicotinate as starting material) in THF (0.8 ml) was added LiOH (0.5M, 331 μl, 0.165 mmol). The mixture was stirred at r.t. for 4 hr. The solvent was evaporated under vacuum. The crude product was submitted for purification to give (S)-2- ((3 -( 1 -(4-methoxypheny l)-5 -oxo-4, 5 -dihydro- 1 H- 1 , 2,4-triazol -3 -y 1 )pi p eri di n - 1 - yl)methyl)isonicotinic acid, TFA (Compound 105). MS m'z (M+H+) 410.2. (400 MH1Hz, NMR DMSO-d6 ) δ 13.91 (s, 1H), 10.16 (s, 1H), 8.87 (d, J= 5.0 Hz, 1H), 8.03 (s, 1H), 7.90 (d, J= 5.0 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.02 - 6.93 (m, 2H), 4.59 (s, 2H), 3.74 (s, 3H), 3.68 - 3.59 (m, 1H), 3.23 - 3.14 (m, 4H), 2.10 - 2.04 (m, 1H), 1.90 - 1.80 (m, 2H), 1.67 - 1.58 (m, 1H).Example 2b

[0244] The process below describes the synthesis of an exemplary compound.

[0245] Methyl (5)-2-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)methyl)isonicotinate (140 mg, 0.331 mmol) was dissolved in 7N ammonia (3 ml, 21.00 mmol) in methanol. The solution was stirred in a sealed vial at 60 °C for overnight. After the reaction was completed, the solvent was removed. The crude product was purified by ISCO (0-20%, MeOH / DCM) to give (S)-2-((3-(l-(4-methoxyphenyl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-3-yl)piperidin-l-yl)methyl)isonicotinamide (Compound 121). MS m / z (M+H+) 409.3. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.60 (dd, J= 5.1, 0.8 Hz, 1H), 8.21 (s, 1H), 7.83 - 7.77 (m, 1H), 7.69 (dd, J= 8.7, 6.6 Hz, 3H), 7.63 (dd, J= 5.1, 1.6 Hz, 1H), 7.00 - 6.91 (m, 2H), 3.73 (d, J= 0.6 Hz, 3H), 3.68 (s, 2H), 3.02 - 2.94 (m, 1H), 2.78 (td, J= 10.5, 5.4 Hz, 2H), 2.26 (t, J= 10.7 Hz, 1H), 2.15 - 2.05 (m, 1H), 1.94 (dd, J= 12.8, 4.1 Hz, 1H), 1.70 (dd, J= 13.0, 3.1 Hz, 1H), 1.64 - 1.39 (m, 2H).Example 3

[0246] The process below describes the synthesis of an exemplary compound.

[0247] To a solution of (S)-2-(4-methoxyphenyl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (50 mg, 0.182 mmol) in DCM (2 ml) were added DIPEA (0.127 ml, 0.729 mmol) and cyclohexanesulfonyl chloride (0.031 ml, 0.219 mmol). The mixture was stirred at r.t. for 3 hr. The reaction was quenched with water, and extracted with EtOAc (3x). The combined organic layer was dried and concentrated. The crude product was purified by ISCO ( 0-80%, EtOAc / hexane) to obtain (S)-5-(l-(cyclohexylsulfonyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 27). MS m / z (M+H+) 421.2, 1H NMR (400 MHz, chloroform-d) δ 11.97 (s, 1H), 7.84 - 7.75 (m, 2H), 7.00 - 6.91 (m, 2H), 4.05 (dd, J= 12.8, 3.9 Hz, 1H), 3.82 (s, 3H), 3.75 (d, J= 12.3 Hz, 1H), 3.18 (dd, J= 12.7, 10.0 Hz, 1H), 2.95 (dddd, J = 19.1, 15.5, 11.4, 3.3 Hz, 2H), 2.20 (dt, J= 8.4, 4.2 Hz, 1H), 2.14 - 2.06 (m, 2H), 1.89 - 1.78 (m, 4H), 1.79 - 1.62 (m, 3H), 1.58 - 1.40 (m, 2H), 1.31 - 1.15 (m, 3H).Example 4

[0248] The process below describes the synthesis of an exemplary compound.

[0249] A mixture of (5)-2-(4-bromophenyl)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (50 mg, 0.115 mmol, prepared according to Example 1 using (4- bromophenyl)hydrazine*HCl in Step 1 and according to Example 2 using (2- bromoethyl)cyclohexane as starting materials) and copper(I) iodide (21 .97 mg, 0.115 mmol) in 2-(pyrrolidin-l-yl)ethanol (1 ml, 8.50 mmol) was stirred at 160 °C for 2 days. EtOAc was added to the mixture, washed with water. The organic layer was dried over MgSO4 and concentrated. The crude product was purifed by ISCO (0-20%, MeOH / DCM) to obtain (S )-5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2-(4-(2-(pyrrolidin- 1 -yl)ethoxy)phenyl)-2,4-dihydro-3H- 1 ,2,4- triazol-3-one (Compound 75). MS m / z (M+H+) 468.2, 1H NMR (400 MHz, methanol-^) 8 7.77 -7.66 (m, 2H), 7.04 - 6.96 (m, 2H), 4.15 (t, J= 5.6 Hz, 2H), 3.21 - 3.09 (m, 1H), 2.94 (t, J= 5.6 Hz, 2H), 2.89 - 2.80 (m, 1H), 2.75 - 2.65 (m, 5H), 2.50 - 2.42 (m, 2H), 2.23 (t, J= 11.1 Hz, 1H), 2.14 - 1.98 (m, 3H), 1.84 (h, J= 4.0, 3.6 Hz, 6H), 1.77 - 1.52 (m, 7H), 1.49 - 1.39 (m, 2H), 1.34 - 1.12 (m, 4H), 1.03 - 0.88 (m, 2H).Synthesis of (*S)-5-(l-(cyclohexylmethyI)piperidin-3-yl)-2-(4-(2-(pyrroIidin-l- yl)ethoxy)phenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 76):

[0250] The title compound was prepared according to Example 1 using (4- bromophenyl)hydrazine*HCl in Step 1 , according to Example 2 using (bromomethyl)cyclohexane, and according to Example 4. MS m / z (M+H+) 454.2,1H NMR (400MHz, methanol -d 4) δ 7.83 - 7.61 (m, 2H), 7.12 - 6.90 (m, 2H), 4.15 (t, J = 5.6 Hz, 2H), 3.05 (d, J= 11.4 Hz, 1H), 2.95 (t, J= 5.6 Hz, 2H), 2.92 - 2.80 (m, 2H), 2.81 - 2.64 (m, 5H), 2.21 (d, J = 7.0 Hz, 3H), 2.13 - 1.95 (m, 3H), 1.92 - 1.64 (m, 10H), 1.58 (tt, J= 10.8, 3.5 Hz, 1H), 1.37 - 1.11 (m, 4H), 0.91 (q, J= 12.1 Hz, 2H).Example 5

[0251] The process below describes the synthesis of an exemplary compound.

[0252] Step 1: To a solution of 5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one hydrochloride (0.1 g, 0.489 mmol) in DMF (5 ml) were added potassium carbonate (0.338 g,2.443 mmol) and (2-bromoethyl)cyclohexane (0.084 ml, 0.537 mmol). The reaction mixture was stirred at r.t. for 30 min. Water was added to the mixture, and extracted with EtOAc. The organic layer was washed with NaHCO3 (3x), dried over MgSCU and concentrated. The crude 5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one was used in the next step without further purification. MS m / z (M+H+) 279.1.

[0253] Step 2: To a suspension of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (50 mg, 0.180 mmol), copper(I) iodide (6.84 mg, 0.036 mmol) and potassium carbonate (124 mg, 0.898 mmol) in DMF (2 ml) under N2 was added l-iodo-3 -methoxybenzene (42.8 μl, 0.359 mmol) followed by (17?,27?)-A,A’-dimethyl-cyclohexane-l,2-diamine (11.33 pl, 0.072 mmol). The reaction mixture was stirred at 100 °C over the weekend. The reaction mixture was cooled to r.t., quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with sat. NaHCO3, dried over MgSO4 and concentrated. The crude product was submitted for purification to obtain 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(3- methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Compound 85). MS m / z (M+H+) 385.3, 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.55 - 7.42 (m, 2H), 7.34 (t, J= 8.1 Hz, 1H), 6.79 (ddd, J= 8.3, 2.5, 1.0 Hz, 1H), 3.77 (s, 3H), 3.53 (d, J= 12.1 Hz, 1H), 3.23 - 3.12 (m, 3H), 3.07 (q, J= 11.4, 10.3 Hz, 2H), 2.89 (q, J= 11.6 Hz, 1H), 2.13 (d, J= 13.3 Hz, 1H), 1.97 (d, J= 14.3 Hz, 1H), 1.80 - 1.64 (m, 7H), 1.65 - 1.54 (m, 3H), 1.33 - 1.09 (m, 3H), 1.04 - 0.86 (m, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 86):Compound 86

[0254] The title compound was prepared according to Example 5 using 5-iodoisoquinoline in Step 2 as starting material. MS m / z (M+H+) 406.3,(400 MHz, DMSO-c / 6) 6 11.90 (s, 1H), 9.41 (d, J= 1.0 Hz, 1H), 8.54 (d, J= 6.0 Hz, 1H), 8.19 (dt, .7 = 8.1, 1.1 Hz, 1H), 7.85 (dd, J = 7.5, 1.3 Hz, 1H), 7.81 - 7.73 (m, 2H), 3.02 (q, J= 14.1, 11.5 Hz, 1H), 2.87 - 2.69 (m, 2H),2.44 - 2.23 (m, 3H), 2.15 (ddd, J= 17.7, 10.5, 4.8 Hz, 1H), 1.97 (dt, J= 15.7, 6.9 Hz, 2H), 1.80- 1.45 (m, 8H), 1.41 - 1.30 (m, 2H), 1.30 - 1.04 (m, 3H), 0.88 (q, J= 10.9, 10.2 Hz, 2H).Synthesis of (5)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 97):Compound 97

[0255] The title compound was prepared according to Example 5 using 5-iodoisoquinoline in Step 2 as starting material, followed by chiral separation. MS m / z (M+H+) 406.3, 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 9.40 (s, 1H), 8.53 (d, J= 5.9 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.84 (dd, J= 7.5, 1 .3 Hz, 1H), 7.80 - 7.72 (m, 2H), 2.89 (q, J= 7.3 Hz, 2H), 2.06 - 1 .99 (m, 1H), 1.81 (d, J= 8.4 Hz, 1H), 1.62 (q, .7 = 14.7, 13.8 Hz, 7H), 1.46 - 1.40 (m, 2H), 1.30 - 1.20 (m, 3H), 1.21 - 1.04 (m, 6H), 0.94 - 0.79 (m, 2H).Synthesis of (lf)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (98):Compound 98

[0256] The title compound was prepared according to Example 5 using 5-iodoisoquinoline in Step 2 as starting material, followed by chiral separation. MS m / z (M+H+) 406.3, 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 9.40 (s, 1H), 8.53 (d, J= 6.0 Hz, 1H), 8.18 (d, J= 8.2 Hz, 1H), 7.84 (dd, J= 7.5, 1.3 Hz, 1H), 7.80 - 7.72 (m, 2H), 2.89 (q, J= 7.3 Hz, 2H), 2.04 - 1.97 (m, 1H), 1.82 - 1.72 (m, 1H), 1.70 - 1.49 (m, 7H), 1.48 - 1.35 (m, 1H), 1.31 - 1.19 (m, 2H), 1.23 - 1.01 (m, 7H), 0.94 - 0.75 (m, 3H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(naphthalen-l-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 106):Compound 106

[0257] The title compound was prepared according to Example 5 using 1 -iodonaphthalene in Step 2 as starting material. MS mz' (M+H+) 405.2.Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-phenyl-2,4-dihydro-3H-l,2,4-triazol- 3-one (Cpd 107):Compound 107

[0258] The title compound was prepared according to Example 5 using iodobenzene in Step 2 as starting material. MS m / z (M+H+) 355.2,1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.88 - 7.81 (m, 2H), 7.44 - 7.36 (m, 2H), 7.20 - 7.12 (m, 1H), 2.99 - 2.93 (m, 1H), 2.74 - 2.69 (m, 2H), 2.33 - 2.27 (m, 2H), 2.11 - 2.06 (m, 1H), 1.94 - 1.89 (m, 2H), 1.70 - 1.53 (m, 7H), 1.49 (s, 2H), 1.32 (d, J= 7 A Hz, 2H), 1.26 - 1.05 (m, 3H), 0.93 - 0.80 (m, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(2,3-dihydrobenzo[6][l,4]dioxin-6-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 108):Compound 108

[0259] The title compound was prepared according to Example 5 using 6-iodo-2,3- dihydrobenzo[b ][l,4]dioxine in Step 2 as starting material. MS m / z (M+H1) 413.3, 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.35 (d, J= 2.5 Hz, 1H), 7.26 (dd, J= 8.8, 2.5 Hz, 1H), 6.87(d, J= 8.8 Hz, 1H), 4.22 (tt, J= 5.1, 2.9 Hz, 4H), 2.95 (d, J= 9.7 Hz, 1H), 2.69 (ddt, J= 14.3, 7.0, 3.0 Hz, 2H), 2.28 (t, J= 7.8 Hz, 2H), 2.05 (t, J= 10.5 Hz, 1H), 1.96 - 1.85 (m, 2H), 1.74 - 1.54 (m, 7H), 1.46 (q, J= 10.5 Hz, 2H), 1.30 (p, J= 6.7 Hz, 2H), 1.26 - 1.05 (m, 3H), 0.85 (d, J = 11.2 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-4-yl)-2-(isoquinolin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 110):Compound 110

[0260] The title compound was prepared according to Example 5 using 5-(piperidin-4-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one hydrochloride in Step 1 and 5-iodoisoquinoline in Step 2 as starting materials. MS m / z (M+H+) 406.3. 1H NMR (400 MHz, DMSO-d6,) δ 11.87 (s, 1H), 9.40 (s, 1H), 8.53 (d, 5.3 Hz, 1H), 8.17 (d, J= 8.1 Hz, 1H), 7.85 (dd, J= 7.5, 1.2 Hz, 1H), 7.80 -7.71 (m, 2H), 2.88 (d, J= 10.9 Hz, 2H), 2.57 (d, J= 12.3 Hz, 1H), 2.32 - 2.23 (m, 2H), 1.93 (q, J = 10.5, 9.0 Hz, 4H), 1.77 - 1.48 (m, 8H), 1.31 (dt, J= 9.0, 6.6 Hz, 2H), 1.27 - 1.06 (m, 3H), 0.94 - 0.77 (m, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-4-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 114):Compound 114

[0261] The title compound was prepared according to Example 5 using 5-(piperidin-4-yl)-2,4- dihy dro-3H-l, 2, 4-triazol-3 -one hydrochloride in Step 1 and 6-iodo-2,3-dihydrobenzo[b ][l,4]dioxine in Step 2 as starting materials. MS m / z (M+H+) 413.3.1H NMR (400 MHz, DM SOM,) δ 9.18 (s, 1H), 7.36 (dd, J= 14.2, 2.5 Hz, 1H), 7.29 (ddd, J= 19.0, 8.8, 2.5 Hz, 1H), 6.89 (dd, J= 8.8, 1.8 Hz,1H), 4.27 - 4.18 (m, 4H), 3.57 (d, J = 12.1 Hz, 2H), 3.13 - 2.92 (m, 4H), 2.84 (tt, J= 12.1, 3.6 Hz, 1H), 2.18 (d, J= 14.1 Hz, 2H), 2.07 - 1.93 (m, 1H), 1.81 (qd, J= 13.4, 3.8 Hz, 2H), 1.71 - 1.42 (m, 6H), 1.32 - 1.07 (m, 4H), 0.91 (dt, J = 20.1, 9.6 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(8-methoxyisoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Cpd 115):Compound 115

[0262] The title compound was prepared according to Example 5 using 5-bromo-8- methoxyisoquinoline in Step 2 as starting material. MS m / z (M+H+) 436.3, (400 MHz, 1H NMR DMSO-d 6) δ 1 1 .79 (s, 1H), 9.55 (s, 1H), 8.57 (s, 1H), 7.73 (d, J= 8.3 Hz, 1H), 7.56 (d, J= 5.1 Hz, 1H), 7.17 (d, J= 8.4 Hz, 1H), 4.05 (s, 3H), 3.01 (d, J = 11.1 Hz, 1H), 2.73 (d, 10.9 Hz,2H), 2.35 - 2.26 (m, 2H), 2.10 (t, J= 10.1 Hz, 1H), 1.96 - 1.90 (m, 2H), 1.72 - 1.53 (m, 7H), 1.54 - 1.43 (m, 2H), 1.39 - 1.05 (m, 5H), 0.86 (q, J= 11.0, 10.3 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(isoquinolin-8-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 116):Compound 116

[0263] The title compound was prepared according to Example 5 using 8-iodoisoquinoline in Step 2 as starting material. MS m z (M+H+) 406.3,1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.32 (s, 1H), 8.55 (d, J= 5.7 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.90 (dd, J= 5.8, 1.0 Hz, 1H), 7.84 (t, J= 7.8 Hz, 1H), 7.70 (dd, J= 7.4, 1.1 Hz, 1H), 3.11 (s, 1H), 2.84 (s, 2H), 2.40 (s, 2H), 2.12 - 2.06 (m, 1H), 2.01 - 1.93 (m, 1H), 1.74 (t, J = 6.6 Hz, 1H), 1.70 - 1.45 (m, 8H), 1.36 (q, J= 7.3 Hz, 2H), 1.30 - 1.00 (m, 4H), 0.86 (dp, J= 13.9, 4.7, 3.9 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(2-methoxyquinolin-8-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Cpd 117):Compound 117

[0264] The title compound was prepared according to Example 5 using 8-bromo-2- methoxyquinoline in Step 2 as starting material. MS m / z (M+H+) 436.3,1H NMR (400 MHz, DMSO-d6 ) δ 11.57 (s, 1H), 8.30 (d, J= 8.8 Hz, 1H), 7.95 (dd, J= 8.1, 1.5 Hz, 1H), 7.72 (dd, J = 7.5, 1.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.05 (d, J= 8.8 Hz, 1H), 3.83 (s, 3H), 3.03 - 2.95 (m, 1H), 2.77 - 2.65 (m, 2H), 2.28 (q, J= 6.9 Hz, 2H), 2.03 (t, J= 10.7 Hz, 1H), 1.90 (td, J= 13.0, 6.6 Hz, 2H), 1.73 - 1.58 (m, 6H), 1.58 - 1.35 (m, 2H), 1.30 (q, J= 7.2 Hz, 2H), 1.27 - 1.02 (m, 4H), 0.85 (q, J= 11.2, 10.4 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyI)piperidin-4-yl)-2-(8-methoxyisoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one, TEA (Cpd 118):Compound 118

[0265] The title compound was prepared according to Example 5 using 5-(piperidin-4-yl)-2,4- dihydro-3H-l, 2, 4-triazol-3-one hydrochloride in Step 1 and 5-bromo-8-methoxyisoquinoline in Step 2 as starting materials. MS m / z (M+H+) 436.3. ’H NMR (400 MHz, DMSO-d6) δ99.54 (s, 1H), 8.56 (s, 1H), 7.73 (d, J= 8.3 Hz, 1H), 7.57 (d, J= 5.7 Hz, 1H), 7.17 (d, J= 8.4 Hz, 1H), 6.67 (s, 1H), 4.05 (s, 3H), 2.85 (dd, J= 20.7, 11.4 Hz, 4H), 2.33 - 2.20 (m, 4H), 1.96 (dt, J= 35.4, 12.5 Hz, 3H), 1.79 (d, J= 11.8 Hz, 1H), 1.76 - 1.40 (m, 6H), 1.36 - 1.23 (m, 2H), 1.24 - 1.09 (m, 2H), 0.85 (q, J= 11.3 Hz, 2H).Synthesis of 2-(l -aminoisoquinolin-5-yl)-5-(l -(2-cyclohexylethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 120

[0266] The title compound was prepared according to Example 5 using 5-bromoisoquinolin-l- amine in Step 2 as starting material. MS m / z (M+H+) 421.3.Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(6-methylisoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 122

[0267] The title compound was prepared according to Example 5 using 5-bromo-6- methylisoquinoline in Step 2 as starting material. MS m / z (M+H+) 420.3.Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(4-methylisoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Cpd 123):

[0268] The title compound was prepared according to Example 5 using 5-bromo-4- methylisoquinoline in Step 2 as starting material. MS m / z (M+H+) 420.3. (400 MHz,1H NMR DMSO-d 6) δ 11.79 (s, 1H), 9.27 (s, 1H), 8.35 (s, 1H), 8.29 (dd, J= 6.0, 3.6 Hz, 1H), 7.76 (q, J = 3.7, 3.1 Hz, 2H), 3.11 - 2.93 (m, 2H), 2.72 (d, J = 30.9 Hz, 2H), 2.42 - 2.30 (m, 3H), 2.25 (m, 3H), 2.08 - 1.85 (m, 3H), 1.76 - 1.35 (m, 6H), 0.96 - 0.69 (m, 5H).Synthesis of 2-([l,2,4]triazolo[4,3-a]pyridin-8-yl)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 124):Compound 124

[0269] The title compound was prepared according to Example 5 using 8-bromo- [l,2,4]triazolo[4,3-a]pyridine in Step 2 as starting material. MS m'z (M+H+) 396.3. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.58 (dd, J= 6.9, 1.0 Hz, 1H), 7.51 (dd, J= 7.2, 1.0 Hz, 1H), 7.05 (t, J = 7.0 Hz, 1H), 3.01 (d, J= 11.0 Hz, 1H), 2.88 - 2.64 (m, 3H), 2.32 (m, 2H), 2.08 (m, 1H), 1.94 (q, J= 11.2, 9.6 Hz, 3H), 1.68 (m, 6H), 1.55 - 1.42 (m, 1H), 1.33 (q, J= 7.2 Hz, 2H), 1.18 (m, 3H), 0.97 - 0.76 (m, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(5,6-dimethoxypyridin-2-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Cpd 125):Compound 125

[0270] The title compound was prepared according to Example 5 using 6-iodo-2,3- dimethoxypyridine in Step 2 as starting material. MS m / z (M+H+) 416.3. 1H NMR (400 MHz, DMSO-d6) δ 11.99 (d, J= 18.0 Hz, 1H), 9.31 (s, 1H), 7.40 (d, J= 8.3 Hz, 1H), 7.36 - 7.21 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.74 (d, J= 8.9 Hz, 1H), 3.51 (d, J= 12.2 Hz, 1H), 3.20 - 2.96(m, 3H), 2.87 (q, J= 11.5 Hz, 1H), 2.12-1.98 (m, 2H), 1.78 - 1.43 (m, 10H), 1.36 - 1.01 (m, 4H), 0.93 (t, J= 11.7 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(lH-indazol-4-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 126):Compound 126

[0271] The title compound was prepared according to Example 5 using 4-iodo-lH-indazole in Step 2 as starting material. MS m'z (M+H+) 395.3. (4001MHH NzM, DRMSO-t76) 8 13.14 (s, 1H), 11.93 (s, 1H), 8.39 (s, 1H), 7.77 (q, J= 4.5 Hz, 1H), 7.36 (d, J = 4.4 Hz, 2H), 3.13 - 2.96 (m, 1H), 2.90 - 2.70 (m, 2H), 2.39 - 2.28 (m, 2H), 2.18 (t, J= 10.6 Hz, 1H), 2.00 (q, J= 6.4, 5.2 Hz, 2H), 1.86 - 1.49 (m, 7H), 1.40 - 1.27 (m, 3H), 1.23 - 1.02 (m, 3H), 0.96 - 0.77 (m, 3H).Synthesis of 3-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)benzonitrile (Cpd 130):Compound 130

[0272] The title compound was prepared according to Example 5 using 3 -bromobenzonitrile in Step 2 as starting material. MS m / z (M+H+) 380.2.(400 MHz, DMSO-d6) δ 12.32 (d, J = 12.7 Hz, 1H), 9.40 (s, 1H), 8.40 - 8.11 (m, 2H), 7.75 - 7.58 (m, 2H), 3.79 (d, J= 9.0 Hz, 1H), 3.63 - 3.42 (m, 1H), 3.26 - 3.02 (m, 4H), 2.90 (d, J= 11.7 Hz, 1H), 2.14 (d, J= 13.2 Hz, 1H), 1.98 (d, .7= 14.2 Hz, 1H), 1.84 - 1.47 (m, 9H), 1.38 - 1.06 (m, 4H), 0.94 (m, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 138):Compound 138

[0273] The title compound was prepared according to Example 5 using 4-iodo-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazole in Step 2 as starting material. MS m / z (M+H+) 479.3. (400 1H NMR MHz, DMSO-d6) δ 12.38 - 12.05 (m, 1H), 9.38 (s, 1H), 8.47 (d, J= 6.4 Hz, 1H), 7.86 (dd, J = 17.6, 7.6 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.52 - 7.37 (m, 1H), 5.88 (dd, J= 9.5, 2.6 Hz, 1H), 3.87 (q, J= 5.2, 4.0 Hz, 2H), 3.76 (m, 1H), 3.65 - 3.47 (m, 1H), 3.29 - 3.05 (m, 3H), 2.93 (q, J= 11.7 Hz, 1H), 2.49 - 2.32 (m, 3H), 2.20 (d, J= 13.1 Hz, 1H), 2.12 - 1.90 (m, 3H), 1.87 - 1.51 (m, 11H), 1.41 - 1.07 (m, 4H), 1.04 - 0.85 (m, 2H).Synthesis of 6-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)isoindolin-l-one (Cpd 139):Compound 139

[0274] The title compound was prepared according to Example 5 using 6-bromoisoindolin-l- one in Step 2 as starting material. MS m / z (M+H1) 410.3. 1H NMR (400 MHz, DMSO-d6)8 11.93 (s, 1H), 8.61 (s, 1H), 8.16 (d, J= 2.0 Hz, 1H), 8.10 (dd, J= 8.3, 2.1 Hz, 1H), 7.61 (d, J= 8.3 Hz, 1H), 4.36 (s, 2H), 2.99 (broad s, 1H), 2.74 (broad s, 2H), 2.31 (broad s, 1H), 1.94 (braod s, 2H), 1.63 (m, 11H), 1.34 (broad s, 1H), 1.15 (m, 4H), 0.87 (q, J= 11.3, 10.6 Hz, 2H).Synthesis of 5-(l -(2-cyclohexylethyl)piperidin-3-yl)-2-(phthalazin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 140):Compound 140

[0275] The title compound was prepared according to Example 5 using 5-bromophthalazine in Step 2 as starting material. MS m / z (M+H+) 407.3,(400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.85 - 9.80 (m, 1H), 9.70 (d, J= 1.5 Hz, 1H), 8.16 - 8.02 (m, 3H), 3.07 - 2.98 (m, 1H), 2.75 (ddd, J= 13.8, 10.2, 6.9 Hz, 2H), 2.36 - 2.25 (m, 2H), 2.14 (t, J= 10.6 Hz, 1H), 1.96 (t, J = 8.1 Hz, 3H), 1.77 - 1.59 (m, 6H), 1.53 (q, J= 10.9, 9.3 Hz, 2H), 1.36 - 1.29 (m, 2H), 1.29 - 1.19 (m, 1H), 1.19 - 1.04 (m, 2H), 0.86 (qd, J= 11.8, 11.2, 2.8 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(l-(ethoxymethoxy)isoquinolin-7-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 146):

[0276] The title compound was prepared according to Example 5 using 7-bromo-l- (ethoxy methoxy )isoquinoline in Step 2 as starting material. MS m / z (M+H+) 480.3. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J= 2.3 Hz, 1H), 8.29 (dd, J= 8.7, 2.3 Hz, 1H), 7.73 (d, J= 8.7 Hz, 1H), 7.42 (d, J= 7.4 Hz, 1H), 6.65 (d, J= 7.4 Hz, 1H), 5.37 (s, 2H), 3.53 (q, J= 7.0 Hz, 2H), 3.01 (d, J= 11.1 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.32 (dd, J= 8.9, 6.0 Hz, 2H), 2.12 (t, J= 10.6 Hz, 1H), 2.06 - 1.90 (m, 3H), 1.60 (m, 5H), 1.40 - 1.30 (m, 2H), 1.23 (m, 5H), 1.11 (m, 4H), 0.95 - 0.76 (m, 2H).Example 5a

[0277] The process below describes the synthesis of an exemplary compound.

[0278] To a solution of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(2-methoxyquinolin-8-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (0.22 g, 0.505 mmol, prepared according to Example 5 using 8- bromo-2-methoxyquinoline in Step 2 as starting material) in THF (2 ml) was added HC1 (6N, 0.168 ml, 1.010 mmol). The mixture was stirred at 60 °C for overnight. The reaction mixture was cooled to r.t., quenched with 4N NaOH until pH=10, and extracted with EtOAc (2x). The combined organic layer was washed with brine and dried over MgSO4 and concentrated. The crude product was purified by ISCO to obtain 8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo- 4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one (Compound 119). MS m^z (M+H+) 422.3, 1H NMR (400 MHz, DMSO-d6,) δ 11.73 (s, 2H), 7.94 (d, J= 9.6 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.60 (d, ,7 = 7.7 Hz, 1H), 7.20 (t, J= 7.8 Hz, 1H), 6.52 (dd, .7= 9.5, 1.8 Hz, 1H), 3.05 - 2.98 (m, 1H), 2.76 (d, J= 11.2 Hz, 1H), 2.70 - 2.59 (m, 1H), 2.39 - 2.21 (m, 2H), 2.01 (t, J= 10.7 Hz, 1H), 1.90 (q, J= 10.8, 9.6 Hz, 2H), 1.79 - 1.51 (m, 7H), 1.53 - 1.36 (m, 2H), 1.36 - 1.23 (m, 2H), 1.27 - 1.02 (m, 3H), 0.93 - 0.79 (m, 2H).Synthesis of 6-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)-3-methoxypyridin-2(lH)-one (Cpd 127):

[0279] The title compound was prepared according to Example 5a using 5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2-(5,6-dimethoxypyridin-2-yl)-2,4-dihydro-3H-l,2,4-triazol-3- one as starting material. MS m / z (M+H+) 402.3.Synthesis of 7-(3-(l -(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-l H-l ,2,4-triazol-l - yl)isoquinolin-l(2H)-one (Cpd 148):Compound 148

[0280] The title compound was prepared according to Example 5a using 5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2-(l -(ethoxymethoxy )isoquinolin-7-yl)-2,4-dihydro-3H- 1,2, 4- triazol-3-one as starting material. MS m / z (M+H+) 402.2. 1H NMR (400 MHz, methanol-d4) δ 8.77 (d, J= 2.3 Hz, 1H), 8.48 - 8.28 (m, 1H), 7.73 (dt, J= 8.8, 3.2 Hz, 1H), 7.16 (d, J= 7.1 Hz, 1H), 6.69 (dt, J= 7.3, 2.2 Hz, 1H), 3.62 (m, 1H), 3.35 (s, 3H), 3.22 (s, 2H), 3.07 (t, J= 8.4 Hz, 2H), 2.90 (s, 1H), 2.21 (s, 1H), 2.10 - 1.98 (m, 1H), 1.93 (m, 1H), 1.83 - 1.59 (m, 6H), 1.47- 1.14 (m, 4H), 1.12 - 0.94 (m, 2H).Synthesis of 8-(5-oxo-3-(piperidin-3-yl)-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)- one (Cpd 235):Compound 235

[0281] The title compound was prepared according to Example 5a using 2-(2-methoxyquinolin- 8-yl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one as starting material. MS m / z (M+H+) 312.1.Synthesis of 8-(3-(l -(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-l H-l ,2,4-triazol-l - yl)-5-methoxyquinolin-2(lH)-one (Cpd 257):Compound 257

[0282] The title compound was prepared according to Example 5a using 5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2-(2,5-dimethoxyquinolin-8-yl)-2,4-dihydro-3H-l,2,4-triazol-3- one as starting material. MS m / z (M+H+) 452.3. 1H NMR (400 MHz, DMSO-d6) δ 8 11.91 (d, J = 68.4 Hz, 1H), 10.96 (d, J= 83.7 Hz, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.10 (dd, J= 9.8, 4.9 Hz, 1H), 7.48 (dd, J = 37.5, 8.7 Hz, 1H), 6.84 (t, J= 9.1 Hz, 1H), 6.50 (dd, J= 9.8, 1.8 Hz, 1H), 3.95 (s, 3H), 3.79 - 3.61 (m, 1H), 3.53 (d, J= 11.8 Hz, 1H), 3.16 (dt, J = 11.1, 5.1 Hz, 2H), 3.03 (t, J = 9.5 Hz, 2H), 2.90 (m, 1H), 2.13 (d, J= 12.7 Hz, 1H), 1.98 (d, J= 14.3 Hz, 1H), 1.92 - 1.73 (m, 1H), 1.73 - 1.42 (m, 7H), 1.21 (m, 5H), 0.92 (m, 2H).Synthesis of (5)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl)-5-methoxyquinolin-2(lH)-one (Cpd 263):Compound 263

[0283] The title compound was prepared according to Example 5a using (5)-5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2-(2,5-dimethoxyquinolin-8-yl)-2,4-dihydro-3H-l,2,4-triazol-3- one as starting material. MS m / z (M+H+) 452.3. 1H NMR (400 MHz, DMSC-d6,) δ 12.21 - 11.67 (m, 1H), 10.96 (d, J= 83.9 Hz, 1H), 9.38 (d, J = 42.8 Hz, 1H), 8.10 (dd, J= 9.8, 5.0 Hz, 1H),7.48 (dd, J= 37.5, 8.7 Hz, 1H), 6.84 (t, J = 9.2 Hz, 1H), 6.50 (dd, J= 9.7, 1.8 Hz, 1H), 3.95 (s, 3H), 3.79 - 3.61 (m, 1H), 3.53 (d, J= 11.8 Hz, 1H), 3.16 (dt, J= 11.1, 5.1 Hz, 2H), 3.03 (t, J= 9.5 Hz, 2H), 2.90 (m, 1H), 2.13 (d, J= 12.7 Hz, 1H), 1.98 (d, J= 14.3 Hz, 1H), 1.92 - 1.73 (m, 1H), 1.73 - 1.42 (m, 7H), 1.21 (m, 5H), 0.92 (m, 2H).Synthesis of (8-(3-(l-(2-azaspiro[3.3]heptan-6-yl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)quinolin-2(lH)-one (Cpd 266):Compound 266

[0284] The title compound was prepared according to Example 5a using Zc’ / V-butyl 6-(3-(5-oxo- 1 -(2-oxo- 1 ,2-dihydroquinolin-8-yl)-4, 5-dihydro- 1H- 1 ,2,4-triazol-3 -yl)piperidin- 1 -y 1 )-2- azaspiro[3.3]heptane-2-carboxylate as starting material. MS m / z (M+H+) 407.2. (400 1H NMR MHz, DMSO-d6) δ 12.09 (d, J= 101.1 Hz, 1H), 10.93 (d, J= 75.0 Hz, 1H), 8.60 (s, 2H), 7.99 (d, J= 9.6 Hz, 1H), 7.73 (d, J= 7.8 Hz, 1H), 7.56 (dd, J= 47.0, 7.8 Hz, 1H), 7.26 (q, J= 7.8, 7.0 Hz, 1H), 6.70 - 6.38 (m, 1H), 4.00 (t, J= 6.1 Hz, 2H), 3.90 (t, J= 6.0 Hz, 2H), 3.55 (t, J= 15.3 Hz, 3H), 3.11 - 2.82 (m, 2H), 2.82 - 2.52 (m, 4H), 2.13 (d, J= 12.6 Hz, 1H), 1.99 (d, J= 13.4 Hz, 1H), 1.79 - 1.44 (m, 3H).Example 5b

[0285] The process below describes the synthesis of an exemplary compound.

[0286] To a solution of 5-((5)-l-(2-cyclohexylethyl)piperidin-3-yl)-2-(l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (0.25 g, 0.522 mmol, prepared according to Example 5 using 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole in Step 2 as starting material) in DCM (4 ml) was added TFA (0.402 ml, 5.22 mmol). The mixture wasstirred at r.t. for overnight. LCMS indicated only 50% of product. To the mixture was added additional TFA (0.402 ml, 5.22 mmol). The reaction mixture was stirred at r.t. overnight. LCMS indicated 22% of starting material remaining. To the mixture was added additional TFA (0.402 ml, 5.22 mmol), and the reaction mixture was stirred at r.t. overnight. The solvent was removed. The crude product was purified by ISCO (0-20%, MeOH / DCM) and then reverse phase ISCO (0-100% ACN / H2O, 0.1%TFA) to obtain (5)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(lH- indazol-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Compound 149). MS m 'z (M+H+) 395.3, 'H NMR (400 MHz, DMSO-d6 ) δ 13.19 (s, 1H), 12.22 (d, J= 7.7 Hz, 1H), 9.55 (s, 1H), 8.42 (d, J= 7.1 Hz, 1H), 7.78 (ddd, J= 16.7, 6.1, 2.2 Hz, 1H), 7.42 - 7.31 (m, 2H), 3.86 (d, J= 11.5 Hz, 1H), 3.54 (d, J= 11.9 Hz, 1H), 3.28 - 3.06 (m, 4H), 2.92 (dt, J= 12.3, 9.3 Hz, 1H), 2.23 - 2.15 (m, 1H), 1.99 (dt, J= 14.1, 2.9 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.73 - 1.52 (m, 8H), 1.29 (ddt, J = 14.2, 6.8, 3.7 Hz, 1H), 1.24 - 1.08 (m, 2H), 1.00 - 0.86 (m, 2H).Synthesis of (S)-5-(l-(6-aminospiro[3.3]heptan-2-yl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-oneCompound 261

[0287] The title compound was prepared according to Example 5b using tert-butyl (S)-(6-(3-(l- (isoquinolin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)spiro[3.3]heptan-2- yl)carbamate as the starting material. MS m / z (M+H+) 405.3.Synthesis of (S )-5-(l-(2-azaspiro [3.3] heptan-6-yl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-oneCompound 262

[0288] The title compound was prepared according to Example 5b using tert-butyl (S)-6-(3-(l- (isoquinolin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)-2- azaspiro[3.3]heptane-2-carboxylate as starting material. MS m / z (M+H+) 391.3. ’H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.54 (d, J= 6.0 Hz, 1H), 8.19 (d, J= 8.1 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.81 - 7.72 (m, 2H), 3.61 (m, 3H), 3.03 - 2.84 (m, 2H), 2.80 - 2.61 (m, 2H), 2.61 - 2.51 (m, 2H), 2.37 - 2.08 (m, 2H), 2.07 - 1.81 (m, 3H), 1.74 (m, 2H), 1.56 - 1.37 (m, 2H).Synthesis of 8-(3-(l-(6-aminospiro [3.3] heptan-2-yl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)quinolin-2(lH)-one (Cpd 268):Compound 268

[0289] The title compound was prepared according to Example 5b using tert-butyl (6-(3-(5-oxo- 1 -(2-oxo- 1 ,2-dihydroquinolin-8-yl)-4, 5-dihydro- 1 H- 1 ,2,4-triazol-3 -yl)piperidin- 1 - yl)spiro[3.3]heptan-2-yl)carbamate as starting material. MS m / z (M+H+) 421.3. 1H NMR (400 MHz, DMSO-d6 ) δ 12.09 (d, J= 84.6 Hz, 1H), 11.04 (s, 1H), 10.06 (s, 1H), 8.00 (d, J= 9.5 Hz, 1H), 7.75 (d, J= 7.8 Hz, 1H), 7.66 - 7.49 (m, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.58 (dd, J= 9.6, 1.8 Hz, 1H), 3.90 - 3.18 (m, 8H), 2.97 (m, 1H), 2.80 - 2.61 (m, 1H), 2.48 - 2.34 (m, 1H), 2.34 - 2.06 (m, 5H), 2.06 - 1.50 (m, 3H).Example 6

[0290] The process below describes the synthesis of an exemplary compound.

[0291] Step 1: A mixture of tert-butyl 3-(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidine-l- carboxylate (1.34 g, 4.99 mmol), 8-bromo-2-methoxyquinoline (1.308 g, 5.49 mmol), potassium phosphate (2.120 g, 9.99 mmol), and copper(I) iodide (0.380 g, 1.998 mmol) in DMF (25 mL) was purged with N2 for 5 min. (17?,27?)-A,A’-dimethylcyclohexane-l,2-diamine (0.630 ml, 4.00 mmol) was then added. The dark brown mixture was stirred at 100 °C for 22 h. LC / MS showed only starting materials. Another portion of copper(I) iodide (0.380 g, 1.998 mmol) was added, followed by 8-bromo-2-methoxyquinoline (600 mg). The mixture was purged with N2 for 5 min, and was treated with (lA,2J?)-A,A’-dimethylcyclohexane-l,2-diamine (0.630 ml, 4.00 mmol). The reaction mixture was stirred at 100 °C for another 24 h. LC / MS showed formation of a new peak with the desired mass, along with some starting materials. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, and concentrated. The solvent was removed, and the residue was purified by flash chromatography (50 g cartridge, flow rate 25 ml / min, gradient elution from hexanes to EtOAc in 10 min, kept at EtOAc for 5 min, then gradient elution to 15% MeOH / CLECE in 10 min, then kept at 15% MeOH / CH2CI2 for 10 min). Fractions containing the desired product (eluted at EtOAc and 5% MeOH / CH2CI2) were pooled and concentrated to provide / crz-butyl 3-(l-(2-methoxyquinolin-8- yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidine-l -carboxylate (Compound 237, 1.2 g, 2.82 mmol, 56.5 % yield) as a brown solid. MS m'z (M+H+) 426.2, 1H NMR (400 MHz, DMSO- d6) δ 11.78 (s, 1H), 8.33 (dd, J= 8.9, 5.5 Hz, 1H), 8.03 - 7.92 (m, 1H), 7.75 (dd, J= 7.2, 5.8 Hz,1H), 7.57 - 7.46 (m, 1H), 7.08 (dd, J= 8.9, 5.2 Hz, 1H), 4.03 (m, 1H), 3.85 (s, 3H), 3.81 (m, 1H), 3.16 - 2.97 (m, 1H), 2.85 (t, J= 12.1 Hz, 1H), 2.66 (d, J= 3.9 Hz, 1H), 2.08 (dd, J= 35.8, 11.5 Hz, 1H), 1.69 (m, 3H), 1.38 (s, 9H).

[0292] Step 2: To a solution of tert-butyl 3-(l-(2-methoxyquinolin-8-yl)-5-oxo-4,5-dihydro-lH-1.2.4-triazol-3-yl)piperi dine- 1 -carboxylate (Compound 237, 0.23 g, 0.541 mmol) in DCM (5 ml) was added TFA (0.5 ml, 6.49 mmol). The reaction mixture was stirred at r.t overnight. LCMS indicated complete reaction. The solvent was removed. The crude product, 2-(2-methoxyquinolin- 8-yl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 236), was used in the next reaction without further purification. MS m / z (M+H+) 326.2.

[0293] Step 3: To a solution of 2-(2-methoxyquinolin-8-yl)-5-(piperidin-3-yl)-2,4-dihydro-3H-1.2.4-triazol-3-one (Compound 236, 50 mg, 0.154 mmol) in DMF (1.5 ml) were added potassium carbonate (106 mg, 0.768 mmol) and l-(2-bromoethyl)-2,4-dichlorobenzene (27.1 pl, 0.169 mmol). The reaction mixture was stirred at 50 °C for 48 hr. The reaction mixture was cooled to r.t., quenched with water and extracted with EtOAc (3x). The combined organic layer was dried over MgSC>4 and concentrated. The crude product, 5-(l-(2,4- dichlorophenethyl)piperidin-3-yl)-2-(2-methoxyquinolin-8-yl)-2,4-dihydro-3H-l,2,4-triazol-3- one, was used without further purification. MS m / z (M+H+) 498.2.

[0294] Step 4: To a solution of 5-(l-(2,4-dichlorophenethyl)piperidin-3-yl)-2-(2- methoxyquinolin-8-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (29 mg, 0.058 mmol) in THF (1 ml) was added HO (6N, 38.8 μl, 0.233 mmol). The mixture was stirred at 60 °C for 5 hr. The reaction mixture was cooled to r.t., the solvent was removed. The crude product was submitted for purification to obtain 8-(3-(l-(2,4-dichlorophenethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-1.2.4-triazol-l-yl)quinolin-2(lH)-one, TFA (Compound 241). MS m / z (M+H+) 484.1. 1H NMR (400 MHz, DMSO-d 6) δ 11.97 (s, 1H), 11.07 - 11.02 (m, 1H), 7.99 (d, J= 9.5 Hz, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.65 (s, 1H), 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.45 (s, 2H), 7.25 (t, J = 7.8 Hz, 1H), 6.56 (dd, J= 9.5, 1.9 Hz, 1H), 3.83 (d, J= 11.2 Hz, 1H), 3.64 (d, J= 11.3 Hz, 1H), 3.39 - 2.94 (m, 6H), 2.16 (d, J= 12.6 Hz, 1H), 2.02 (d, J= 15.0 Hz, 1H), 1.96 - 1.72 (m, 2H), 1.63 (q, J = 14.5, 13.5 Hz, 1H).Synthesis of 8-(3-(l -(isoindolin-4-ylmethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l ,2,4- triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 238):Compound 238

[0295] The title compound was prepared according to Example 6 using tert-butyl 4- (bromomethyl)isoindoline-2-carboxylate in Step 3 as starting material. MS m / z (M+H+) 443.3, 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.97 (s, 1H), 9.85 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.74 (d, .7= 5.5 Hz, 1H), 7.55 (dd, J= 7.8, 1.4 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.30 - 7.22 (m, 1H), 6.59 (d, J= 9.7 Hz, 1H), 4.67 - 4.62 (m, 2H), 4.61 - 4.54 (m, 3H), 4.45 - 4.38 (m, 2H), 3.22 (dd, J= 13.2, 8.6 Hz, 1H), 3.10 - 3.00 (m, 2H), 2.20 - 1.90 (m, 2H), 1.88 - 1.68 (m, 2H), 1.59 - 1.54 (m, 1H).Synthesis of 8-(3-(l -(2,4-dichlorobenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-l H-l ,2,4-triazol- l-yl)quinolin-2(lH)-one, TEA (Cpd 239):Compound 239

[0296] The title compound was prepared according to Example 6 using l-(bromomethyl)-2,4- dichlorobenzene in Step 3 as starting material. MS m / z (M+H+) 470.1, 1H NMR (400 MHz, DMSO-d6,) δ 11.92 (s, 1H), 11.00 (s, 1H), 9.69 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.72 (d, J= 8.0 Hz, 2H), 7.65 - 7.58 (m, 1H), 7.53 (d, J= 1.1 Hz, 1H), 7.25 (t, J= 7.8 Hz, 1H), 6.56 (dd, J= 9.5, 1.9 Hz, 1H), 4.54 - 4.48 (m, 2H), 3.74 - 3.48 (m, 1H), 3.20 - 3.05 (m, 3H), 2.14 - 2.07 (m, 1H), 1.98 - 1.91 (m, 2H), 1.81 - 1.74 (m, 1H), 1.62 - 1.57 (m, 1H).Synthesis of 8-(3-(l-(2-chlorobenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)quinolin-2(lH)-one,Compound 240

[0297] The title compound was prepared according to Example 6 using l-(bromomethyl)-2- chlorobenzene in Step 3 as starting material. MS m / z (M+H+) 436.1,1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 11.01 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.60 (dd, J= 5.8, 3.2 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.35 - 7.20 (m, 2H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 4.52 (s, 2H), 3.73 - 3.47 (m, 2H), 3.38 - 2.99 (m, 2H), 2.11 (dd, J= 12.6, 6.7 Hz, 1H), 2.03 - 1.91 (m, 2H), 1.79 (dd, J= 18.0, 11.5 Hz, 1H), 1.68 - 1.53 (m, 1H).Synthesis of 8-(5-oxo-3-(l-(2-(pyridin-2-yl)ethyl)piperidin-3-yl)-4,5-dihydro-lH-l,2,4- triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 242):Compound 242

[0298] The title compound was prepared according to Example 6 using 2-(2- bromoethyl)pyridine in Step 3 as starting material. MS m / z (M+H+) 417.2, 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.03 (s, 1H), 8.47 - 8.41 (m, 1H), 7.99 (d, .7= 9.6 Hz, 1H), 7.80 - 7.70 (m, 2H), 7.52 (dd, J= 7.8, 1.4 Hz, 1H), 7.36 (dt, J= 7.9, 1.1 Hz, 1H), 7.24 (q, J= 7.6 Hz, 2H), 6.56 (dd, J= 9.5, 1.9 Hz, 1H), 3.73 (d, J= 12.0 Hz, 1H), 3.61 - 3.48 (m, 3H), 3.38 - 3.28 (m, 1H), 3.26 - 3.06 (m, 4H), 2.10 (d, J= 12.6 Hz, 1H), 2.02 - 1.94 (m, 1H), 1.89 - 1.67 (m, 2H).Synthesis of 8-(3-(l -(2,4-dimethylbenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-l H-l ,2,4-triazol- l-yl)quinolin-2(lH)-one,Compound 243

[0299] The title compound was prepared according to Example 6 using l-(bromomethyl)-2,4- dimethylbenzene in Step 3 as starting material. MS m / z (M+H+) 430.2,NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 11.01 (s, 1H), 9.29 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.73 (dd, J = 7.8, 1.4 Hz, 1H), 7.50 (dd, .7= 7.8, 1.4 Hz, 1H), 7.37 (dd, J= 7.9, 3.5 Hz, 1H), 7.25 (t, .7= 7.8 Hz, 1H), 7.12 (s, 1H), 6.56 (dd, .7= 9.6, 1.9 Hz, 1H), 4.34 (d, J = 4.9 Hz, 2H), 3.59 (d, J= 12.1 Hz, 1H), 3.21 (q, J= 11.3 Hz, 1H), 3.10 - 3.00 (m, 2H), 2.35 (s, 3H), 2.28 (d, J= 2.7 Hz, 3H), 2.12 (d, J = 12.6 Hz, 1H), 1.97 (d, J= 14.4 Hz, 2H), 1.78 (q, J = 13.7 Hz, 1H), 1.61 (dd, J = 14.3, 10.8 Hz, 1H).Synthesis of 8-(3-(l-((6-methylpyridin-2-yl)methyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 244):Compound 244

[0300] The title compound was prepared according to Example 6 using 2-(bromomethyl)-6- methylpyridine in Step 3 as starting material. MS m / z (M+H+) 417.2, 1H NMR (400 MHz, DMSO- d6) δ 11.94 (s, 1H), 11.00 (s, 1H), 9.96 (s, 1H), 7.98 (d, .7= 9.6 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.73 (dd, .7= 7.9, 1.4 Hz, 1H), 7.50 (dd, J= 7.7, 1.4 Hz, 1H), 7.33 (dd, J= 7.8, 2.8 Hz, 1H), 7.25 (t, J= 7.8 Hz, 1H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 4.47 (s, 2H), 3.64 - 3.56 (m, 1H), 3.42 (d, J = 12.2 Hz, 1H), 3.30 - 3.15 (m, 2H), 3.08 (t, J= 11.8 Hz, 1H), 2.50 (s, 3H), 2.10 (d, J = 12.9 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.84 (dd, J = 14.8, 11.2 Hz, 1H), 1.67 (q, .7= 11.2, 10.8 Hz, 1H).Synthesis of 8-(3-(l -(2-fluoro-4-methoxybenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-l H-l ,2,4- triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 245):Compound 245

[0301] The title compound was prepared according to Example 6 using 1 -(bromomethyl)-2- fluoro-4-methoxybenzene in Step 3 as starting material. MS nv'z (M+H+) 450.2,1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 11.03 (s, 1H), 9.68 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.24 (t, J= 7.8 Hz, 1H), 6.97 (dd, J= 11.8, 2.5 Hz, 1H), 6.91 (dd, J= 8.6, 2.5 Hz, 1H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 4.35 (s, 2H), 3.79 (s, 3H), 3.59 (d, J = 11.0 Hz, 1H), 3.04 (td, J = 26.9, 25.6, 12.2 Hz, 3H), 2.09 (d, J= 12.9 Hz, 1H), 1.97 (d, J= 14.6 Hz, 1H), 1.76 (q, J= 12.7, 11.4 Hz, 1H), 1.58 (q, J= 12.1 Hz, 1H).Synthesis of 8-(5-oxo-3-(l-((l,2,3,4-tetrahydroisoquinolin-8-yl)methyl)piperidin-3-yl)-4,5- dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 246):Compound 246

[0302] The title compound was prepared according to Example 6 using / c77-butyl 8- (bromomethyl)-l,2,3,4-tetrahydroisoquinoline-2(lH)-carboxylate in Step 3 as starting material. MS m / z (M+H-) 457.2, 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.99 (s, 1H), 9.65 (s, 1H), 9.18 (s, 1H), 8.93 (s, 1H), 7.99 (d, J= 9.6 Hz, 1H), 7.73 (s, 1H), 7.53 (dd, J= 7.8, 1.4 Hz, 1H), 7.50 - 7.31 (m, 1H), 7.25 (t, J= 7.9 Hz, 1H), 6.57 (d, J= 9.7 Hz, 1H), 4.41 - 4.35 (m, 3H), 3.44 - 3.21 (m, 3H), 3.13 - 2.95 (m, 5H), 2.65 (s, OH), 2.23 - 1.88 (m, 2H), 1.90 - 1.66 (m, 2H), 1.66 - 1.44 (m, 2H).Synthesis of 8-(3-(l-(2-fluorobenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)quinolin-2(lH)-one,Compound 248

[0303] The title compound was prepared according to Example 6 using l-(bromomethyl)-2- fluorobenzene in Step 3 as starting material. MS zw / z (M+H+) 420.2,1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 11.02 (s, 1H), 7.97 (s, 1H), 7.73 (d, J= 7.8 Hz, 1H), 7.69 - 7.47 (m, 4H), 7.34 (d, J= 5.5 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.56 (dd, J= 9.5, 1.9 Hz, 1H), 4.44 (s, 2H), 3.75 - 3.54 (m, 1H), 3.25 - 2.95 (m, 3H), 2.10 (d, J= 12.8 Hz, 1H), 2.02 - 1.89 (m, 2H), 1.77 (dd, J= 23.4, 9.6 Hz, 1H), 1.65 - 1.52 (m, 1H).Synthesis of 8-(3-(l-(3-methylbenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)quinolin-2(lH)-one,Compound 249

[0304] The title compound was prepared according to Example 6 using l-(bromomethyl)-3- methylbenzene in Step 3 as starting material. MS m / z (M+H~) 416.2, 1H NMR (400 MHz, DMSO-d6 ) δ 11.92 (s, 1H), 11.05 - 11.00 (m, 1H), 7.98 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 7.8, 1.4 Hz, 1H), 7.41 - 7.20 (m, 5H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 4.37 - 4.30 (m, 2H), 3.59 (d, J= 10.0 Hz, 1H), 3.09 - 3.03 (m, 2H), 2.94 (dd, J = 22.5, 11.0 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 1H), 2.11 (d, J = 12.9 Hz, 1H), 1.95 (t, J = 15.0 Hz, 1H), 1.76 (q, J= 12.7, 11.6 Hz, 1H), 1.59 (q, J= 12.7 Hz, 1H).Synthesis of 8-(3-(l -(3,5-dimethylbenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-l H-l ,2,4-triazol- l-yl)quinolin-2(lH)-one,Compound 250

[0305] The title compound was prepared according to Example 6 using l-(bromomethyl)-3,5- dimethylbenzene in Step 3 as starting material. MS m'z (M+H+) 430.2,1H NM (R400 MHz, DMSO-d6 ) δ 11.93 (s, 1H), 11.02 (s, 1H), 7.98 (d, J = 9.6 Hz, 1H), 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.50 (dd, J= 7.8, 1.4 Hz, 1H), 7.24 (t, J= 7.8 Hz, 1H), 7.10 (s, 3H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 4.28 (d, J= 5.4 Hz, 2H), 3.59 (d, J = 9.4 Hz, 1H), 3.07 (t, J= 11.2 Hz, 2H), 3.00 - 2.87 (m, 1H), 2.29 (s, 6H), 2.17 (s, 1H), 2.11 (d, J= 12.8 Hz, 1H), 1.97 (d, J= 14.8 Hz, 1H), 1.76 (q, J= 13.8 Hz, 1H), 1.59 (q, J= 12.6 Hz, 1H).Synthesis of 8-(3-(l-((4,6-dimethylpyridin-2-yl)methyl)piperidin-3-yl)-5-oxo-4,5-dihydro- lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 251):Compound 251

[0306] The title compound was prepared according to Example 6 using 2-(bromomethyl)-4,6- dimethylpyridine in Step 3 as starting material. MS m / z (M+H+) 431.2, 1H NMR (400 MHz, DMSO-d6 ) δ 11.94 (s, 1H), 11.00 (s, 1H), 7.98 (d, .7= 9.6 Hz, 1H), 7.73 (dd, .7= 7.9, 1.4 Hz, 1H), 7.51 (dd, .7= 7.7, 1.4 Hz, 1H), 7.24 (t, .7= 7.8 Hz, 1H), 7.17 (s, 2H), 6.56 (dd, J= 9.6, 1.8 Hz, 1H), 4.40 (s, 2H), 3.57 (d, J= 10.3 Hz, 1H), 3.39 (d, J= 12.1 Hz, 1H), 3.28 - 3.12 (m, 2H), 3.05 \dd, J= 13.2, 9.8 Hz, 1H), 2.46 (s, 3H), 2.30 (s, 3H), 2.13 - 2.05 (m, 1H), 1.96 (dt, J = 14.6, 3.8 Hz, 1H), 1.84 (dd, J= 15.0, 11.4 Hz, 1H), 1.67 (q, J= 10.9 Hz, 1H).Synthesis of 8-(3-(l -(4-chloro-2-fluorobenzyl)piperidin-3-yl)-5-oxo-4,5-dihydro-1 H-l ,2,4- triazol-l-yl)quino!in-2(lH)-one, TFA (Cpd 253):Compound 253

[0307] The title compound was prepared according to Example 6 using 1 -(bromomethyl)-4- chloro-2-fluorobenzene in Step 3 as starting material. MS m / z (M+H+) 454.1, 1H NMR (400 MHz, DMSO-d6 ) δ 11.94 (s, 1H), 11.01 (s, 1H), 9.67 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.52 (d, J= 7.7 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.25 (t, 7= 7.8 Hz, 1H), 6.56 (dd, 7= 9.6, 1.9 Hz, 1H), 4.49 (s, 2H), 3.77 - 3.49 (m, 1H), 3.34 - 3.19 (m, 1H), 3.13 - 3.02 (m, 2H), 2.10 (d, 7 = 12.4 Hz, 1H), 1.97 (dd, J= 18.3, 6.9 Hz, 2H), 1.83 - 1.73 (m, 1H), 1.60 (d, J= 12.8 Hz, 1H).Synthesis of 8-(3-(l-(2-(4-chloropyridin-2-yl)ethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 254):Compound 254

[0308] The title compound was prepared according to Example 6 using 2-(2-bromoethyl)-4- chloropyridine in Step 3 as starting material. MS m / z (M+H+) 451.2, 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.02 (s, 1H), 8.43 (s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.74 (dd, J=7.9, 1.4 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.40 (s, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.60 - 3.52 (m, 5H), 3.23 (dd, 7= 9.0, 6.6 Hz, 2H), 3.19 - 3.01 (m, 1H), 2.13 - 2.06 (m, 1H), 2.02 - 1.94 (m, 1H), 1.85 - 1.62 (m, 2H).Example 6a

[0309] The process below describes the synthesis of an exemplary compound.

[0310] Stepl: To a solution of 2-(2-methoxyquinolin-8-yl)-5-(piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (50 mg, 0.154 mmol, prepared according to Example 6, Step 3) in 1,2- di chloroethane (1.5 ml) were added DIPEA (81 μl, 0.461 mmol), acetic acid (13.20 μl, 0.231 mmol) and 2-(naphthalen-2-yl)acetaldehyde (26.2 mg, 0.154 mmol). The mixture was stirred at r.t. for 10 min, and then sodium triacetoxyborohydride (65.1 mg, 0.307 mmol) was added. The reaction mixture was stirred at r.t. for overnight. The reaction was quenched with water, and extracted with DCM (3x). The combined organic layer was dried and concentrated to obtain 2- (2-m ethoxy quinolin-8-yl)-5-(l-(2-(naphthalen-2-yl)ethyl)piperi din-3 -yl)-2,4-dihy dro-3H- 1,2,4- triazol-3-one. MS m'z (M+H+) 480.2.

[0311] Step 2: To a solution of 2-(2 -methoxy quinolin-8-yl)-5-(l-(2-(naphthalen-2- yl)ethyl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (25 mg, 0.052 mmol) in THF (1 ml) was added HC1 (6N, 34.8 μl, 0.209 mmol). The mixture was stirred at 60 °C for 3 hr. The reaction mixture was cooled to r.t., and the solvent was removed. The crude product was submitted for purification to obtain 8-(3-(l-(2-(naphthalen-2-yl)ethyl)piperidin-3-yl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one, TFA (Compound 247). MS m / z (M+H+) 466.2, 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 11.07 (s, 1H), 9.67 (s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.87 - 7.81 (m, 1H), 7.80 (d, J= 1.7 Hz, 1H), 7.74 (dd, J= 7.9, 1.4 Hz, 1H), 7.55 - 7.41 (m, 3H), 7.26 (t, J = 7.8 Hz, 1H), 6.57 (dd, J= 925, 1.9 Hz, 1H), 3.87 (d, J= 11.4 Hz, 1H), 3.67 (d, J= 12.1 Hz, 1H), 3.54 - 3.45 (m, 4H), 3.23 - 2.97 (m, 2H), 2.17 (d, J= 12.8 Hz, 1H), 2.03 (d, J= 14.3 Hz, 1H), 1.98 - 1.74 (m, 2H), 1.71 - 1.57 (m, 1H).Synthesis of 8-(3-(l-(2-(naphthalen-l-yl)ethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl)quinoIin-2(lH)-one, TFA (Cpd 252):Compound 252

[0312] The title compound was prepared according to Example 6a using 2-(naphthalen-l- yl)acetaldehyde in Step 1 as starting material. MS m / z (M+H+) 466.2,NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.06 (s, 1H), 9.74 (s, 1H), 8.15 - 8.07 (m, 1H), 7.99 (d, J= 9.6 Hz, 1H), 7.95 (dd, .7= 8.0, 1.5 Hz, 1H), 7.86 (dd, J = 7.4, 2.1 Hz, 1H), 7.74 (dd, J= 7.8, 1.5 Hz, 1H), 7.63 - 7.45 (m, 4H), 7.26 (t, J= 7.8 Hz, 1H), 6.56 (dd, J= 9.6, 2.0 Hz, 1H), 3.96 (d, J= 11.3 Hz, 1H), 3.75 (d, J= 11.9 Hz, 1H), 3.48 (s, 4H), 3.28 - 3.01 (m, 2H), 2.19 (d, J= 12.8 Hz, 1H), 2.06 (d, J= 14.8 Hz, 1H), 1.86 (p, J= 15.5, 13.9 Hz, 2H), 1.67 (dd, J= 13.6, 10.1 Hz, 1H).Synthesis of (A)-5-(l -(2-(4,4-difluorocyclohexyl)ethyl)piperidin-3-yl)-2-(2-methoxyquinolin- 8-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one, TFA (Cpd 299):Compound 299

[0313] The title compound was prepared according to Example 6a using 2-(4,4- difhiorocyclohexyl)acetaldehyde in Step 1 as starting material. MS m / z (M+H+) 472.1, 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.33 (s, 1H), 8.32 (d, J= 8.9 Hz, 1H), 7.98 (dd, J= 8.2, 1.4 Hz, 1H), 7.72 (dd, .7= 7.4, 1.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.07 (d, 7= 8.9 Hz, 1H), 3.84 (s, 3H), 3.74 (d, J= 7.5 Hz, 1H), 3.51 (d, J= 12.1 Hz, 1H), 3.13 (q, J= 3.5 Hz, 1H), 3.06 (d, J=7.1 Hz, 1H), 2.88 (q, J= 11.7 Hz, 1H), 2.15 (d, J= 6.8 Hz, 1H), 1.97 (d, J= 14.0 Hz, 4H), 1.73 (d, J= 13.9 Hz, 5H), 1.60 (dd, J= 11.3, 5.8 Hz, 2H), 1.44 - 1.39 (m, 1H), 1.17 (q, J = 11.9 Hz, 3H).Synthesis of (tS)-8-(5-oxo-3-(l -(2-(piperidin-4-yl)ethyl)piperidin-3-yl)-4,5-dihydro-l H-l ,2,4- triazol-l-yl)quinoIin-2(lH)-one, 2TFA (Cpd 300):Compound 300

[0314] The title compound was prepared according to Example 6a using tert-biityl 4-(2- oxoethyl)piperidine-l -carboxylate in Step 1 as starting material. MS m / z (M+H+) 423.1,1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 11.04 (s, 1H), 9.65 (s, 1H), 7.99 (d, J= 9.6 Hz, 1H), 7.74 (d, J= 7.8 Hz, 1H), 7.51 (dd, J = 7.8, 1.4 Hz, 1H), 7.25 (t, J= 7.8 Hz, 1H), 6.61 - 6.52 (m, 1H), 3.71 (d, J= 7.5 Hz, 1H), 3.52 (d, J= 11.9 Hz, 1H), 3.24 (d, J= 12.6 Hz, 2H), 3.14 (d, J = 6.6 Hz, 2H), 3.05 (d, J= 7.7 Hz, 1H), 2.81 (q, J= 12.0 Hz, 2H), 2.15 (d, J= 13.4 Hz, 1H), 1.98 (d, J= 14.2 Hz, 1H), 1.82 - 1.74 (m, 4H), 1.66 - 1.53 (m, 4H), 1.26 (qd, J= 14.1, 3.6 Hz, 3H).Synthesis of (5)-8-(3-(l-(2-(4,4-difluorocyclohexyl)ethyl)piperidin-3-yI)-5-oxo-4,5-dihydro- lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one, TFA (Cpd 301):Compound 301

[0315] The title compound was prepared according to Example 6a using 2-(4,4- difluorocyclohexyl)acetaldehyde in Step 1 as starting material. MS m / z (M+H+) 458.1, 1H NMR (400 MHz, DMSO-d6 ) δ 11.94 (s, 1H), 11.03 (s, 1H), 7.99 (dd, J= 9.7, 4.4 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 (dd, .7= 7.8, 1.4 Hz, 1H), 7.25 (t, .7= 7.7 Hz, 1H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 3.71 (d, J= 8.0 Hz, 1H), 3.53 (d, J= 12.2 Hz, 1H), 3.16 (s, 2H), 3.03 (d, J= 8.9 Hz, 2H), 2.90 (q, J= 11.7 Hz, 1H), 2.14 (d, J= 12.9 Hz, 1H), 1.98 (d, J= 12.2 Hz, 3H), 1.75 (d, J= 14.6 Hz, 5H), 1.62 (dt, J= 12.1, 7.0 Hz, 3H), 1.43 (s, 1H), 1.25 - 1.14 (m, 2H).Synthesis of (A)-8-(5-oxo-3-(l -(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-3-yl)-4,5- dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one, TEA (Cpd 302):Compound 302

[0316] The title compound was prepared according to Example 6a using 2-(tetrahydro-2H- pyran-4-yl)acetaldehyde in Step 1 as starting material. MS m / z (M+H+) 424.1,1H NM (R400 MHz, DMSO-d6,) δ 11.94 (s, 1H), 11.04 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.51 (dd, J= 7.8, 1.4 Hz, 1H), 7.25 (t, J= 7.8 Hz, 1H), 6.56 (dd, J= 9.6, 1.9 Hz, 1H), 3.85 - 3.75 (m, 2H), 3.71 (d, J= 7.9 Hz, 1H), 3.30 - 3.20 (m, 2H), 3.22 - 3.11 (m, 1H), 3.09 - 3.01 (m, 2H), 2.89 (q, J= 11.2 Hz, 1H), 2.14 (d, J= 13.0 Hz, 1H), 1.98 (d, J= 14.2 Hz, 1H), 1.77 (q, J= 13.7 Hz, 1H), 1.67 - 1.47 (m, 7H), 1.19 (dtd, J= 25.7, 11.9, 5.3 Hz, 3H).Example 6b

[0317] The process below describes the synthesis of an exemplary compound.

[0318] Step 1: A mixture of tert-butyl 3-(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidine-l- carboxylate (1.34 g, 4.99 mmol), 5 -bromoisoquinoline (1.308 g, 5.49 mmol), potassium phosphate (2.120 g, 9.99 mmol), and copper(I) iodide (0.380 g, 1.998 mmol) in DMF (25 mL) was purged with N2 for 5 min. Trans -N,N ’-dimethylcyclohexane-l,2-diamine (0.630 ml, 4.00 mmol) was then added. The dark brown mixture was stirred at 100 °C for 22 h. Another portion of copper(I) iodide (0.380 g, 1.998 mmol) was added, followed by 5-bromoisoquinoline (600mg). The mixture was purged with N2 for 5 min, and was treated with trans-N,N’- dimethylcyclohexane-l,2-diamine (0.630 ml, 4.00 mmol). The reaction mixture was stirred at 100 °C for another 24 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, and concentrated. The solvent was removed, and the residue was purified by flash chromatography. Fractions containing the desired product were pooled and concentrated to provide tert-butyl 3-(l-(isoquinolin-5-yl)-5-oxo-4,5-dihydro- lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate (1.2 g, 2.82 mmol, 56.5 % yield) as a brown solid.

[0319] Step 2: To a solution of tert-butyl 3-(l-(isoquinolin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl)piperidine-l -carboxylate (0.23 g, 0.541 mmol) in DCM (5 ml) was added TFA (0.5 ml, 6.49 mmol). The reaction mixture was stirred at r.t. overnight. The solvent was removed. The crude product was used in the next reaction without further purification. MS m / z (M+H+) 326.2.

[0320] Step 3: To a mixture of (5)-2-(isoquinolin-5-yl)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (183 mg, 0.620 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (196 mg, 0.929 mmol) in THF (6 mL) were added Hunig's base (271 μl, 1.549 mmol) and sodium triacetoxyborohydride (197 mg, 0.929 mmol). The slurry reaction mixture was stirred for 1 h. The reaction mixture was quenched with IN NaOH solution (0.2 mL). The mixture was concentrated and purified by flash chromatography. Fractions eluting in 15% MeOH / CFECh and containing the desired product were pooled and concentrated to provide tert-butyl (5)-6-(3-(l- (isoquinolin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)-2- azaspiro[3.3]heptane-2-carboxylate (Compound 258, 230 mg, 0.469 mmol, 76 % yield). MS m / z (M+Hl) 491.3. ‘H NMR (400 MHz, methanol-d4) δ 9.35 (s, 1H), 8.50 (d, J= 6.1 Hz, 1H), 8.22 (d, J= 8.2 Hz, 1H), 7.92 (dd, J= 7.5, 1.1 Hz, 1H), 7.85 (d, J= 6.1 Hz, 1H), 7.81 (t, J= 7.8 Hz, 1H), 3.95 (s, 2H), 3.84 (s, 2H), 3.72 (p, J= 6.6 Hz, 3H), 3.22 (q, J= 7.4 Hz, 2H), 3.09 - 2.85 (m, 2H), 2.50 - 2.29 (m, 3H), 2.25 - 2.10 (m, 3H), 1.82 - 1.58 (m, 2H), 1.42 (s, 9H).Synthesis of tert-butyl 6-((5)-3-(l-(isoquinolin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)-2-azaspiro[3.4]octane-2-carboxylate (Cpd 255):Compound 255

[0321] The title compound was prepared according to Example 6b using tert-butyl 6-oxo-2- azaspiro[3.4]octane-2-carboxylate as starting material in Step 3. MS m / z (M+H+) 505.3. 'H NMR (400 MHz, DMSO-d6) δ 12.31 - 12.14 (m, 1H), 9.51 (m, 2H), 8.58 (dd, J= 6.1, 1.8 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.98 - 7.85 (m, 1H), 7.81 (t, J= 6.9 Hz, 2H), 3.74 (m, 8H), 3.10 (d, J = 8.8 Hz, 2H), 2.90 (t, J= 12.7 Hz, 1H), 2.32 (q, J= 11.0, 8.9 Hz, 1H), 2.18 (d, J= 12.3 Hz, 1H), 2.13 - 1.86 (m, 4H), 1.86 - 1.57 (m, 3H), 1.36 (d, J= 4.0 Hz, 9H).Synthesis of tert-butyl (6-((5)-3-(l-(isoquinolin-5-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)piperidin-l-yl)spiro[3.3]heptan-2-yl)carbamate (Cpd 259):Compound 259

[0322] The title compound was prepared according to Example 6b using tert-butyl (6- oxospiro[3.3]heptan-2-yl)carbamate as starting material in Step 3. MS m / z (M+H+) 505.3. 'H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 9.54 (d, J= 10.3 Hz, 1H), 9.45 (s, 1H), 8.55 (d, J = 6.0 Hz, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.98 - 7.82 (m, 1H), 7.82 - 7.69 (m, 2H), 7.08 (t, J= 6.1 Hz, 1H), 3.82 (m, 5H), 2.99 (m, 2H), 2.81 - 2.61 (m, 1H), 2.38 (s, 1H), 2.34 - 2.05 (m, 6H), 2.04- 1.81 (m, 3H), 1.65 (m, 1H), 1.33 (s, 9H).Synthesis of (5-(l-(2-azaspiro [3.3] heptan-6-yl)piperidin-3-yl)-2-(2-methoxyquinolin-8-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 264):Compound 264

[0323] The title compound was prepared according to Example 5b using tert-butyl 6-(3-( 1 -(2- methoxyquinolin-8-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)-2- azaspiro[3.3]heptane-2-carboxylate, which in turn was prepared according to Example 6b using 8-bromo-2-methoxyquinoline as starting material in Step 1. MS m / z (M+H+) 421.3. 1H NMR (400 MHz, DMSO-d6 ) δ 11.91 (d, J= 34.8 Hz, 1H), 10.02 (d, J= 61.5 Hz, 1H), 8.60 (s, 2H), 8.32 (d, J= 8.8 Hz, 1H), 7.98 (dd, J= 8.2, 1.4 Hz, 1H), 7.71 (dd, J= 7.5, 1.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.07 (d, J= 8.8 Hz, 1H), 3.94 (m, 4H), 3.83 (s, 3H), 3.55 (s, 2H), 3.11 - 2.86 (m, 2H), 2.83 - 2.52 (m, 3H), 2.16 (d, J= 12.4 Hz, 1H), 1.97 (d, J= 14.8 Hz, 1H), 1.71 (d, J= 14.4 Hz, 1H), 1.55 (d, . / = 12.7 Hz, 1H).Example 7

[0324] The process below describes the synthesis of an exemplary compound.

[0325] Step 1: To a suspension of (S)-5-(piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one hydrochloride (1 g, 4.89 mmol) in THF (25 ml) was added DIPEA (1.280 ml, 7.33 mmol), sodium triacetoxyborohydride (1.553 g, 7.33 mmol) and 2-cyclohexylacetaldehyde (0.805 ml, 5.86 mmol). The mixture was stirred at r.t. for 2 hr. The reaction was quenched with water. The solid was filtered and dried. The filtrate was extracted with DCM (3x). The combined organiclayer was dried and concentrated. The crude (S)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one was used in the next reaction without further purification. MS m / z (M+H ) 279.3.

[0326] Step 2: To a suspension of (5)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (1.3 g, 4.67 mmol), copper(I) iodide (0.356 g, 1.868 mmol) and potassium carbonate (3.23 g, 23.35 mmol) in DMF (40 ml) under N2 was added 8-bromo-2- methoxyquinoline (1.668 g, 7.00 mmol) followed by trans-N,N'-dimethylcyclohexane-l,2- diamine (0.589 ml, 3.74 mmol). The reaction mixture was stirred at 100 °C for 2 days. LCMS indicated that a lot of starting material remained. Copper(I) iodide (0.356 g, 1.868 mmol) and trans-N, A-dimethylcyclohexane-1 ,2-diamine (0.589 ml, 3.74 mmol) were added to the reaction mixture. The reaction mixture was stirred at 100 °C for 3 days. The reaction mixture was cooled to r.t. and quenched with water. The solid was filtered and washed with DCM. The filtrate was concentrated. The crude product was purified by ISCO (0-20%, MeOH / EtOAc) to afford (.S’)-5- (l-(2-cy cl ohexylethyl)piperi din-3 -yl)-2-(2-methoxyquinolin-8-yl)-2,4-dihydro-3H- 1,2, 4-triazol- 3-one (0.75g, 36.9%). MS m / z (M+H+) 436.3.

[0327] Step 3. To a solution of (5)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(2- methoxyquinolin-8-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (0.8 g, 1.837 mmol) in THF (16 ml) was added HC1 (6N, 1.224 ml, 7.35 mmol). The mixture was stirred at 60 °C overnight. The reaction mixture was cooled to r.t., and the solvent was removed. Water was added to the residue and extracted with DCM (6x). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by ISCO (0-20%, MeOH / DCM) to obtain (S)-8-(3- (l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)- one, HC1 (Compound 144). MS m / z (M+H+) 422.3, 1H NMR (400 MHz, DMSO-t / 6) 8 11.96 (s, 1H), 11.05 (s, 1H), 7.98 (d, J= 9.6 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.24 (t, J= 7.8 Hz, 1H), 6.55 (dd, J= 9.5, 1.8 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.47 - 3.22 (m, 2H), 3.06 - 3.02 (m, 3H), 2.82 (s, 1H), 2.14 - 2.09 (m, 1H), 1.90 (s, 2H), 1.69 - 1.53 (m, 8H), 1.32 - 1.06 (m, 4H), 0.89 (qd, J= 13.3, 12.5, 3.6 Hz, 2H).Synthesis of 5-(l -(2-cyclohexylethyl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 28):Compound 28

[0328] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and l-iodo-3 -methoxybenzene in Step 2 as starting material. MS m / z (M+H+) 371.3.Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(2-methoxyphenyl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 29):Compound 29

[0329] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and l-iodo-2-methoxybenzene in Step 2 as starting material. MS m / z (M+H+) 371.3. 1H NMR (400 MHz, methanol-d4) δ 7.51 - 7.41 (m, 1H), 7.35 (dd, J = 29.6, 7.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.06 (t, J= 7.7 Hz, 1H), 4.04 (m, 1H), 3.92 (s, 3H), 3.64 (d, J= 12.4 Hz, 1H), 3.23 - 2.88 (m, 3H), 2.37 - 1.59 (m, 11H), 1.45 - 0.78 (m, 4H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(isoquinolin-5-yI)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 62):Compound 62

[0330] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 5-iodoisoquinoline in Step 2 as starting material. MS m ,'z (M+H+) 392.3. 1H NMR (400 MHz, methanol-d4) δ 9.41 (s, 1H), 8.52(s, 1H), 8.27 (d, J= 8.2 Hz, 1H), 7.96 (td, J= 15.5, 14.8, 6.7 Hz, 2H), 7.84 (t, J= 7.9 Hz, 1H), 4.15 (m, 1H), 3.91 (d, J= 11.4 Hz, 1H), 3.66 (d, J= 12.5 Hz, 1H), 3.16 - 2.94 (m, 2H), 2.86 (m, 1H), 2.35 (d, J= 13.2 Hz, 1H), 2.15 (d, J= 16.9 Hz, 1H), 2.01 - 1.54 (m, 7H), 1.49 - 1.15 (m, 3H), 1.07 (d, J= 11.7 Hz, 2H), 0.91 (m, 1H), 0.73 (m, 1H).Synthesis of 5-(3-(l-(cyclohexylmethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)-3,4-dihydroisoquinolin-l(2H)-one (Cpd 72):Compound 72

[0331] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and tert-butyl 5-bromo-l-oxo-3,4- dihydroisoquinoline-2(lH)-carboxylate in Step 2 as starting material. MS m / z (M+H+) 410.3. 1H NMR (400 MHz, methanol-d4) δ 8.05 (dd, J= 7.7, 1.4 Hz, 1H), 7.62 (dd, J= 29.5, 7.9 Hz, 1H), 7.50 (t, J= 7.8 Hz, 1H), 3.97 (m, 1H), 3.71 - 3.37 (m, 3H), 3.24 - 2.78 (m, 8H), 2.19 (m, 2H), 2.05 - 1.61 (m, 7H), 1.44 - 0.82 (m, 5H).Synthesis of 5-(l-(cyclohexylmethyI)piperidin-3-yl)-2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 73):Compound 73

[0332] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 6-iodo-2,3- dihydrobenzo[b ][l,4]dioxine in Step 2 as starting material. MS m / z (M+H+) 399.1. 1H NMR (400 MHz, methanol-d4) δ 7.45 - 7.21 (m, 2H), 6.87 (d, J= 8.8 Hz, 1H), 4.26 (s, 4H), 3.76 (m, 1H),3.55 - 3.39 (m, 1H), 3.27 - 2.84 (m, 4H), 2.35 - 1.64 (m, 11H), 1.32 (m, 3H), 1.08 (d, J= 11.5 Hz, 2H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(benzo[< / | [l,3]dioxol-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Cpd 74):Compound 74

[0333] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 5-bromobenzo[d][l,3]dioxole in Step 2 as starting material. MS m 'z (M+H+) 385.3. (400 M1HH Nz,M mRethanol-d 4) δ 7.36 (s, 2H), 6.87 (d, ,7 = 8.4 Hz, 1H), 5.99 (s, 2H), 4.17 (m, 1H), 3.65 (m, 1H), 3.28 - 2.84 (m, 4H), 2.32- 1.66 (m, 11H), 1.49 - 1.19 (m, 3H), 1.08 (d, J= 12.2 Hz, 2H).Synthesis of tert-butyl 5-(3-(l-(cyclohexylmethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)-l-oxo-3,4-dihydroisoquinoline-2(lH)-carboxylate (Cpd 80):Compound 80

[0334] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and tert-butyl 5-bromo-l-oxo-3,4- dihydroisoquinoline-2(lH)-carboxylate in Step 2 as starting material. MS m / z (M+H+) 510.3. 1H NMR (400 MHz, methanol-d4) δ 8.22 - 8.15 (m, 1H), 7.68 (m, 1H), 7.52 (t, J= 7.1 Hz, 1H), 4.10 (m, 1H), 3.95 (t, .7= 6.2 Hz, 1H), 3.84 (t, J= 13.2 Hz, 1H), 3.65 (d, J= 12.7 Hz, 1H), 3.54 - 3.38 (m, 1H), 3.26 - 2.80 (m, 5H), 2.29 (d, J= 12.9 Hz, 1H), 2.11 (s, 2H), 2.03 - 1.61 (m, 8H), 1.57(s, 9H), 1.46 - 0.81 (m, 5H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(quinolin-8-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (Cpd 84):Compound 84

[0335] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 8-iodoquinoline in Step 2 as starting material. MS m / z (M+H+) 392.3.1H (4 N00M MRHz, methanol-d4) δ 8.92 (dd, J= 15.4, 4.3 Hz, 1H), 8.53 (t, .7 = 9.0 Hz, 1H), 8.14 (d, J= 8.1 Hz, 1H), 7.89 (dd, J= 16.6, 7.4 Hz, 1H), 7.76 (td, J = 7.9, 4.0 Hz, 1H), 7.67 (ddd, J= 12.1, 8.3, 4.3 Hz, 1H), 4.11 (m, 1H), 3.57 - 3.44 (m, 1H), 3.30 - 2.86 (m, 4H), 2.45 - 1.50 (m, 12H), 1.47 - 0.69 (m, 4H).Synthesis of 2-(benzo[* / ][l,3]dioxol-4-yl)-5-(l-(cyclohexylmethyl)piperidin-3-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Cpd 87):Compound 87

[0336] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 4-iodobenzo[d][l,3]dioxole in Step 2 as starting material. MS m'z (M+H+) 385.3. 1H NMR (400 MHz, methanol-6 / 4) 8 6.93 (m, 3H), 6.02 (d, J= 9.2 Hz, 2H), 3.96 (m, 1H), 3.52 (m, 1H), 3.29 - 2.86 (m, 4H), 2.33 - 1.65 (m, 12H), 1 .49 - 1.15 (m, 2H), 1 .03 (m, 2H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(quinolin-5-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (Cpd 89):Compound 89

[0337] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 5-iodoquinoline in Step 2 as starting material. MS m z (M+H+) 392.3. 1H NMR (400 MHz, methanol-d4) δ 8.99 (s, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.18 (dt, J= 8.5, 1.1 Hz, 1H), 7.95 (t, J= 7.8 Hz, 1H), 7.87 - 7.76 (m, 1H), 7.69 (dd, J= 8.6, 4.5 Hz, 1H), 4.15 (m, 1H), 3.91 (m, 1H), 3.30 - 2.84 (m, 4H), 2.25 (m, 3H), 2.04 - 1.57 (m, 8H), 1.53 - 0.69 (m, 5H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(isoquinolin-8-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 99):Compound 99

[0338] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 8-iodoisoquinoline in Step 2 as starting material. MS m / z (M+H+) 392.3. 1H NMR (400 MHz, DMSO-d6)) δ 9.43 (s, 1H), 8.52 (d, .7= 5.7 Hz, 1H), 7.92 (d, J= 8.1 Hz, 1H), 7.87 (d, J= 5.7 Hz, 1H), 7.81 (t, .7 = 7.8 Hz, 1H), 7.73 (d, J= 7.4 Hz, 1H), 3.03 (d, J= 11.3 Hz, 1H), 2.86 - 2.61 (m, 2H), 2.19 - 1.84 (m, 5H), 1.80 - 1.57 (m, 5H), 1.57 - 1.36 (m, 2H), 1.35 - 1.05 (m, 6H), 0.91 - 0.75 (m, 2H).Synthesis of 5-(l -(cyclohexylmethyl)piperidin-3-yl)-2-(l H-indazol-7-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 103):Compound 103

[0339] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 7-bromo-1H-indazole in Step 2 as starting material. MS m / z (M+H+) 381.3. 1H NMR (400 MHz, DMSO-d6) δ 12.76 (m, 1H), 12.30 (m, 1H), 8.19 (dd, J= 4.2, 1.5 Hz, 1H), 7.86 (dd, J= 23.1, 7.5 Hz, 1H), 7.69 (dd, J= 8.1, 4.9 Hz, 1H), 7.18 (t, J= 7.8 Hz, 1H), 4.02 (m, 1H), 3.58 (m, 1H), 3.16 - 2.75 (m, 4H), 2.20 (m, 2H), 2.05 - 1.53 (m, 9H), 1.39 - 0.90 (m, 5H).Synthesis of 8-(3-(l-(cyclohexylmethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)quinolin-2(lH)-one (Cpd 109):Compound 109

[0340] The title compound was prepared according to Example 5a using 5-(l-(cy cl ohexylmethyl)piperi din-3 -yl)-2-(2-m ethoxy quinolin-8-yl)-2,4-dihydro-3H-l, 2, 4-triazol-3- one as starting material, which in turn was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 8-bromo-2-methoxyquinoline in Step 2 as starting material. MS m / z' (M+H+) 408.3.1H NMR (400 MHz, chloroform-d ) δ 10.70 (s, 1H), 8.00 (dd, J= 8.0, 1.4 Hz, 1H), 7.77 (d, J= 9.6 Hz, 1H), 7.48 (dd, J= 7.9, 1.4 Hz, 1H), 7.30 - 7.24 (m, 1H), 6.68 (d, J= 9.5 Hz, 1H), 3.13 (m, 1H), 2.90 - 2.54 (m, 3H), 2.39 - 2.12 (m, 3H), 2.04 (d, J= 4.4 Hz, 1H), 1.95 - 1.61 (m, 8H), 1.56 (ddq, J= 11.1, 7.3, 3.6 Hz, 1H), 1.35 - 1.07 (m, 3H), 1.04 - 0.77 (m, 2H).Synthesis of 5-(l -(cyclohexylmethyl)piperidin-4-yl)-2-(isoquinolin-5-yl)-2,4-dihydro-3H- l,2,4-triazol-3-one (Cpd 112):Compound 112

[0341] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 5-iodoisoquinoline in Step 2 as starting material. MS m z (M+H+) 392.2. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (d, J= 4.5 Hz, 1H), 9.47 (d, J= 4.2 Hz, 1H), 9.08 (m, 1H), 8.57 (t, J= 6.6 Hz, 1H), 8.24 (d, J= 8.2 Hz, 1H), 8.03 - 7.88 (m, 1H), 7.83 (dt, J= 15.7, 7.0 Hz, 2H), 3.70 - 3.37 (m, 4H), 3.31 - 2.85 (m, 5H), 2.31 - 2.05 (m, 2H), 1.98 (qd, J= 14.5, 14.0, 3.6 Hz, 1H), 1.87 - 1.49 (m, 6H), 1.37 - 1.09 (m, 2H), 0.97 (tt, J= 12.1, 6.3 Hz, 2H).Synthesis of 5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(2-methoxyquinolin-8-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 113

[0342] The title compound was prepared according to Example 7 using cyclohexanecarbaldehyde in Step 1 as starting material and 8-bromo-2-methoxyquinoline in Step 2 as starting material. MS m z (M+H+) 422.3.1H NMR (400 MHz, DMSO-76) δ 11.50 (s, 1H), 8.29 (d, 7= 8.9 Hz, 1H), 7.95 (dd, 7= 8.1, 1.5 Hz, 1H), 7.71 (dd, 7= 7.5, 1.5 Hz, 1H), 7.48 (t, 7= 7.8 Hz, 1H), 7.04 (d, 7= 8.8 Hz, 1H), 3.99 (q, 7= 5.2 Hz, 2H), 3.84 (s, 3H), 3.02 - 2.88 (m, 1H), 2.80 - 2.62 (m, 2H), 2.18 - 2.00 (m, 2H), 2.00 - 1.84 (m, 2H), 1.80 - 1.57 (m, 6H), 1.47 (m, 2H), 1.26 - 1.02 (m, 3H), 0.81 (q, 7= 11.9 Hz, 2H).Synthesis of 5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(2,5-dimethoxyquinolin-8-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound 256

[0343] The title compound was prepared according to Example 7 using 8-bromo-2,5- dimethoxy quinoline as starting material in Step 2. MS m / z (M+H+) 466.3.1H NMR (400 MHz, methanol-d4) δ 8.49 - 8.41 (m, 1H), 7.70 (d, J= 8.3 Hz, 1H), 6.94 (dd, J= 8.7, 7.5 Hz, 2H), 4.04 (s, 3H), 3.88 (s, 3H), 3.00 - 2.81 (m, 1H), 2.45 (ddd, J= 11.1, 7.7, 4.4 Hz, 2H), 2.30 - 2.16 (m, 1H), 2.13 - 1.99 (m, 2H), 1.88 - 1.61 (m, 6H), 1.61 - 1.49 (m, 1H), 1.49 - 1.38 (m, 2H), 1.37 - 1.08 (m, 7H), 1.05 - 0.83 (m, 2H).Example 7a

[0344] The process below describes the synthesis of an exemplary compound.

[0345] To a solution of (S)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)-5-methoxyquinolin-2(lH)-one (150 mg, 0.332 mmol) in DCM (3 ml) was added dropwise BBrs (1.329 ml, 1.329 mmol, IM in DCM) at 0 °C. The reaction mixture was stirred at r.t. for 5 days. After the reaction was completed, water (10 ml) was added to the reaction mixture at 0 °C. The mixture was extracted with EtOAc (20 ml x 3). The combined organic layer was washed with sat. NaHCCh. The aq. layer was concentrated to afford (5)-8-(3-(l-(2- cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-5-hydroxyquinolin- 2(lH)-one (Compound 296). MS m / z (M+H+) 438.3,1H NMR (400 MHz, methanol-d4) δ 8.31 (dd, J = 9.7, 1.0 Hz, 1H), 7.50 (ddd, J = 23.2, 8.6, 1.1 Hz, 1H), 6.72 (ddd, J= 8.5, 6.6, 1.0 Hz, 1H),6.57 (dd, J= 9.7, 1.0 Hz, 1H), 4.11 - 4.02 (m, 1H), 3.89 (d, J= 7.9 Hz, 1H), 3.66 (d, J= 12.4 Hz, 1H), 3.52 - 3.33 (m, 1H), 3.31 (d, J= 1.7 Hz, 6H), 3.27 - 3.10 (m, 4H), 2.98 (td, J= 13.1, 3.1 Hz, 1H), 2.31 (d, J= 13.7 Hz, 1H), 2.19 - 2.11 (m, 1H), 2.01 - 1.86 (m, 1H), 1.84 - 1.60 (m, 6H), 1.44 - 1.12 (m, 2H), 1.09 - 0.92 (m, 1H).Example 7b

[0346] The process below describes the synthesis of an exemplary compound.

[0347] Step 1: To a mixture of 5-(piperidin-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one hydrochloride (4.14 g, 20.23 mmol) in THF (50 mb) were added Hunig's base (8.83 ml, 50.6 mmol), cyclohexanecarbaldehyde (2.94 ml, 24.27 mmol) and sodium triacetoxyborohydride (6.43 g, 30.3 mmol). The reaction mixture was stirred for 1.5 h. The reaction mixture was quenched with IN NaOH solution (5 mL). The mixture was concentrated and purified by flash chromatography. Fractions eluting in 20-25% MeOH / CH2CI2 were pooled and concentrated to provide 5-(l-(cyclohexylmethyl)piperidin-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (3.42 g, 9.04 mmol, 44.7 % yield) as an off-white solid.

[0348] Step 2: A mixture of 5-(l-(cyclohexylmethyl)piperidin-4-yl)-2,4-dihydro-3H-l,2,4- triazol-3-one (65 mg, 0.246 mmol), l-iodo-4-methoxybenzene (86 mg, 0.369 mmol), potassium carbonate (104 mg, 0.492 mmol), and copper(I) iodide (18.73 mg, 0.098 mmol) in DMF (1 mL) was purged with N2 for 3 min. (1R ,2R )-N,N’-dimethylcyclohexane-l,2-diamine (31.0 pl, 0.197 mmol) was then added. The blue mixture was stirred at 100 °C for 44 h. The reaction mixture was quenched with 1 N NaOH solution. The mixture was extracted with EtOAc, washed with water followed by brine, and concentrated. The residue was purified by flash chromatography to provide 5-(l-(cyclohexylmethyl)piperidin-4-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 111). MS m / z (M+H+) 371.2. 1H NMR (400 MHz, DMSO-d6) δ 1 1.98 (d, J= 2.7 Hz, 1H), 9.15 (broad s, 1H), 7.83 - 7.66 (m, 2H), 7.08 - 6.95 (m, 2H), 3.76 (s, 3H), 3.59 (d, J= 12.2 Hz, 2H), 3.22 - 2.78 (m, 5H), 2.28 - 2.06 (m, 3H), 2.06 - 1.86 (m, 1H), 1.86 - 1.53 (m, 6H), 1.38 - 1.07 (m, 3H), 0.94 (m, 2H).Example 8

[0349] The process below describes the synthesis of an exemplary compound.

[0350] Step 1: To a solution of (5)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-l-yl)-5-hydroxyquinolin-2(lH)-one (34 mg, 0.078 mmol) in DMF (1 ml) was added NaH (9.32 mg, 0.233 mmol). The mixture was stirred at r.t. for 30 mins. Tertbutyl (3-bromopropyl)carbamate (20.35 mg, 0.085 mmol) was added to the reaction mixture. The reaction mixture was stirred at r.t. overnight. Water was added to the mixture and extracted with EtOAc (2x). The combined organic layer was washed with brine, dried over MgSCX and concentrated. The crude product was used in the next reaction without further purification.MS m z (M+H") 595.4.

[0351] Step 2: To a solution of tert-butyl (S)-(3-((8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5- oxo-4, 5-dihy dro- 1H- 1 ,2,4-triazol- 1 -yl)-2-oxo- 1 ,2-dihy droquinolin-5-yl)oxy)propyl)carbamate (20 mg, 0.034 mmol) in DCM (1 ml) was added TFA (0.1 ml, 1 .298 mmol). The reaction mixture was stirred at r.t. overnight. The solvent was removed. The crude product was submitted for purification to obtain (5)-5-(3-aminopropoxy)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5- oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one, 2 TFA (Compound 298). MS m / z (M+H+) 495.3,1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 11.06 (s, 1H), 8.13 (d, J= 9.7 Hz, 1H), 7.76 (s, 2H), 7.42 (d, J= 8.6 Hz, 1H), 6.80 (d, J= 8.7 Hz, 1H), 6.51 (d, J= 9.7 Hz, 1H), 4.21 (t, J= 5.9 Hz, 2H), 3.67 (d, J= 8.4 Hz, 1H), 3.51 (d, J= 11.9 Hz, 1H), 3.16 - 3.09 (m, 2H),3.06 - 2.99 (m, 3H), 2.87 (d, J = 11.0 Hz, 1H), 2.09 (p, J= 7.5, 6.3 Hz, 3H), 1.96 (d, J= 14.5 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.67 - 1.43 (m, 8H), 1.18 (ddt, J= 30.9, 20.6, 10.7 Hz, 5H), 0.97 - 0.76 (m, 2H).Example 8a

[0352] The process below describes the synthesis of an exemplary compound.

[0353] To a solution of (S)-5-(3-aminopropoxy)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5- oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one (Compound 298, 32 mg, 0.065 mmol) in DMF (0.6 ml) were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l, 3-dione (21.44 mg, 0.078 mmol) and DIPEA (56.5 μl, 0.323 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled, and then water was added to the mixture. The resulting solid was filtered and washed with water. The crude product was dissolved in DMF and submitted for purification to obtain 4-((3-((8-(3-((S)-l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo- 4,5-dihydro-lH-l,2,4-triazol-l-yl)-2-oxo-l,2-dihydroquinolin-5-yl)oxy)propyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione, TFA (Compound 297). MS m / z (M+H+) 751.1.Example 9

[0354] The process below describes the synthesis of an exemplary compound.

[0355] To a solution of 2-(4-methoxyphenyl)-5-((35)-l-(piperidin-3-ylmethyl)piperidin-3-yl)- 2,4-dihydro-3H-l,2,4-triazol-3-one (65 mg, 0.175 mmol) in DCM (2 mL) was added isocyanatotrimethylsilane (46.9 μl, 0.350 mmol). The reaction mixture was stirred at r.t. for 3 h. Another portion of isocyanatotrimethylsilane (46.9 μl, 0.350 mmol) was added. The reaction mixture was stirred at r.t. for 2 d. The solvent was evaporated, and the crude product waspurified by ISCO (0-20% MeOH / EtOAc) to obtain 2-(4-methoxyphenyl)-5-((3S)-l-(l - carboxamide-piperi din-3 -ylmethyl)piperi din-3 -yl)-2,4-dihydro-3H-l, 2, 4-triazol-3 -one (Compound 91). MS m / z (M+Hl) 415.2. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (broad s, 1H), 7.73 (d, J= 8.9 Hz, 2H), 7.00 (d, J= 8.9 Hz, 2H), 6.05 (s, 2H), 3.91 - 3.77 (m, 2H), 3.70 - 3.55 (m, 3H), 3.24 - 2.97 (m, 4H), 2.92 (dd, J= 16.1, 6.3 Hz, 1H), 2.68 (m, 1H), 2.13 (d, J= 12.7 Hz, 1H), 1.97 (d, J= 13.7 Hz, 2H), 1.81 (d, J= 12.8 Hz, 2H), 1.61 (m, 2H), 1.45 - 1.34 (m, 1H), 1.24 (d, J= 10.5 Hz, 1H).Example 10

[0356] The process below describes the synthesis of an exemplary compound.

[0357] To a solution of 8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl)quinolin-2(lH)-one (18 mg, 0.043 mmol) in EtOH (2 mL) / H20 (0.1 mb) were added Pd / C, 10 wt % (5 mg), and ammonium formate (26.9 mg, 0.427 mmol). The reaction mixture was stirred at 80 °C for 15 h. The mixture was filtered through a syringe filter, and washed with MeOH. The filtrate was concentrated and purified by flash chromatography to obtain 8-(3-(l-(2- cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-3,4-dihydroquinolin- 2(lH)-one (Compound 129). MS m / z (M+H+) 424.3.1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.24 (d, J= 7.5 Hz, 2H), 7.03 (t, J= 7.7 Hz, 1H), 2.96 (dd, J= 8.6, 6.3 Hz, 2H), 2.00 (broad s, 1H), 1.81 - 1.40 (m, 9H), 1.40 - 1.07 (m, 5H), 0.91 (q, J= 11.9 Hz, 2H).Example 11

[0358] The process below describes the synthesis of an exemplary compound.

[0359] To a vial containing 3-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl)benzonitrile (30 mg, 0.079 mmol) was added concentrated HC1 solution. The brown mixture was stirred at r.t. for 28 h. The solvent was removed, and the residue was purified by flash chromatography to provide 3-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-l-yl)benzamide (Compound 132). MS m / z (M+Hl) 398.3. 1H NMR (400 MHz, DMSO-d6) δ 12.29 - 12.07 (m, 1H), 9.39 (s, 1H), 8.36 (s, 1H), 8.16 - 7.93 (m, 2H), 7.70 (dt, J= 7.9, 1.3 Hz, 1H), 7.52 (td, J= 8.0, 2.4 Hz, 1H), 7.45 (s, 1H), 3.67 (m, 2H), 3.14 (m, 5H), 2.92 (t, J= 11.7 Hz, 1H), 2.15 (d, J= 13.0 Hz, 1H), 1.98 (d, J= 14.3 Hz, 1H), 1.80 - 1.48 (m, 9H), 1.39 - 1.07 (m, 3H), 0.94 (m, 2H).Example 12

[0360] The process below describes the synthesis of an exemplary compound.To a mixture of (5)-5-(l-(2-azaspiro[3.3]heptan-6-yl)piperidin-3-yl)-2-(isoquinolin-5-yl)-2,4- dihydro-3H-l,2,4-triazol-3-one (90 mg, 0.230 mmol) in CH2CI2 (2 mL) / THF (2 mb) was added Hunig's base (161 μl, 0.922 mmol). After stirring for 3 min, a suspension was formed. Paraformaldehyde (69.2 mg, 2.305 mmol) and sodium triacetoxyborohydride (147 mg, 0.691 mmol) were then added. The reaction mixture was stirred at r.t. for 3 h. The reaction mixture was quenched with a few drops of IN NaOH solution, concentrated and purified by reverse-phase flash chromatography (5 g of C18 gold cartridge, gradient elution from water containing 0.1% NH4OH to 40% CH3CN / H2O containing 0.1% NH4OH) to provide (5)-2-(isoquinolin-5-yl)-5-(l-(2-methyl-2-azaspiro[3.3]heptan-6-yl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Compound 260, 8 mg, 0.020 mmol, 8.58 % yield) as a while powder. MS m / z (M+H+) 405.2.Synthesis of 8-(3-(l-(2-methyl-2-azaspiro [3.3] heptan-6-yl)piperidin-3-yl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one (Cpd 265):Compound 265

[0361] The title compound was prepared according to Example 12 using 8-(3-(l-(2- azaspiro[3.3]heptan-6-yl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin- 2(lH)-one as starting material. MS m / z (M+H+) 421.3.Synthesis of 2-(2-methoxyquinolin-8-yl)-5-(l-(2-methyl-2-azaspiro[3.3]heptan-6- yl)piperidin-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 267):Compound 267

[0362] The title compound was prepared according to Example 12 using 5-(l-(2- azaspiro[3.3 ]heptan-6-yl)piperi din-3 -yl)-2-(2-methoxyquinolin-8-yl)-2,4-dihydro-3H- 1,2,4- triazol-3-one as starting material. MS m / z (M+H+) 435.3.1H NMR (400 MHz, methanol-^)6 8.19 (d, J= 8.9 Hz, 1H), 7.94 (dd, J= 8.2, 1.4 Hz, 1H), 7.77 (dd, J= 7.5, 1.4 Hz, 1H), 7.51 (dd, J = 8.1, 7.4 Hz, 1H), 7.00 (d, J= 8.9 Hz, 1H), 3.91 (s, 3H), 3.42 - 3.33 (m, 3H), 3.27 - 3.20 (m, 3H), 3.09 (d, J= 11.4 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.72 - 2.61 (m, 1H), 2.32 (s, 3H), 2.09 (d, J = 13.0 Hz, 1H), 2.05 - 1.95 (m, 3H), 1.93 - 1.75 (m, 2H), 1.72 - 1.43 (m, 2H).Example 13 - Chiral Separation of EnantiomersPreparation of (>S)-5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 4) and (7?)-5-(l-(cyclohexylmethyl)piperidin-3-yl)-2-(4- methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 5):

[0363] The title compounds were prepared by chiral separation of the racemate 5-(l- (cyclohexylmethyl)piperidin-3-yl)-2-(4-methoxyphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (33 mg) by chiral HPLC using ChiralCel® OJ (5 x 50 cm, 20 pm) with mobile phase consisting of methanol / diethylamine 100:0. 1. Compound 4: Optical rotation - positive; ee 97.7%; MS m / z (M+H+) 371.5. Compound 5: Optical rotation - negative; ee > 98%. MS m z (M+H ) 371.5.Preparation of (»S)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl)-3,4-dihydroquinolin-2(lH)-one (Cpd 142) and (lf)-8-(3-(l-(2- cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-3,4- dihydroquinolin-2(lH)-one (Cpd 143):

[0364] The title compounds were prepared by chiral separation of the racemate 8-(3-( 1 -(2- cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)-3,4-dihydroquinolin- 2(lH)-one (33 mg) by chiral HPLC using ChiralPak® IG (5 x 50 cm, 20 pm) with mobile phase consisting of methanol / diethylamine 100:0.1. Compound 142: Optical rotation - positive; ee 97.7%; MS m / z (M+H+) 424.3. Compound 143: Optical rotation - negative; ee 97.7%. MS m / z (M+H+) 424.3.Preparation of ($)-8-(3-(l-(2-cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl)quinolin-2(lH)-one (Cpd 144) and (l?)-8-(3-(l-(2-cyclohexylethyl)piperidin-3- yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one (Cpd 145):Compound 144 Compound 145

[0365] The title compounds were prepared by chiral separation of the racemate 8-(3-(l-(2- cyclohexylethyl)piperidin-3-yl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)quinolin-2(lH)-one (33 mg) by chiral HPLC using ChiralPak® IG (5 x 50 cm, 20 pm) with mobile phase consisting of methanol / diethylamine 100:0.1. Compound 144: Optical rotation - positive; ee 97.7%; MS m / z (M+H+) 422.3. Compound 145: Optical rotation - negative; ee 97.7%. MS m / z (M+H+) 422.3.Preparation of (5)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(lH-indazol-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 149) and (l?)-5-(l-(2-cyclohexylethyl)piperidin-3-yl)-2-(lH- indazol-4-yI)-2,4-dihydro-3H-l,2,4-triazol-3-one (Cpd 150):Compound 149 Compound 150

[0366] The title compounds were prepared by chiral separation of the racemate 5-(l-(2- cyclohexylethyl)piperidin-3-yl)-2-(lH-indazol-4-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (33 mg) by chiral HPLC using ChiralPak® IG (5 x 50 cm, 20 pm) with mobile phase consisting of hexane s / EtOH / iPrNfh 40:60:0.04. Compound 149: Optical rotation - positive; ee 97.7%; MS m / 'z (M+H+) 395.2. Compound 150: Optical rotation - negative; ee 97.7%; MS m / z (M+H+) 395.2.

[0367] Table 2 shows additional compounds that were synthesized using similar procedures as described herein.Table 2Biological Studies of CompoundsExample 14. High-throughput screening (HTS) NNMT inhibition assayDetermining HTS assay parameters

[0368] KM values of nicotinamide for nicotinamide / V-methyl transferase (NNMT) were determined using the method of initial rates. Briefly, MTase enzymes were diluted to 5-30 nM in 20 mM Tris (pH 8.0), 150 mMNaCl, 12 mM MgCl2, 4 mM EDTA, 0.1% BSA, and 100 pM S-adenosyl-L- methionine (SAM). Reactions were initiated by adding substrate at various concentrations.Reactions were allowed to proceed for discreet time points, and progress was terminated by adding the MTase-Glo™ reagent (Promega, Madison, Wisconsin) to deplete excess SAM. Reaction progress was measured as a function of conversion of SAM to 5-adenosyl-L-homocysteine (SAH) using the MTase-Glo™ Kit (Promega). KM values for SAM were determined by the same method, but by holding nicotinamide concentration constant at 100 pM and varying the concentration of SAM. Initial rates were determined by plotting the generation of SAH as a function of time to generate a linear slop. These rates were then plotted as a function of substrate concentration and fitted to the Michaelis-Menten equation to determine KM.

[0369] HTS assay duration was determined by running a time course experiment using the previously determined KM values for nicotinamide and SAM. A solution of 5 pM SAM and5 pM nicotinamide were prepared in 20 mM Tris (pH 8.0), 150 mM NaCl, 12 mM MgCh, 4 mM EDTA, and 0.1% BSA. Reactions were initiated by adding a small-molecule methyltransferase (SMMTase) to a final concentration of 7.5, 15, or 30 pM. Reaction progress was recorded at regular intervals by quenching the reaction with the addition of MTase-Glo™ reagent to consume excess SAM. The 20% conversion point was identified by comparing reaction progressto an SAH standard curve. Ideal reaction duration and enzyme concentration were selected based on the combination which achieved 10-20% conversion in 20-30 minutes.

[0370] The NNMT activity assay for HTS was performed according to the protocol described in Table 3.Table 3. Protocol for NNMT HTS MTase-Glo™ assay

[0371] Table 4 shows the IC50 for compounds disclosed herein in the NNMT activity HTS assay. In Table 4, the plus symbols denote the following: ++++ = IC5o < 100 nM; +++ = ICso> 100 nM and < 1 pM; ++ = IC50 > 1 pM and < 10 pM; + = IC50 > 10 pM; and null = insignificant inhibition.Table 4Example 15. Assessment of Compounds 144 and 145 in murine tumor modelsMurine tumor models

[0372] In a high-grade serous ovarian cancer model, two million ID8-luc ovarian cancer cells were intraperitoneally (i.p.) injected into female C57BL / 6 mice, and their body weight was measured weekly. Mice were sacrificed at indicated time points, and omental tumors were weighed. In subcutaneous tumor models, one million MC38 colon cancer cells or 5 million cells of the low- grade serous ovarian cancer cell line LG-6406 were subcutaneously (s.c.) injected into the flank of C57BL / 6 mice or nude mice, respectively. Tumor volumes were measured twice weekly along three axes (length a, width b and height c) and calculated as follows: tumor volume = (a x b x c) / 2. Mice were euthanized before reaching the maximal tumor size (2,000 mm3) or before the diameter of the tumor reached 1.5 cm as approved by the IACUC of the University of Chicago. In an intravenous tumor model, 100,000 EO771-LMB breast cancer cells were inoculated via retro- orbital intravenous (i.v.) injection into C57BL / 6 mice during the administration of continuous inhalation anesthesia using isoflurane, and mice were sacrificed after 12-16 days. To analyze the number and size of metastases, lungs were removed, formalin fixed, paraffin embedded, and H&E stained by the University of Chicago Human Tissue Resource Center. One slide per lung was analyzed. Slides were scanned using the Olympus VS200 Whole Slide Scanner, and metastases were measured in QuPath (v0.3.0). Metastasis size was normalized to the total lung area of the respective slide, and the average size of the five biggest metastases was plotted per mouse.Treatment with Compound 144 or 145

[0373] For i.p. treatment, either the active NNMT inhibitor (NNMTi) Compound 144 or its distomer (NNMTi-D), Compound 145, was dissolved in 10% DMSO and mixed in a 1 : 1 ratio with alginic acid (Millipore Sigma, 180947). 100 pL of a solution containing a final concentration of 10 mg / mL alginic acid and 4 mg / kg of the NNMTi or the distomer was i.p. injected per mouse [Downs et al., J. Cell. Physiol., 152:422-429 (1992)]. The mice were i.p. injected with either the vehicle (10% DMSO, 10 mg / kg alginic acid), the NNMTi (100 pg / mouse) or the distomer (100 pg / mouse). The first treatment was administered seven days after ID8-luc injection, and treatment was conducted three times weekly until the end of the study. Tumor burden was assessed using In Vivo Imaging System (IVIS) (PerkinElmer IVIS® Spectrum). Mice were injected with a 200 pL solution of luciferin-PB S (15 mg / mL) and anesthetized with isoflurane, and imaging was conducted after a seven-minute incubation period utilizing the following settings: auto-exposure, medium binning, and F / stop 1. Radiance was quantified with the Living Image® software (version 4.7.3, PerkinElmer). Fig. 1 shows that treatment with Compound 144 (NNMTi) significantly reduced tumor burden compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D) in the murine model of high- grade serous ovarian cancer.

[0374] For intratumoral (i.t.) injections into subcutaneous MC38 or LG-6406 tumors, the NNMTi or the distomer was dissolved in 10% DMSO and mixed in a 1 : 1 ratio with alginate (Millipore Sigma, 180947). Tumors were injected with a total volume of 50 pL of a solution containing 4 mg / kg of the NNMTi or the distomer and a final concentration of 10 mg / ml alginate. Treatment with either the vehicle (10% DMSO, 10 mg / kg alginic acid), the NNMTi (100 pg / mouse) or the distomer (100 pg / mouse) was started 5 days after MC38 cancer cell injection and was conducted every three days until day 20 for the MC38 model, and was started 7 days after LG-6406 cancer cell injection and was conducted twice weekly until the end of the study for the LG-6406 model. Tumor burden was measured twice weekly. Fig. 2 shows that treatment with Compound 144 (NNMTi) significantly reduced tumor volume compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D) in the murine model of subcutaneous MC38 tumors. Five days after s.c. injection of MC38 colon cancer cells, other mice started treatment with the NNMTi or the distomer in combination with a PD-1 inhibitor monoclonal antibody (aPDl, InVivoMAb anti-mouse PD-1, clone RPM1-14, BioXCell,Cat#BE0146; RRTD: AB_10949053) or an IgG control antibody (InVivoMAb rat IgG2a Isotype Control, clone 2A3, BioXCell Cat#BE0089; RRID: AB_1107769). Combination of NNMTi and immune checkpoint inhibitors: Figs. 3A and 3B show that treatment with both Compound 144 (NNMTi) and the PD-1 inhibitor (aPDl) dramatically and synergistically reduced tumor volume in the murine subcutaneous MC38 tumor model. Fig. 4 shows that treatment with Compound 144 (NNMTi) significantly reduced tumor volume compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D) in the murine model of low-grade serous ovarian cancer. This result is noteworthy because low-grade serous ovarian cancer is particularly resistant to conventional cancer therapies.

[0375] For the intravenous tumor model, mice were anesthetized with isoflurane and 50 pL of the vehicle, the NNMTi (4 mg / kg) or the distomer (4 mg / kg) was dispersed into the throat as previously described [Nielsen etal., J. Vis. Exp., 57672 (2018), doi : 10.3791 / 57672], Oropharyngeal (o.p.) inhalation of the treatment by the mice resulted in topical treatment of the lungs. Treatment with either the vehicle (10% DMSO, 10 mg / kg alginic acid), the NNMTi (100 pg / mouse) or the distomer (100 pg / mouse) was started two days before cancer cell injection and continued daily until five days after cancer cell injection (prevention study). The lungs were excised after 13 days. Fig. 5 shows that treatment with Compound 144 (NNMTi) significantly reduced metastasis size compared to treatment with vehicle or the distomer Compound 145 (NNMTi-D) in the murine model of an intravenous tumor. Other mice i.v. injected with EO771 breast cancer cells oropharyngeally inhaled treatment with the NNMTi or the distomer in combination with a PD-1 inhibitor monoclonal antibody (aPDl, InVivoMAb anti -mouse PD-1, clone RPM1-14, BioXCell, Cat#BE0146; RRID: AB 10949053) or an IgG control antibody (InVivoMAb rat IgG2a Isotype Control, clone 2 A3, BioXCell Cat#BE0089; RRID: AB_1107769) until five days after cancer cell injection, and the lungs were excised after 16 days. Fig. 6 shows that treatment with Compound 144 (NNMTi) plus the IgG control antibody or the PD-1 inhibitor (aPDl) significantly reduced metastasis size in the murine intravenous tumor model.Whole-body Nnmt- / -mice show reduced tumor burden.

[0376] Figs. 7A and 7B show that whole-body Nnmt- / -mice show reduced tumor burden. Fig.7A: Nnmt+ / +(n=6) and Nnmt- / -mice (n=6) were injected into the bursa of the left ovary with themurine HGS-2 ovarian cancer cell line and 42 days later, primary ovarian and omental tumor burden was assessed (Student’s t test). Fig. 7B: Nnmt+ / + (n=6) and Nnmt mice (n=6) were injected into the bursa of the left ovary with the murine HGS-3 ovarian cancer cell line and 42 days later, primary ovarian and omental tumor burden was assessed (Student’s t test). Fig. 8 shows that whole-body Nnmt- / -mice show reduced tumor burden. Nnmt-knockout in the tumor microenvironment reduces tumor burden. Nnmt+ / + wild type (n=10) and Nnmt- / -knock out mice (n=l 1) were injected into the mammary fat pad with the murine EO771-LMB breast cancer cell line and tumor growth was monitored twice weekly by caliper measurement (One-way ANOVA).NNMTi treatment reduces tumor burden

[0377] Figs. 9A and 9B show that NNMT -inhibition significantly reduces tumor burden and metastases in orthotopic mouse models of ovarian cancer. Fig.9A: C57B16 mice were injected with the ovarian cancer cell line HGS-2 into the bursa of the left ovary and starting 4 days post- cancer cell injection, treated daily with NNMTi at 25mg / kg via i.p. injection for 5 weeks (Formulation: 10% NMP, 20% PEG400, 70% Solutol). Fig 9B: C57B16 mice were injected with BPPNM ovarian cancer cells into the bursa of the left ovary and starting 4days post-cancer cell injection, treated daily with NNMTi at 25mg / kg via i.p. injection for 12 days (Formulation: 10% NMP, 20% PEG400, 70% Solutol). The BPPNM (Trp53- / -R172HBrcal- / -Pten- / -Nfl- / -MycOE genotype) is HR deficient (S lyer Cancer Discovery 2021).

[0378] Fig. 10 shows that NNMT-inhibition significantly reduces tumor burden in an orthotopic mouse models of breast cancer. C57B16 mice were injected into the mammary fat pad with the murineEO771-LMB breast cancer cell line and starting 4 days post cancer cell injection mice were treated daily with the NNMTi (25mg / kg) or vehicle control by i.p. injection. (Formulation: 10% NMP, 20% PEG400, 70% Solutol) (One-way ANOVA).Combination of NNMTi and irradiation therapy

[0379] Fig. 11 shows that NNMT inhibition improves the treatment response to local irradiation. C57BL / 6 mice were injected s.c. with LLC (Lung Lewis Carcinoma) cells and treated daily by i.p. injection with either vehicle or NNMTi, starting on day 4. On day 13, the tumors were locally irradiated with 20 Gy (10 mice per group, two-way ANOVA).Effect of NNMT inhibition on CAFs in vivo

[0380] Figs. 12A, 12B, and 12C show the effect of NNMT inhibition on CAFs in vivo. Fig. 12A: Effect of NNMT inhibition on CAFs in vivo in breast cancer model. NNMT inhibition reduces the abundance of established CAF subtypes in vivo. Flowcytometry: C57B16 mice were injected into the mammary fat pad with the murine EO771-LMB breast cancer cell line and 4days post-injection mice were treated daily with the NNMTi (25mg / kg) or vehicle control by i.p. injection. 18 days post cancer cell injection, tumors were dissociated, and flow cytometry performed. Ly6C+ inflammatory CAFs(iCAFs), a-SMA+ myofibroblastic CAFs (myCAFs), MHCII + antigen-presenting CAFs (apCAFs), and PDGFRa + vascular CAFs (vCAFs). Fig. 12B: NNMTi treatment reduces the abundance of Ly6C + iCAFs and MHCII + myCAFs in an orthotopic ovarian cancer model. Flowcytometry (Gating): C57B16 mice were injected into the ovarian bursa with the murine HGS-2 ovarian cancer cell line and 4days post-injection mice were treated daily with the NNMTi (25mg / kg) or vehicle control by i.p. injection. 19 days post cancer cell injection, tumors were dissociated, and flow cytometry performed. Fig. 12C: NNMTi treatment increases H3K27 trimethylation of CAFs in vivo. Flow cytometry: Absolute quantification of H3K27 melow CD45- EPCAM- CD31- Podoplanin+ CAFs and EPCAM + Podoplanin-cancer cells in primary EO771-LMB tumors treated with either NNMTi or vehicle control.Effect of NNMT inhibition on the abundance of complement factor C3

[0381] Fig. 13 shows the effect of NNMT inhibition on the abundance of complement factor C3. NNMTi treatment reduces complement factor secretion in vivo. Enzyme-linked immunosorbent assay (ELISA): EO771-LMB primary tumors treated with either NNMTi or vehicle control were homogenized 18 days after cancer cell injection and complement factor C3 protein was detected (Student’s t-test).Effect of NNMTi treatment on tumor immune cell infiltration

[0382] Figs. 14A, 14B, and 14C show the effect of NNMTi treatment on tumor immune cell infiltration. NNMTi treatment reduces the abundance of immune suppressive monocytic myeloid-derived suppressor cells (M-MDSCs; Ly6Chigh PD-Llhigh) and increases the CD8+ T cell response. Fig. 14A: C57BL / 6 mice were subcutaneously (s.c.) injected with MC38 colon carcinoma cells (day 0) and 5 days later, once the tumor was palpable, treated by intratumoralinj ection (i.t.) every 3 days with either the NNMTi, or NNMTi-D control. 15 days after cancer cell injection, MC38 tumors were dissociated, and 19-color spectral flow cytometry was performed (6-8 mice per group, student’s t-test). Fig. 14B: 15 days after cancer cell injection, MC38 tumors were dissociated, stimulated with PMA / Ionomycin, and effector cytokine production quantified (Student’s t-test). Fig. 14C: C57B16 mice were orthotopically injected with either the ovarian cancer cellsHGS-2 or the breast cancer cells EO771-LMB. 4 days post- cancer cell injection, the mice were treated daily with NNMTi at 25 mg / kg via i.p. injection. 18 days after cancer cell injection, the primary tumors were dissociated and flow cytometry performed (Student’ s t-test).Effect of NNMTi treatment on the tumor metabolome

[0383] Figs. 15A and 15B show the effect of NNMTi treatment on the tumor metabolome. NNMTi treatment locally reduces levels of 1 -methylnicotinamide (1-MNA) and its metabolite Nl-methyl-2-pyridone-5-carboxamide (2PY) in tumor tissue, while leading to an accumulation of S-adenosylmethionine (SAM). Fig.l5A: Experimental plan. C57BL / 6 mice were injected s.c.with MC38 cells, and 13 days later, they were treated intratum orally with either vehicle, NNMTi-D or NNMTi. The tumors were then sampled at different time points after the injection. Fig.l5B: Tumors were extracted for liquid chromatography-mass spectrometry analysis. Central metabolites of the methionine and nicotinamide cycles are shown to demonstrate the consequences of NNMT inhibition on the levels of these metabolites (n=5 mice / group. Ordinary one-way ANOVA).NNMT inhibition exerts its tumor-reducing effects by targeting the tumor microenvironment (TME)

[0384] Fig. 16 shows that NNMT inhibition exerts its tumor-reducing effects by targeting the TME, rather than by altering cancer cell growth. To determine whether NNMT inhibition in cancer cells reduces tumor growth in vivo, we injected whole-body Nnmt- / -mice with MC38 colon carcinoma cells and administered either the vehicle or NNMTi. These mice completely lack NNMT, so NNMTi treatment should have no specific effect on cells of the TME. Since the cancer cells are Nnmt-wildtype and express NNMT, any impact of NNMT inhibition on cancer cell growth would be detectable. Nonetheless, no tumor reduction was seen in our experiments.

[0385] It is understood that, while particular embodiments have been illustrated and described, various modifications can be made thereto and are contemplated herein. It is also understood that the disclosure is not limited by the specific examples provided herein. The description and illustration of embodiments and examples of the disclosure herein are not intended to be construed in a limiting sense. It is further understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein, which may depend upon a variety of conditions and variables. Various modifications and variations in form and detail of the embodiments and examples of the disclosure will be apparent to a person skilled in the art. It is therefore contemplated that the disclosure also covers any and all such modifications, variations and equivalents.

Claims

What Is Claimed Is:

1. A compound of Formula I or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:wherein:X is aryl or heteroaryl, wherein the aryl or heteroaryl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, C1-6 alkyl, -CF3, -OH, -OR1, -NH2, -NR2R3, -(C=O)NR4R5and proteolysis-targeting moieties (e g., thalidomide-based, proteolysis-targeting moieties), and wherein the C1-6 alkyl can optionally be substituted with - OH, -OR1, -NH2or -NR2R3;Y is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl can optionally have one or more (e.g., 2 or 3) substituents independently selected from halide, cyano, nitro, C1-6 alkyl, -CF3, -OH, -OR1, -NH2, -NR2R3and - (C=O)NR4R3, and wherein the C1-6 alkyl can optionally be substituted with -OH, -OR1, -NH2or - NR2R3;R1is hydrogen, C1-6 alkyl, -CHF2, -CF3 or C3-6 cycloalkyl, wherein the alkyl or cycloalkyl can optionally be substituted with -OH, C1-4 alkoxy, -NH2or -NR2R3;R2and R3independently are hydrogen, C1-6 alkyl or -C(=O)-(C1-6 alkyl), or R2and R3and the nitrogen atom to which they are attached form a 3-6-membered heterocyclic ring or a 5- or 6- membered heteroaryl ring;R4and R5independently are hydrogen or C1-6 alkyl; n is 1, 2 or 3; and the stereocenter marked by an asterisk * can have the (.^-stereochemistry or the (R)- stereochemistry or can be racemic; with the proviso that:X is not unsubstituted phenyl or 4-chlorophenyl; and the compound of Formula I is not:or a tautomer or salt thereof.

2. The compound of claim 1, wherein X is optionally substituted, 5-10 membered, monocyclic or bicyclic, aryl or heteroaryl.

3. The compound of claim 1 or 2, wherein X is selected from 2-CN-phenyl, 3-CN-phenyl, 3-CH3-phenyl, 3-OCH3-phenyl, 3-(C(=O)NH2)-phenyl, 4-Br-phenyl, 4-OCH3-phenyl, 4-OCHF2-phenyl, 4-(morpholin-N -yl)-phenyl, 3-CN-4-CH3-phenyl, 3-F-4-OCH3-phenyl, 3-F-5- CFF-phcnyl, 3,5-dimethyl-phenyl, 1 -naphthyl, / V-CHs-pyrazol -4-yl, 4-CH3-pyridin-2-yl, 5-CN- pyridin-2-yl, 5-CH3-pyridin-2-yl, 5-CF3-pyridin-2-yl, 6-CH3-pyridin-2-yl, 2-CH3-pyridin-3-yl, 4-CH3-pyridin-3-yl, 5-CH3-pyridin-3-yl, 6-CH3-pyridin-3-yl, 2-CH3-pyridin-4-yl,4. The compound of any one of the preceding claims, wherein for Y : cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl; heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; aryl is phenyl, naphthyl, phthalanyl, benzodioxolyl, benzodioxanyl, isoindolinyl, 1, 2,3,4- tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl; and heteroaryl is furanyl (furyl), thiophenyl (thienyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl (pyridyl), pyrimidinyl, quinolinyl or isoquinolinyl; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl can optionally be substituted as defined in claim 1.

5. The compound of claim 4, wherein Y is selected from cyclohexyl, l,l-diF-cyclohex-4-yl,2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, piperidin-3-yl, TV-CHs-piperidin-3-yl, rV-acetyl-piperi din-3 -yl, piperidin-4-yl, JV-CH3-piperidin-4-yl, jV-acetyl-piperidin-4-yl, phenyl, 2-F-phenyl, 2-Cl-phenyl, 2-CF3-phenyl, 2-OCH3-phenyl, 2-OCH2CH3-phenyl, 2- OCFhCFFCHs-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH3-phenyl, 3-CF3-phenyl, 3-OCH3-phenyl, 3-(OCH2CH2OH)-phenyl, 3-(piperidin-JV-yl)-phenyl, 3-(morpholin-Y-yl)-phenyl, 3- (186midazole-JV-yl)-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-Br-phenyl, 4-CH3-phenyl, 4-ethyl- phenyl, 4-isopropyl-phenyl, 4-CH2OH-phenyl, 4-CF3-phenyl, 4-OH-phenyl, 4-OCH3-phenyl, 4- OCHF2-phenyl, 4-OCF3-phenyl, 4-(OCH2CH2OCH3)-phenyl, 4-(O-cyclopentyl)-phenyl, 4- N(CH3)2-phenyl, 4-(JV-acetyl)-phenyl, 4-(186midazole-JV-yl)-phenyl, 4-(pyrazol-JV-yl)-phenyl, 2- CH3-3-F-phenyl, 2-OCH3-3-F-phenyl, 2-F-4-Cl-phenyl, 2,4-diCl-phenyl, 2,4-dimethyl-phenyl, 2- F-4-methoxy-phenyl, 2-F-4-ethoxy -phenyl, 2-OH-4-OCH3-phenyl, 3-F-4-Cl-phenyl, 3,4-diCl-phenyl, 3-CH3-4-F-phenyl, 3-CF3-4-CH3-phenyl, 3,5-dimethyl-phenyl, 1 -naphthyl, 2-naphthyl, l,2,3,4-tetrahydroisoquinolin-8-yl, 4-isoindolinyl, 5-phthalanyl, l,3-benzodioxol-5-yl, 1,4- benzodioxan-6-yl, 2V-CH3-pyrazol-4-yl, JV-CH3-3-CH3-pyrazol-4-yl, JV-methyl-imidazol-2-yl, N- ethyl-imidazol-2-yl, 5-CH3-isoxazol-3-yl, 2-pyridyl, 3-F-pyridin-2-yl, 3-CH3-pyridin-2-yl, 4-C1- pyridin-2-yl, 4-CH3-pyridin-2-yl, 4-OCH3-pyridin-2-yl, 5-Cl-pyridin-2-yl, 6-CH3-pyridin-2-yl, 4,6-dimethyl-pyridin-2-yl, 3-pyridyl, 2-OCH3-pyri din-3 -yl, 6-OCH3-pyridin-3-yl, 4,6-diCl- pyridin-3-yl, 4-CH3-pyrimidin-2-yl, 5-CH3-pyrimidin-2-yl, 2-quinolinyl, and 5-isoquinolinyl.

6. The compound of any one of the preceding claims, wherein n is 1 or 2.

7. The compound of any one of the preceding claims, which is one of the following compounds, or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereofwherein the stereocenter marked by an asterisk * is racemic or has the (5)-stereochemistry, and compounds having a shown (S)-stereochemistry can alternatively be racemic at that stereocenter.

8. The compound of any one of claims 1 to 6, which is one of the following compounds, or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof:wherein the stereocenter marked by an asterisk * is racemic or has the (S)-stereochemistry, and compounds having a shown (.^-stereochemistry can alternatively be racemic at that stereocenter.

9. A compound selected from the following compounds, and tautomers, pharmaceutically acceptable salts, solvates, hydrates, clathrates and polymorphs thereofwherein the stereocenter marked by an asterisk * is racemic or has the (5)-stereochemistry, and compounds having a shown (S)-stereochemistry can alternatively be racemic at that stereocenter, and wherein Boc denotes tert-butyloxycarbonyl.

10. The compound of any one of the preceding claims, wherein the stereocenter marked by an asterisk * has the (5)- stereochemistry.

11. A pharmaceutical composition comprising a compound of any one of the preceding claims or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, and one or more pharmaceutically acceptable excipients or carriers.

12. The pharmaceutical composition of claim 11, which is an oral dosage form such as a tablet, capsule or pill.

13. The pharmaceutical composition of claim 11 or 12, further comprising an additional therapeutic agent.

14. A method of treating a tumor or cancer, comprising administering to a subject an amount of a compound of any one of claims 1 to 10, or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, effective to treat a tumor or cancer.

15. The method of claim 14, wherein the tumor or cancer is selected from solid tumors, head and neck tumors and cancers (e.g., oral squamous cell carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and papillary thyroid cancer), tumors and cancers of the CNS (e g., glioblastoma, glioma and neuroblastoma), lung cancer (e.g., non-small cell lung cancer), gynecological cancers (e.g., breast cancer, ovarian cancer [e.g., high-grade serous carcinoma], and uterine cancer [e.g., cervical cancer and endometrial cancer]), cancers of the gastrointestinal tract (e.g., stomach cancer [e.g., gastric carcinoma] and colorectal cancer), liver cancer (e.g., hepatocellular carcinoma and intrahepatic cholangiocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), urological cancers (e.g., kidney cancer [e.g., renal clear cell carcinoma and renal papillary cell carcinoma], bladder cancer and prostate cancer), skin cancer (e.g., melanoma), sarcomas, and hematological and lymphoid cancers (e.g., leukemias and lymphomas [e.g., non-Hodgkin lymphomas such as diffuse large B-cell lymphoma]).

16. The method of claim 14 or 15, wherein the tumor or cancer is characterized by intra- abdominal, peritoneal or / and omental metastasis, such as ovarian cancer (e.g., ovarian carcinoma), endometrial cancer, gastrointestinal cancer (e.g., gastric cancer or colorectal cancer), or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).

17. The method of any one of claims 14 to 16, wherein the compound is administered orally.

18. The method of any one of claims 14 to 16, wherein the compound is administered intratum orally.

19. The method of any one of claims 14 to 18, further comprising administering one or more additional antitumor / anticancer agents.

20. A method of treating a metabolic disorder or a liver disorder, comprising administering to a subject an amount of a compound of any one of claims 1 to 10, or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof, effective to treat a metabolic disorder or a liver disorder.

21. The method of claim 20, wherein the metabolic disorder is selected from obesity, obesity - associated disorders (e g., cardiovascular disorders and hypertension), hyperlipidemia (e g., hypercholesterolemia and hypertriglyceridemia), metabolic syndrome, hyperglycemia, impaired glucose tolerance, insulin resistance, type 2 diabetes, polycystic ovary syndrome (PCOS), and aging-related disorders (e.g., sarcopenia).

22. The method of claim 21, wherein the metabolic disorder is obesity, an obesity-associated disorder, or type 2 diabetes.

23. The method of claim 20, wherein the liver disorder is selected from liver steatosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), hepatitis, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis.

24. The method of claim 23, wherein the liver disorder is ALD, NAFLD, ASH or NASH.

25. The method of any one of claims 20 to 24, wherein the compound is administered orally.

26. The method of any one of claims 20 to 25, further comprising administering one or more additional therapeutic agents.

27. The method of claim 26, wherein the one or more additional therapeutic agents comprise one or more anti-obesity agents, or / and one or more antidiabetics.

28. A method of inhibiting nicotinamide A -methyl transferase (NNMT), comprising contacting a cell with a compound of any one of claims 1 to 10 or a tautomer, pharmaceutically acceptable salt, solvate, hydrate, clathrate or polymorph thereof.

29. The method of claim 28, wherein the contacting occurs in vivo, ex vivo or in vitro.

30. A method of modulating metabolites in the NAD+, methionine and S-adenosyl-L- methionine (SAM) / S-adenosyl-L-homocysteine (SAH) pathway with a compound of any one of claims 1 to 10.

31. A method of modulating gene expression or the epigenome with a compound of any one of claims 1 to 10.

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