Prodrugs of nicotinamide n-methyltransferase (NNMT) inhibitors and uses thereof

Abstract

The present disclosure generally relates to compounds as a therapeutic intervention, particularly to compounds which are potent and specific NNMT inhibitors incorporating targeted delivery groups that can be selectively activated under a reducing environment, for example a solid tumor environment. Pharmaceutical compositions of those compounds and methods of using them in the treatment of diseases caused by abnormal NNMT pathway, including cancer, inflammation, neurodegenerative and cardiovascular diseases, are within the scope of this disclosure.

Description

PRODRUGS OF NICOTINAMIDE N-METHYLTRANSFERASE (NNMT) INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 535,246, filed August 29, 2023, the disclosure of which is incorporated by reference as if fully set forth herein.TECHNICAL FIELD

[0002] The present disclosure generally relates to compounds as a therapeutic intervention, particularly to compounds which are potent and specific NNMT inhibitors incorporating targeted delivery groups that can be selectively activated under a reducing environment, such as found in a solid tumor environment. The prodrugs of the present disclosure are effective therapeutic agents for NNMT associated disease, especially cancer.BACKGROUND

[0003] This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.

[0004] NNMT utilizes S-adenosylmethionine (SAM) as a methyl donor to methylate nicotinamide, a precursor to NAD+. NNMT is implicated in both cancer and metabolic diseases. Knockdown of NNMT has demonstrated its ability to suppress tumor growth and metastasis. However, there is lack of specific and potent NNMT inhibitors for cellular and animal studies to validate the therapeutic potential of NNMT. Based on our NNMT bisubstrate inhibitors, we designed and developed prodrugs of NNMT bisubstrate analogs to selectively deliver to tumor cells because of their reductive activation mechanism.

[0005] Cancer is a group of most diverse diseases involving abnormal cell growth. Currently there are more than 100 types of identified cancer that affect human beings as well as animals. In 2016, there were an estimated 1,685,210 new human cancer cases diagnosed and 595,690 cancer deaths in the U.S. alone (Cancer Statistics 2016 - American Cancer Society, Inc.). There are unmet and increasing needs for new and novel therapies for fighting cancers.SUMMARY

[0006] These and other features, aspects and advantages of the present disclosure will become better understood with reference to the following associated descriptions and claims.

[0007] The present disclosure provides for compounds useful for the therapeutic treatment of disease in mammals. In particular, the disclosure provides for compounds which are useful as potent and specific inhibitors of NNMT activity.

[0008] The present disclosure provides for compounds useful for the therapeutic treatment of disease states in mammals which involve NNMT activity, and in particular cancer. The present disclosure provides for compound useful for the treatment of cancer, in particular solid tumor cancers.

[0009] The present disclosure provides for pharmaceutical formulations comprising compounds of the present disclosure and suitable diluents, excipients, carriers and salts thereof. The present disclosure provides for pharmaceutically acceptable formulations which comprise therapeutically effective amounts of the disclosed compounds. The present disclosure provides for formulations which comprise one or more of the disclosed compounds, alone or in combination with other therapeutic agents. The present disclosure provides for combination formulations that comprise therapeutic agents for treating or ameliorating symptoms and related physiological or psychological effects of the disease condition, and therapeutically effective amounts of the disclosed compounds. Thus the present disclosure also provides for the use of the disclosed compounds for the formulation of a suitable pharmaceutical composition.

[0010] The present disclosure provides for formulations of the disclosed compounds suitable for administration via suitable routes of administration, including and not limited to oral, intravenous, intra muscular, sub-dermal, implanted capsule, dispenser or micropellet, topical, or other effective routes.

[0011] The present disclosure provides for the administration of therapeutic amounts of the disclosed compounds for the treatment of a patient in need thereof. The need of the patient may include treatment of active disease, such as detected cancer cells, tumor formation(s), metastatic cancer or the like. The need of the patient may include the prevention of, or limitation of recurrence of the active disease state, maintenance of remission, and other such prophylactic therapeutic administration of the disclosed compounds.

[0012] In some illustrative embodiments, this present disclosure is related to a compound having a general formula (I):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andY is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

[0013] In some illustrative embodiments, this present disclosure is related to a compound having a general formula (II):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andZ is selected from the group consisting ofeach of which is optionally substituted.

[0014] In some illustrative embodiments, this present disclosure is related to a compound having a general formula (III):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

[0015] In some illustrative embodiments, this present disclosure is related to a compound having a general formulaor a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

[0016] In some illustrative embodiments, this present disclosure is related to a compound having a general formula (I), (II), (III), (IV), (A) or (B), wherein R3is o-Cl, Br phenyl; p- C1 phenyl; o,p-Cl phenyl.

[0017] In some illustrative embodiments, the present disclosure provides for compounds having a general formula (I), wherein said compound is:pharmaceutically acceptable salt thereof.

[0018] In some illustrative embodiments, this present disclosure is related to a compound having a general formula (II) or (III), wherein said compound is:salt thereof.

[0019] In some illustrative embodiments, this present disclosure is related to a compound having a general formula (IV), wherein said compound is:pharmaceutically acceptable salt thereof.

[0020] In some other embodiments, this present disclosure is related to a pharmaceutical composition comprising one or more compounds disclosed herein, together with one or more pharmaceutically acceptable diluents, excipients, or carriers. In a more particular embodiment, the present disclosure provides for pharmaceutical compositions which comprise a therapeutic amount of a compound of the disclosure.

[0021] In another embodiment, this present disclosure is related to a pharmaceutical composition comprising one or more compounds disclosed herein, together with one or more other therapeutically effective compounds and pharmaceutically acceptable diluents, excipients, or carriers.

[0022] In another embodiment, this present disclosure is related to a pharmaceutical composition comprising a compound disclosed herein, and a therapeutically effective amount of one or more other compounds targeting a NNMT pharmacological pathway, together with one or more therapeutically one or more pharmaceutically acceptable excipients.

[0023] In some embodiments, this present disclosure is related to a method for treating a patient with a cancer, the method comprising the step of administering a therapeutically effective amount of the compound disclosed herein to the patient in need of relief from said cancer.

[0024] In some embodiments, this present disclosure is related to a method for treating a patient with a solid tumor cancer, such as glioblastoma, prostate, lung, breast, or pancreatic cancer, the method comprising the step of administering a therapeutically effective amount of the compound disclosed herein to the patient in need thereof.

[0025] In some embodiments, this present disclosure is related to a method for treating a patient with a cancer, the method comprising the step of administering a therapeutically effective amount of the compound disclosed herein, together with a therapeutically effective amount of a compound of the same or different mode of action, to the patient in need of relief from symptoms or effects of said cancer.

[0026] In some embodiments, this present disclosure is related to a method for treating a patient with a cancer, the method comprising the step of administering a therapeutically effective amount of the compound disclosed herein, together with a therapeutically effective amount of a compound targeting a NNMT pharmacological pathway, to the patient in need of relief from said cancer.

[0027] In another embodiment, the present disclosure provides for the prevention of disease, inhibition or prevention of recurrence of disease, inhibition or prevention of metastisis of disease and similar prophylactic therapeutic treatments to a patient in need thereof.

[0028] In some embodiments, this present disclosure is related to a method for treating a patient with a glioblastoma, prostate, lung, breast, or pancreatic cancer, the method comprising the step of administering a therapeutically effective amount of the compound disclosed herein, together with a therapeutically effective amount of a compound targeting a NNMT pharmacological pathway, to the patient in need of relief from said cancer.

[0029] In some embodiments of the present disclosure encompasses methods for treating a patient in need thereof with a therapeutically effective amount of the compounds or pharmaceutical composistions thereof.

[0030] The present disclosure provides for administerning a therapeutically effective amount of a compound of the present disclosure as a pharmaceuctial composition together with the appropriate dilutents, excipients and or carriers.

[0031] Thus the present disclosure also provides for the pharmaceutical compositios and the use thereof, which comprise pharmaceutically acceptable salts of the prodrug compounds of the disclosure, and other pharmaceutically acceptable formulations, copoundings, combinations and mixtures. In some embodiments of the present disclosure, the disclosed copounds may be administered alone or in combination with other therapeutic agents. The other therapeutic agents may be the different compounds disclosed herein. The other therapeutic agents may other therapeutic agents such as anti-cancer drugs, anti- inflamatory treatments, anti-nasuea medications, and agents used to ameolorate other symptoms the patient may have.DESCRIPTION OF THE DRAWINGS

[0032] The above and other objects, features, and advantages of the present invention will become more apparent when taken in conjunction with the following drawings, and wherein:

[0033] Fig. 1 Shows a graph depicting the growth inhibition curves of II624 (top line, black) and II630 (lower line, red) on MDA-MB231 cells.

[0034] Fig. 2 shows diagram and graphs of the Kinetics of prodrug II630 (Red) activation to release active drug II624 (Blue) in MDA-MB-231. Fig. 2A Diagram of conversion of prodrug to active drug. Fig. 2B Graph of II630 concentration over time. Fig. 2C Graph of II624 concentration over time.

[0035] Fig. 3 shows molecular model of co-crystal structure NNMT (grey cartoon) in complex with II334 (Fig. 3A) and II624 (Fig. 3B) (yellow stick). Hydrogen bonding in yellow dash, halogen bonding shown in orange dash.

[0036] Fig. 4 shows relative enzyme selectivity of II624 against a panel of methyltransferases through a radioactive assay (Reaction Biology Corp.).

[0037] Fig. 5 Shows a graph depicting cellular MNA Level % in response to NNMT inhibition by II624 and 11630 after 24 Hours. (Top curve II624 - black; bottom curve II630 - red).

[0038] Fig. 6 Shows a graph depicting Growth Inhibition Curves of II630 and II679 on 7860 cells. (Top curve II630 - black; bottom curve II679 - red).

[0039] Fig. 7 shows Scheme 1. Synthesis of trimethyl lock (TML) prodrugsDESCRIPTION

[0040] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of this disclosure is thereby intended.

[0041] Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. The implementations should not be limited to the particular limitations described. Other implementations may be possible.

[0042] The present disclosure provides for:A compound having the formula (I):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andY is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

[0043] A compound, as described above, selected from the group consisting of:a pharmaceutically acceptable salt thereof.

[0044] A compound having the formula (II):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andZ is selected from the group consisting ofeach of which is optionally substituted.

[0045] A compound, as described above, having the formula (III):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and X is a halogen NH2, NHMe, or N(Me)2.

[0046] A compound, as described above, selected from the group consisting of:

[0047] A compound, as described above, having the formula (IV):or a pharmaceutically acceptable salt thereof, wherein,R is a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

[0048] The disclosure also relates to a compound, as described above, having the formula

[0049] The disclosure also relates to a compound of the formula (A):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is Cffcor O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,X1is X, H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)2;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofeach of which is optionally substituted.

[0050] In the compounds of the formula (A), or a pharmaceutically acceptable salt thereof, Y1can be H. Alternatively, in the compounds of the formula (A) or a pharmaceutically acceptable salt thereof, Y1can be optionally substituted alkyl. Alternatively, in the compounds of the formula (A), or a pharmaceutically acceptable salt thereof, Y1can be acyl. Thus, for example, in the compounds of the formula (A), or a pharmaceutically acceptable salt thereof, Y1can be:

[0051] Alternatively, in the compounds of the formula (A), or a pharmaceutically acceptable salt thereof, Y1can be, acyl, such as:

[0052] In the compounds of the formula (A), or a pharmaceutically acceptable salt thereof, R1and R2can each independently be H or alkyl.

[0053] Compounds of the formula (A) include compounds of the formula:pharmaceutically acceptable salt thereof.

[0054] Compounds of the formula (A) include compounds of the formula:pharmaceutically acceptable salt thereof.

[0055] In the compounds of the formula (A), Q can be O. Thus, for example, the disclosure relates to a compound of the formula (B):R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl, aryl,o heteroaryl, each of which is optionally substituted; andX1is H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl),HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted.

[0056] In the compounds of the formula (B), or a pharmaceutically acceptable salt thereof,X1can be N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN(heterocyclyl), HN(heterobicyclyl), HN(aryl), HN(heteroaryl), or heterocyclyl, each of which is optionally substituted. Thus, for example, in the compounds of the formula (B), or a pharmaceutically acceptable salt thereof, X can be, amino, such as:

[0057] Compounds of the formula (A) or (B) include compounds of the formula:

[0058] In the compounds of the formula (I), (II), (III), (IV), (A) or (B), R3can be a halogen, or an alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl, aryl,o heteroaryl, each of which is optionally substituted.

[0059] The disclosure also relates to a method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound to the patient in need of relief from said disease, wherein the compound is of the formula (A):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is CH2 or O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,O z’ or , wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,each of which is optionally substituted; andX1is H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl),HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)?;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofeach of which is optionally substituted.

[0060] The present disclosure provides for:

[0061] A method for treating a patient with a disease caused by abnormal activities of nicotinamide N-methyltransferase (NNMT) comprising the step of administering a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (A) or (B) to the patient in need of relief from said disease.

[0062] The method as described above, wherein said disease is a cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease.

[0063] The method as described above, wherein said cancer is a glioblastoma, prostate, lung, breast, or pancreatic cancer.

[0064] A method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (A) or (B), together with a therapeutically effective amount of one or more other compounds of the same (e.g., 6-methoxynicotinamide and 5-amino-l- methylquinoline) or different mode of action (e.g., sunitinib, pazopanib, cabozantinib, axitinib, sorafenib, lenvatinib, and tivozanib, which are all VEGF inhibitors that can be used to treat, among other conditions, renal cell cancer), to the patient in need of relief from said disease. “Abnormal activities of NNMT” include, but are not limited to, overexpression of NNMT, which is correlated to low survival rate of renal cancers, glioblastoma, colorectal cancer, other cancers, obesity, and other diseases. See, e.g., Oncotarget. 2016 Jul 19; 7(29): 45837-45848; Oncol Lett. 2018 Apr; 15(4): 4592-4598; and Biochem Pharmacol. 2018 Jan:147: 141-152; each of which is incorporated by reference as if fully set forth herein.

[0065] A method for treating a patient with a cancer, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (A) or (B), together with a therapeutically effective amount of one or more other compounds targeting NNMT pharmacological pathway, to the patient in need of relief from said cancer.

[0066] A method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound to the patient in need of relief from said disease, wherein said compound has a formula (I)or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is NH2, NHMe, or N(Me)2; andY selected from the group consisting ofeach of which is optionally substituted.

[0067] The method as described above, wherein said disease is a cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease.

[0068] The method as described above, wherein said compound is:

[0069] A method for treating a patient with a disease caused by abnormal activities of NNMT (e.g., cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease) comprising the step of administering a therapeutically effective amount of a compound to the patient in need of relief from said disease, wherein the compound having the formula:or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, absent, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is Cffcor O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,each of which is optionally substituted; andX1is X, H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)2;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofoptionally substituted.

[0070] One example of such a compound of formula (A) is a compound having the formula:or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, absent, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X1is NH2, NHMe, or N(Me)2; andZ i selected from the group consistingeach of which is optionally substituted.

[0071] A pharmaceutical composition comprising one or more compounds as described above together with one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0072] A pharmaceutical composition consisting of one or more compounds as described above together with one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0073] The present disclosure provides for prodrug compounds as described above. The prodrug compounds of the disclosure are directed towards release of active components within a reducing environment such that the active components are effective therapeutics for NNMT mediated disease.

[0074] In a further embodiment, the present disclosure provides for a pharmaceutical composition which comprises a pro-drug compound as described above with a pharmaceutically acceptable carrier, excipient or diluent.

[0075] Thus the present disclosure provides for a pharmaceutical composition for treating solid tumor cancer, comprising one or more pro-drug compound of the present disclosure in combination with additional therapeutic agents for treating cancer and related symptoms.

[0076] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. In the present disclosure the term “about” can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range. In the present disclosure the term “substantially” can allow for a degree ofvariability in a value or range, for example, within 90%, within 95%, or within 99% or more of a stated value or of a stated limit of a range.

[0077] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0078] In each of the foregoing and following embodiments, it is to be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and / or solvates of the compound formulae or salts thereof. It is to be appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and / or coordination compounds with water and / or various solvents, in the various physical forms of the compounds. Accordingly, the above formulae are to be understood to include and represent those various hydrates and / or solvates. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non-crystalline and / or amorphous forms of the compounds.

[0079] The compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the disclosure described herein is not limited to any particular stereochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, othermixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

[0080] Similarly, the compounds described herein may be include geometric centers, such as cis, trans, e.g. E, and Z, double bonds. It is to be understood that in another embodiment, the disclosure described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.

[0081] The term “organic group” as used herein refers to but is not limited to any carbon- containing functional group. For example, an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group, a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups.

[0082] The term “substituted” as used herein refers to an organic group as defined herein or molecule in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.

[0083] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms (Ci- C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (Ci-Cs), or, in some embodiments, from 1 to 6 carbon atoms (Ci-Ce), 3 to 6 carbon atoms (Cs-Ce), 2 to 8 carbon atoms (C2-C8), 2 to 6 carbon atoms (C2-C6), 3 to 5 carbon atoms(C3-C5) or 5 to 10 carbon atoms (C5-C10). Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0084] The term “alkenyl” as used herein refers to substituted or unsubstituted straight chain and branched divalent alkenyl and cycloalkenyl groups having from 2 to 20 carbon atoms(C2-C2o), 2 to 12 carbons (C2-C12), 2 to 8 carbon atoms (C2-C8) or, in some embodiments, from 2 to 4 carbon atoms (C2-C4) and at least one carbon-carbon double bond. Examples of straight chain alkenyl groups include those with from 2 to 8 carbon atoms such as -CH=CH-, -CH=CHCH2-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and the like.

[0085] The term “alkylene” as used herein refers to substituted or unsubstituted straight chain and branched divalent alkylene groups and cycloalkylene groups having from 1 to 40 carbon atoms (C1-C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (Ci-Cs) or, in some embodiments, from 1 to 4 carbon atoms (C1-C4), from 1 to 5 carbon atoms (C1-C5), from 2 to 5 carbon atoms (C2-C5) or from 3 to 4 carbon atoms (C3-C4). Examples of straight chain alkylene groups include those with from 1 to 8 carbon atoms such as methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (- CH2CH2CH2-), n-butylene (-CEE CEh^CEh-) and the like. Examples of branched alkylene groups include, but are not limited to, isopropylidene (CEECE^CEE)) and the like. Examples of cycloalkylene groups include, but are not limited to, cyclopropylidene, cyclobutylidene, cyclopentylidene and the like.

[0086] The term “hydroxyalkyl” as used herein refers to alkyl groups as defined herein substituted with at least one hydroxyl (-OH) group.

[0087] The term “cycloalkyl” as used herein refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups can have 3to 6 carbon atoms (Cs-Ce). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0088] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a “formyl” group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-40, 6-10, 1-5 or 2-5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3 -carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridyl acetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group.

[0089] The term “heterocyclylcarbonyl” is an example of an acyl group that is bonded to a substituted or unsubstituted heterocyclyl group, as the term “heterocyclyl” is defined herein. An example of a heterocyclylcarbonyl group is a prolyl group, wherein the prolyl group can be a D- or an L-prolyl group.

[0090] The term “aryl” as used herein refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (Ce-Cu) or from 6 to 10 carbon atoms (Ce-Cio) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0091] The term “aralkyl” and “arylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0092] The term “heterocyclyl” as used herein refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (Cs-Cs), 3 to 6 carbon atoms (Cs-Ce) or 6 to 8 carbon atoms (Ce-Cs). A heterocyclyl group designated as a C2- heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups.Representative heterocyclyl groups include, but are not limited to pyrrolidinyl, azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, and benzimidazolinyl groups.

[0093] The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0094] The term “amine” as used herein refers to primary, secondary, and tertiary amines. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines,triarylamines, and the like. The term “amine” also includes ammonium ions as used herein.

[0095] The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR.3 , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.

[0096] The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0097] The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, polyhalo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1 -di chloroethyl, perfluorobutyl, - CF(CH3)2and the like.

[0098] As used herein, the term “salts” and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0099] Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference.

[0100] The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0101] The term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the disclosure. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of the disclosure that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well- known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0102] Various embodiments of the present disclosure also contemplate pharmaceutical compositions comprising one or more compounds of the various embodiments of the present disclosure and one or more pharmaceutically acceptable carriers, diluents, excipients or combinations thereof. A “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal). Such compositions may be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. In addition, administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.

[0103] A “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” comprises a carrier, sometimes a liquid, in which an active therapeutic agent is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it may provide chemical and / or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety.

[0104] As used herein “pharmaceutically acceptable carrier” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0105] Pharmaceutical compositions may be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0106] In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the compounds described herein can be formulated in a time release formulation, for example in a composition that includes a slow release polymer. Theactive compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.

[0107] Oral forms of administration are also contemplated herein. The pharmaceutical compositions of the present disclosure may be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension). The formulations may be conveniently prepared by any of the methods well-known in the art. The pharmaceutical compositions of the present disclosure may include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.

[0108] For each of the recited embodiments, the compounds can be administered by a variety of dosage forms as known in the art. Any biologically-acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusions, and combinations thereof.

[0109] Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrosesaccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone;disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

[0110] Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions. The syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and / or mannitol and / or sorbitol. The suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

[0111] The amount of active compound in a therapeutic composition according to various embodiments of the present disclosure may vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.

[0112] “Dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. In therapeutic use for treatment of conditions in mammals (e.g., humans) for which the compounds of the present disclosure or an appropriate pharmaceutical composition thereof are effective, the compounds of the present disclosure may be administered in an effective amount. The dosages as suitable for this disclosure may be a composition, a pharmaceutical composition or any other compositions described herein.

[0113] For each of the recited embodiments, the dosage is typically administered once, twice, or thrice a day, although more frequent dosing intervals are possible. The dosage may be administered every day, every 2 days, every 3 days, every 4 days, every 5days, every 6 days, and / or every 7 days (once a week). In one embodiment, the dosage may be administered daily for up to and including 30 days, preferably between 7-10 days. In another embodiment, the dosage may be administered twice a day for 10 days. If the patient requires treatment for a chronic disease or condition, the dosage may be administered for as long as signs and / or symptoms persist. The patient may require “maintenance treatment” where the patient is receiving dosages every day for months, years, or the remainder of their lives. In addition, the composition of this disclosure may be to effect prophylaxis of recurring symptoms. For example, the dosage may be administered once or twice a day to prevent the onset of symptoms in patients at risk, especially for asymptomatic patients.

[0114] The compositions described herein may be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal. The preferred routes of administration are buccal and oral. The administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease. Local administration can be administration to the cell, tissue, organ, and / or organ system, which encompasses and / or is affected by the disease, and / or where the disease signs and / or symptoms are active or are likely to occur. Administration can be topical with a local effect, composition is applied directly where its action is desired. Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract. Administration can be parenteral, where the desired effect is systemic, composition is given by other routes than the digestive tract.

[0115] In some embodiments, the present disclosure contemplates compositions comprising a therapeutically effective amount of one or more compounds of the various embodiments of the present disclosure. In some embodiments, the compositions are useful in a method for treating cancer, the method comprising administering a therapeutically effective amount of one or more compounds of any claim to a patient in need thereof. In some aspects, the various embodiments of the present disclosure contemplate a compound of the formula (I)(II) and (III) for use as a medicament for treating a patient in need of relief from cancers, including, but not limited to, prostate cancer, lung cancer, breast cancer, or pancreatic cancer.

[0116] In one embodiment of the present disclosure, it is contemplated that the compounds disclosed herein may be formulated into pharmaceutical compositions which consist of a therapeutically effective amount of a compound of the disclosure with an appropriate diluent, excipient, carrier or salt thereof. In some other embodiments, the present disclosure contemplates compositions comprising a therapeutically effective amount of a compound of the present disclosure, together with a therapeutically effective amount of one or more other compounds of the same or different mode of action to a patient in need of relief from said cancer.

[0117] The term “therapeutically effective amount” as used herein, refers to that amount of one or more compounds of the various embodiments of the present disclosure that elicits a biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In some embodiments, the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.

[0118] In addition to the illustrative dosages and dosing protocols described herein, it is to be understood that an effective amount of any one or a mixture of the compounds described herein can be determined by the attending diagnostician or physician by the use of known techniques and / or by observing results obtained under analogouscircumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician or physician, including, but not limited to the species of mammal, including human, its size, age, and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.

[0119] Treating a patient with a disease encompasses the therapeutic intervention of a patient with a disease state, or a patient who is susceptible to a future disease state, or a patient who has been previously treated for a disease state. Therapeutic intervention includes treatment to control, stop or reduce target disease state, effects and or metabolic impacts on the patent. Theraeputic intervention includes the prevention of disease state, preventon of metastisis or other spread of disease, prevention of growth of turmor or expansion of disease state. A further embodiment of therapeutic intervention includes the reduction of recurrence, prevention of recurrence or otherwise inhibition or amelioration of the recurrence of a disease state.

[0120] The term “patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human being.

[0121] The disclosure also relates to the subject matter of the following clauses, which are listed in no particular order of importance:

[0122] Clause 1 : A compound of the formula (A):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, absent, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is CH2or O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,each of which is optionally substituted; andX1is X, H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)2;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofeach of which is optionally substituted.

[0123] Clause 2: The compound of Clause 1, or a pharmaceutically acceptable salt thereof, of the formula (A) wherein Q is CH2.

[0124] Clause 3: A compound of Clause 1, or a pharmaceutically acceptable salt thereof, of the formula (A) wherein Q is O.

[0125] Clause 4: The compound of Clause 2, wherein the compound of the formula (A) is a compound of the formula (I):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andY is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

[0126] Clause 5: The compound of Clause 4, or a pharmaceutically acceptable salt thereof, wherein Y is H.

[0127] Clause 6: The compound of Clause 4, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted alkyl.

[0128] Clause 7: The compound of Clause 4, or a pharmaceutically acceptable salt thereof, wherein Y is acyl.

[0129] Clause 8: The compound of Clause 6, or a pharmaceutically acceptable salt thereof, wherein Y is:

[0130] Clause 9: The compound of Clause 7, or a pharmaceutically acceptable salt thereof, wherein Y is

[0131] Clause 10: The compound of Clause 2, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently H or alkyl.

[0132] Clause 11 : The compound of Clause 4 or 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:pharmaceutically acceptable salt thereof.

[0133] Clause 12: The compound of Clause 4 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:pharmaceutically acceptable salt thereof.

[0134] Clause 13: The compound of Clause 6 or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula::pharmaceutically acceptable salt thereof.

[0135] Clause 14: The compound of Clause 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:pharmaceutically acceptable salt thereof.

[0136] Clause 15: The compound of Clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula (II):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andZ is selected from the group consisting ofeach of which is optionally substituted.

[0137] Clause 16: The compound of Clause 7, wherein the compound is a compound of the formula (III):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

[0138] Clause 17: The compound of Clause 16, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula:

[0139] Clause 18: The compound of Clause 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula (IV):or a pharmaceutically acceptable salt thereof, wherein,R is a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

[0140] Clause 19: The compound of Clause 18, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula:

[0141] Clause 20: The compound of Clause 3, wherein the compound is a compound of the formula (B):R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl, aryl,o heteroaryl, each of which is optionally substituted; andX1is H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted.

[0142] Clause 21 : The compound of Clause 20, or a pharmaceutically acceptable salt thereof, wherein X1is N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN(heterocyclyl), HN(heterobicyclyl), HN(aryl), HN(heteroaryl), or heterocyclyl, each of which is optionally substituted.

[0143] Clause 22: The compound of Clause 21, or a pharmaceutically acceptable salt thereof, wherein X1is:

[0144] Clause 23: The compound of Clause 21 of the formula:

[0145] Clause 24: A compound of the formula:

[0146] Clause 25: A method for treating a patient with a disease caused by abnormal activities of nicotinamide N-methyltransferase (NNMT) comprising the step of administering a therapeutically effective amount of a compound of Clause 1 to the patient in need of relief from said disease.

[0147] Clause 26: The method of Clause 25, wherein said disease is a cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease.

[0148] Clause 27: The method according to Clause 25, wherein said cancer is a glioblastoma, prostate, lung, breast, or pancreatic cancer.

[0149] Clause 28: A method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound of Clause 1, together with a therapeutically effective amount of one or more other compounds of the same or different mode of action, to the patient in need of relief from said disease.

[0150] Clause 29: A method for treating a patient with a cancer, the method comprising the step of administering a therapeutically effective amount of a compound of Clause 1, together with a therapeutically effective amount of one or more other compounds targeting NNMT pharmacological pathway, to the patient in need of relief from said cancer.

[0151] Clause 31 : A method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound to the patient in need of relief from said disease, wherein the compound having the formula:or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is CH2or O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,each of which is optionally substituted; andX1is X, H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)2;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofeachofwhich is optionally substituted.

[0152] Clause 32: The method of Clause 30, wherein the compound having the formula (I):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andY is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

[0153] Clause 33: The method according Clause 30, wherein said disease is a cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease.

[0154] Clause 34: The method according to Clause 30, wherein said compound is:

[0155] Clause 35: A pharmaceutical composition comprising one or more compounds of Clause 1, together with one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0156] Clause 36: The use of a compound of Clause 1 in the formulation of a pharmaceutical composition comprising a compound of claims 1 in combination with a pharmaceutically acceptable carrier, excipient or diluent, or salt thereof.

[0157] EXPERIMENTAL PROCEDURES

[0158] The present disclosure can be better understood by reference to the following examples which are offered by way of illustration. The present disclosure is not limited to the examples given herein.

[0159] Materials and Reagents

[0160] All Reagents and Chemicals were obtained from commercial suppliers such as P3 Biosystems, Chem-Impex, Fisher and used without further purification. Nickel-nitrilotriacetic acid resin was used as purchased from Fisher. Human NTMT1 clone (AD- 003) was obtained from Addgene. The AdoHcy hydrolase (SAHH) clone was obtained through a Materials Transfer Agreement with Dr. Raymond C. Trievel (University of Michigan).

[0161] Instruments. All peptides were synthesized on a CEM Liberty microwave automatic peptide synthesizer.

[0162] Flash column chromatography was performed over silica gel (grade 60, 230-400 mesh) on a Teledyne Isco CombiFlash purification system. Final compounds were purified by preparative reversed-phase high-pressure liquid chromatography (RP- HPLC) that was performed on an Agilent 1260 Series system. The Agilent 1260 Infinity II Variable Wavelength Detector (G7114A, UV = 254 nM) and a WatersBEHC18 (130A, 5pm, 10mmx250mm) at a flow rate of 4 mL / min using a solvent system of 100% water with 0.1% TFA to 50% methanol over 30 min were used to purify the final compounds. NMR spectra were acquired on a Bruker AV500 instrument (500 MHz for 1H NMR, 126 MHz for 13C NMR). TLC-MS was carried out using an Advion CMS-L MS. Matrix- assisted laser desorption ionization mass spectrometry (MALDI-MS) data were acquired in the positive-ion mode using a Sciex 4800 MALDI TOF / TOF MS. The Agilent 1260 Infinity II Variable Wavelength Detector (G7114A, UV = 254 nM) and an Agilent ZORBAX RR SB-C18 (80 A, 3.5 pm, 4.6 * 150 mm) at a flow rate of 1 mL / min using a solvent system of 100% water with 0.1% TFA to 40% or 60% methanol over 20 min were used to assess the purity of final compounds. All the purity of target compounds showed >95% in RP-HPLC. Agilent 6470 QQQ coupled to an Agilent 1290 UPLC system with an Imtakt Intrada Amino acid column (2.0 * 150 mm) was used to analyze the metabolite in the cellular methylation studies. Mobile phase A was composed of 100% CH3CN + 0.3% formic acid, and mobile phase B was composed of 20:80 (v / v): CH3CN / 100 mM ammonium formate in water. The flow rate started at 0.3 mL / min. The gradient started with 0% B and increased linearly to 100% B over 11 min with a flow rate of 0.3 ml / min, followed by an isocratic gradient of 100% B for 2 min at 0.4 ml / min. Then, the column was equilibrated with 0% B for 7 min. All the purity of target compounds showed >95% purity.

[0163] All ICso studies were performed on a BMG ClarioStar microplate reader.

[0164] Design and Synthesis

[0165] Compound 1 was synthesized as previously described (Angew. Chem.Int. Ed. 2022, 61, e202114813). The reductive amination with the aldehyde from compound 1 with 3 -aminoprop- l-yn-l-yl)benzamide led to 2a which was deprotected to afford II334.

[0166] To improve its lipophilicity and enhance cell permeability, compound II624 was synthesized from 3 -aminoprop- l-yn-l-yl)-2 -bromobenzamide.

[0167] In order to further improve the cellular uptake, II624 was converted into a prodrug (II630) by coupling it with 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4- dien-l-yl)butanoic acid to convert it into a trimethyl lock (TML). Compound II630 rapidly releases II624 on getting into the cell through the action of cellular reductase.

[0168] Scheme 1. Synthesis of trimethyl lock (TML) prodrugs11630 R = Br

[0169] Scheme 1. (Fig. 7) Reagents and conditions: Compound 1 was synthesized as previously reported (See lyamu et al., Angew. Chem.Int. Ed. 2022, 61, e202114813) (a) DMP, DCM, then, for 2a: 3 -(3 -aminoprop- l-yn-l-yl)benzamide, NaBEECN, AcOH, MeOH, 2 h, 59%; for 2b: 5-(3-aminoprop-l-yn-l-yl)-2-chlorobenzamide, NaBEECN, AcOH, MeOH, 2 h, 61%; for 2b: 5-(3-aminoprop-l-yn-l-yl)-2-bromobenzamide, NaBHsCN, AcOH, MeOH, 2 h, 63%; (b) 3-methyl-3-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dien-l-yl)butanoic acid, PyBOP, DIPEA, DMF, 0 °C, 3 h, 46%; (c) TFA, H2O, 1 h, 61 - 82%

[0170] Synthesis of II630

[0171] Scheme 1. Reagents and conditions: 1 was synthesized as previously reported (Angew. Chem.Int. Ed. 2022, 61, e202114813)

[0172] (a) DMP, DCM, then 5-(3-aminoprop-l-yn-l-yl)-2-bromobenzamide,NaBH3CN, AcOH, MeOH, 2 h, 63%; (b) 3-methyl-3-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dien-l-yl)butanoic acid, PyBOP, DIPEA, DMF, 0 oC, 3 h, 46%;

[0173] (c) TFA, H2O, 1 h, 61%

[0174] Prodrug II630uM

[0175] Para nitrobenzene prodrug

[0176] In addition to the TML prodrugs, we also synthesized the para nitrobenzene prodrug in order to compare their activity against cancer cells. Compound II679 wassynthesized by amidation of the secondary amine 2c with 4-nitrobenzyl carb onochlori date and subsequent deprotection to the final prodrug. Activation of the para nitro prodrugs is via the action of cellular nitro reductase.

[0177] Scheme 2. Synthesis of para nitro prodrugs.

[0178] Scheme 2. Reagents and conditions: (a) 4-nitrobenzyl carb onochlori date, pyridine, THF 2 h, 76%; (b) TFA, H2O, 1 h, 67%.

[0179] Prodrug II679M

[0182] Active II334

[0186] Inhibition

[0187] Table 1. Comparison for the acetyl part of the bisubstrate inhibitors"with MB 231 cells

[0188] The inhibition activity of the active NNMT inhibitors was evaluated with SAHH-coupled flourescene assay (see for example Huang, Rong et al., 2020 ACS Comb. Sci. 22, 422-432). Interestingly, II334 displayed a Ki of 24 + / - 1.7 nM in this coupling assay. Co-crystal structure of II334 with NNMT confirmed that II334 binds in the active site of NNMT (Fig 1A). Furthermore, II334 did not exhibit any inhibitory effects toward other 37 methyltransferases at 10 mM, indicating the high specificity of II334 against NNMT. The presence of the chloro and bromo group in II624 resulted in about 3.5-fold improvement in inhibition resulting in a Ki of 7 + / - 1.2 nM. However, only II624 displayed a GI50 of 6.5 pM in MDA-MB 231 cells.

[0189] As expected, the prodrug II630 displayed better GIso of 1.5 pM suggesting that the bulky lipophilic group improved cellular uptake. As shown in Figure 1, Growth Inhibition Curves of II624 and II630 on MDA-MB231 cells where II624 Gbo = 7.7 + / - 1.2 pM and II630 Gbo = 1.8 + / - 0.9 pM demonstrated II630 performed better. Kinetic study of prodrug 11630 demonstrated that 11630 activation released active drug II624 in MDA-MB231 cells within 30 seconds and kept constant (Figure 2).

[0190] Co-crystal structure of II334 and II624 with NNMT confirmed that II334 and II624 bind in the active site of NNMT by simutaneously engaging both NAM and SAM binding sites of NNMT (Figure 3). Furthermore, II624 did not exhibit any inhibitory effects toward other 37 methyltransferases at 10 pM, indicating the high specificity of II624 against NNMT (Figure 4).

[0191] The effect of these bisubstrate inhibitors on the cellular MNA level in renal cancer cell 769P was determined as MNA levels represented the catalytical activity of NNMT. Both active drug II624 and prodrug II630 displayed a cellular ICso of 12 pM and 0.9 pM at 24 h, respectively (Figure 5). Notably, prodrug II630 exhibited over 12-fold enhanced cellular inhibition.

[0192] With renal cancer cell line, the active drugs II350, 11611 and II624 displayed GIso of 29, 24, and 12 pM, respectively.

[0193] With the same active drug (II624), different prodrugs 11630 and II679 demonstrated comparable potency on a renal cancer cell line 7860, with a GI50 value of 12 pM and 8 pM respectively. See Figure 6.

[0194] NNMT Biochemical Assays and Enzyme Kinetics Study.

[0195] The fluorescence-based SAHH-coupled assay was applied to study the IC50 values of compounds to monitor the production of SAH. The assay was performed under the following conditions in a final well volume of 100 pL: 25 mM Tris (pH = 7.5), 50 mM KC1, 0.01% Triton X-100, 5 pM SAHH, 0.1 pM NNMT, 10 pM AdoMet, and 10 pM ThioGlo4. After 30 min incubation with inhibitors at 37 °C, reactions were initiated by the addition of 10 pM nicotinamide (Km value). The fluorescence signal was monitored on a BMG CLARIOstar microplate reader with excitation 400 nm and emission 465 nm. Data were processed by using GraphPad Prism software 7.0.

[0196] Fluorescence Polarization Assay.

[0197] The FP measurements were performed on a BMG CLARIOstar microplate reader in black opaque 384-well microplates (Coming #3820) with excitation 482 nm and emission 530 nm. All experiments were performed in a volume of 20 pL per well in 25 mM Tris, 50 mM KC1, 0.01% Tween pH 7.5 in duplicates. NNMT (0.5 pM) was incubated with the inhibitor at different concentrations at room temperature for 30 min. Then, the FP probe was added to the above mixture for a final concentration of 5 nM. After incubation for 30 min, polarization was measured. The FP values were plotted against the log of inhibitor concentrations into a nonlinear regression model. The Xi were calculated from Binding- Competitive model in GraphPad Prism.

[0198] Cellular MNA Inhibition

[0199] The 769-P cells were seeded into a 24-well plate with a density of 0.1 x 106cells / well in 500 pL media and incubated at 5% CO2 and 37 °C overnight for cells to attach. The next day, the inhibitors diluted in media (to a final concentration of 1% DMSO) were added at different concentrations including DMSO as a control. The cells were incubated for the required time (24 and 48 h). At the end of the incubation, media was aspirated and the cells were washed with cold PBS twice. Then 80 pL of extraction buffer (100% MeOH) containing internal standards (40 ng / mL NAMd4 and 20 ng / mL MNAas) was added to the cells and the cells were incubated at room temperature for 20 mins with mild shaking. Then 20 pL of ddH2O was added and the mixture was centrifuged at 5000g for 10 min. Thesupernatant was collected and analyzed by Agilent 6470 QQQ coupled to an Agilent 1290 UPLC system with an Imtakt Intrada Amino acid column (2.0 x 150 mm). Mobile phase A was composed of 100% CH3CN + 0.3% formic acid, and mobile phase B was composed of 20:80 (v / v): CH3CN / 100 mM ammonium formate in water. The flow rate started at 0.3 mL / min. The gradient started with 0% B and increased linearly to 100% B over 11 min with a flow rate of 0.3 mL / min, followed by an isocratic gradient of 100% B for 2 min at 0.4 ml / min. Then, the column was equilibrated with 0% B for 7 min. Each run was an injection of 20 pL. The Dwell time for MNA was set to 80 ms and the fragmentor voltage was set to 100 V. The drying gas temperature was set to 325 °C, the drying gas flow was at a rate of 8 1 / min, and the nebulizer pressure was 40 psi. MRM analysis was performed on Agilent MassHunter Quantification Analysis Software (version 10.1), monitoring the transition of m / z from 140 to 97 for t / j-MNA and 137 to 94 for MNA (positive ionization mode).

[0200] Cell viability assay.

[0201] Renal cancer cells were seeded as 5,000 cells / well on 96-well plates in the presence of the inhibitors diluted in media (to a final concentration of 1% DMSO) at different concentrations for the specified time. The inhibitors and culture media were changed every 2 days. Cell viability was assessed using 0.2 mg / ml resazurin solutions prepared from resazurin sodium salt (Acros Organics™, AC418900050) dissolved in sterile 1 x PBS. Then, the cells were incubated with 10 pl resazurin solution (10% of cell culture volume) for 3 hours at 37 °C. The fluorescence was measured using a CLARIOstar microplate reader (Ex = 540 nm, Em = 620 nm) at 37 °C. Cell viability was calculated as 100% x (fluorescence of treated cells - fluorescence of background controls) / (fluorescence of DMSO controls - fluorescence of background controls).

[0202] Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. The implementations should not be limited to the particular limitations described. As NNMT has been implicated in other diseases, other implementations are be possible.

[0203] It is intended that that the scope of the present methods and compositions be defined by the following claims. However, it must be understood that this disclosure may be practiced otherwise than is specifically explained and illustrated without departing from its spirit or scope. It should be understood by those skilled in the art that variousalternatives to the embodiments described herein may be employed in practicing the claims without departing from the spirit and scope as defined in the following claims.

Claims

What is claimed is:

1. A compound of the formula (A):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, absent, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is CH2or O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,each of which is optionally substituted; andX1is X, H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)2;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofeach of which is optionally substituted.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, of the formula (A) wherein Q is CH2.

3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, of the formula (A) wherein Q is O.

4. The compound of claim 2, wherein the compound of the formula (A) is a compound of the formula (I):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andY is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein Y is H.

6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted alkyl.

7. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein Y is8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Y is:

9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Y is10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently H or alkyl.

11. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:pharmaceutically acceptable salt thereof.

12. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:pharmaceutically acceptable salt thereof.

13. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: :pharmaceutically acceptable salt thereof.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:pharmaceutically acceptable salt thereof.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula (II):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andZ is selected from the group consisting of16. The compound of claim 7, wherein the compound is a compound of the formula (III):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula:

18. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula (IV):or a pharmaceutically acceptable salt thereof, wherein,R is a halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andX is a halogen, NH2, NHMe, or N(Me)2.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the formula:

20. The compound of claim 3, wherein the compound is a compound of the formula (B):R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocyclyl, aryl,o heteroaryl, each of which is optionally substituted; andX1is H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein X1is N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN(heterocyclyl), HN(heterobicyclyl), HN(aryl), HN(heteroaryl), or heterocyclyl, each of which is optionally substituted.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein X1is:

23. The compound of claim 21 of the formula:

24. A compound of the formula:

25. A method for treating a patient with a disease caused by abnormal activities of nicotinamide N-methyltransferase (NNMT) comprising the step of administering a therapeutically effective amount of a compound of claim 1 to the patient in need of relief from said disease.

26. The method of claim 25, wherein said disease is a cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease.

27. The method according to claim 25, wherein said cancer is a glioblastoma, prostate, lung, breast, or pancreatic cancer.

28. A method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound of claim 1, together with a therapeutically effective amount of one or more other compounds of the same or different mode of action, to the patient in need of relief from said disease.

29. A method for treating a patient with a cancer, the method comprising the step of administering a therapeutically effective amount of a compound of claim 1, together with a therapeutically effective amount of one or more other compounds targeting NNMT pharmacological pathway, to the patient in need of relief from said cancer.

30. A method for treating a patient with a disease caused by abnormal activities of NNMT comprising the step of administering a therapeutically effective amount of a compound to the patient in need of relief from said disease, wherein the compound having the formula:or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, halogen, alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;R1and R2are each independently H, halogen, alkyl, or together form a cycloalkyl;Q is Cffcor O;Y1is Y, H, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted,wherein Z1is Z, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,X1is X, H, halogen, NH2, NHMe, or N(Me)2, or N(alkyl)2, HN(alkyl), HN(cycloalkyl), HN (cycloalkyl alkyl), HN(heterocyclyl), HN(heterocyclylalkyl), HN(heterobicyclyl), HN(heterobicyclyl alkyl), HN(aryl), HN(arylalkyl), HN(heteroaryl), HN(heteroarylalkyl), HN(alkylcycloalkyl), HN(alkylheterocyclyl), HN(alkylaryl), HN(alkylheteroaryl), or heterocyclyl, each of which is optionally substituted, wherein:X is a halogen, NH2, NHMe, or N(Me)2;Y is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; andZ is selected from the group consisting ofeach of which is optionally substituted.

31. The method of claim 30, wherein the compound having the formula (I):or a pharmaceutically acceptable salt thereof, wherein,R3is hydrogen, a halogen, or an alkyl, alkenyl, alkynyl, acyl, arylalkylacyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;X is a halogen, NH2, NHMe, or N(Me)2; andY is H, or an alkyl, alkenyl, alkynyl, acyl, aryl alkyl acyl, arylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

32. The method according claim 30, wherein said disease is a cancer, an inflammation disease, a neurodegenerative disease, or a cardiovascular disease.

33. The method according to claim 30, wherein said compound is:

34. A pharmaceutical composition comprising one or more compounds of claim 1, together with one or more pharmaceutically acceptable diluents, excipients, or carriers.

35. The use of a compound of claim 1 in the formulation of a pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier, excipient or diluent, or salt thereof.

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