ALDH-2 Inhibitory Compounds and Methods of Use

Abstract

In this specification, the use of aldehyde dehydrogenase (ALDH-2) inhibitory compounds such as compounds of structural formula (I) or (II), pharmaceutical compositions containing these inhibitory compounds, and these compounds or compositions in a method for safely treating, individually or simultaneously, chemical dependence or dependence syndromes on substances such as alcohol, nicotine, cocaine, opiates, amphetamines, and compulsive eating disorders and / or anxiety disorders is disclosed.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 352,002, filed on June 14, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] Field The present disclosure relates to novel compounds that selectively inhibit aldehyde dehydrogenase - 2 (ALDH - 2). The present disclosure also relates to pharmaceutical compositions containing such inhibitory compounds, and to the use of such compounds or compositions in methods for safely treating chemical dependencies or addictive states to substances such as alcohol, nicotine, cocaine, opioids, amphetamines, binge - eating disorder, and / or anxiety disorders, either individually or simultaneously.

Background Art

[0003] Background Addiction remains a major health problem worldwide. The U.S. Surgeon General has stated that drug abuse is the nation's medical breakdown, and it is estimated to have caused a reduction in average U.S. life expectancy of more than three months, 155,000 related deaths annually, a treatment need for 23 million people, and an economic burden of $400 billion annually. See “Facing Addiction in America,” Surgeon General's Report, 2016. The Centers for Disease Control and Prevention estimated that in 2016, 64,000 people died in the United States from overdose of illegal drugs, 14,000 of which were due to prescription opioids.

[0004] Inhibition of aldehyde dehydrogenase-2 (ALDH-2) has been shown to reduce the pathophysiological dopamine surge without changing basal dopamine levels in a rat model of cue-induced cocaine relapse-like behavior. See, e.g., Yao et al., “Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis,” Nature Medicine (2010), Vol. 16, No. 9, Diamond and Yao, “From Ancient Chinese Medicine to a Novel Approach to Treat Cocaine Addiction,” CNS & Neurological Disorders-Drug Targets (2015) Vol. 14, No. 6. Recent studies have concluded that dopamine surges above normal levels are part of the reward system circuitry common to all addictive drugs. See, e.g., Volkow et al., “Neurobiologic Advances from the Brain Disease Model of Addiction,” N. Engl. J. Med. (2016) 374:363-371. The genus of compounds having a structural core related to 2,6-dichloro-N-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide has been shown to selectively inhibit ALDH-2 against the monoamine oxidase (MAO) pathway and exhibit efficacy in the treatment of rat models of alcohol, nicotine, and cocaine dependence. See, for example, U.S. Pat. Nos. 8,558,001, 8,575,353, 9,000,015, 9,610,299, International Patent Publication WO2013 / 006400, and Rezvani et al., “Inhibition of Aldehyde Dehydrogenase-2 (ALDH-2) Suppresses Nicotine Self-Administration in Rats,” (2015) Journal of Drug and Alcohol Research, vol. 4:1-6. However, the compound 2,6-dichloro-N-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide has been found to exhibit high levels of hepatotoxicity in humans. See, for example, O’Malley et al., “Phase 2 Study of ANS-6637, a Specific Inhibitor of ALDH2, in Treatment Seeking Individuals With Alcohol Use Disorder: A Combined Human Laboratory and Outpatient Clinical Trial,” (2021) Neuropsychopharmacology. Vol. 46:416-417. In view of the problematic hepatotoxicity of 2,6-dichloro-N-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide, an ALDH-2 inhibitory compound without hepatotoxicity is still needed.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] [Non-Patent Document 1] “Facing Adplication in America,” Sugion general’s Report, 2016 [Non-Patent Document 2] Yao et al., “Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis,” Nature Medicine (2010), Vol. 16, No. 9 [Non-Patent Document 3] Diamond and Yao, “From Ancient Chinese Medicine to a Novel Approach to Treat Cocaine Addiction,” CNS & Neurological Disorders - Drug Targets (2015) Vol. 14, No. 6 [Non-Patent Document 4] Volkow et al., “Neurobiologic Advances from the Brain Disease Model of Addiction,” N. Engl. J. Med. (2016) 374:363 - 371 [Non-Patent Document 5] Rezvani et al., “Inhibition of Aldehyde Dehydrogenase-2 (ALDH-2) Suppresses Nicotine Self-Administration in Rats,” (2015) Journal of Drug and Alcohol Research, vol.4:1-6 [Non-Patent Document 6] O’Malley et al., “Phase 2 Study of ANS-6637, a Specific Inhibitor of ALDH2, in Treatment Seeking Individuals With Alcohol Use Disorder: A Combined Human Laboratory and Outpatient Clinical Trial,” (2021) Neuropsychopharmacology. Vol.46:416-417 [Summary of the Invention]

[0007] The present disclosure generally relates to compounds that inhibit ALDH-2, pharmaceutical compositions comprising these compounds, and the use of these compounds for the treatment of addiction and compulsive eating disorders and / or anxiety disorders in mammals. This summary is intended to introduce the subject matter of the present disclosure but is not intended to cover every embodiment, combination, or variation contemplated and described within the present disclosure. Further embodiments are contemplated and described by the disclosure of the detailed description, drawings, and claims.

[0008] In at least one embodiment, the present disclosure provides a compound of structural formula (I): [Chemical Formula] (wherein, X 1 is N or CR 3 and X 2 is N or CR 4 and X 3 is N or CR 6 is, provided that X1 , X 2 , and X 3 One or less of them is N, X 4 and X 5 Each of them is, independently, N or CR 10 and R 11 is H, halogen, optionally substituted C 1-6 alkyl, or cycloalkyl, R 7 is H, or optionally substituted C 1-6 alkyl, R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , and R 10 Each of them is, independently, H, halogen, -CF3, -OH, -CH2OH, -CN, optionally substituted alkyl, optionally substituted alkylene, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, aminocarbonyl, acyl, acylamino, -O-(C1-C6-alkyl)-O-(C1-C6-alkyl), -CH2OP(O)(OR 20 )(OR 21 ), -SO2NR 24 R 25 , or -NR 24 R 25 wherein, when X 1 is CR 3 and X 2 is CR 4 and X 3 is CR 6 and X 4 is CR 10 and X 5 is CR 10 and when R 11 is H, R 2 and R6 Both are not Cl, R 20 and R 21 each independently is Na + , Li + , K + , hydrogen, C 1-6 alkyl, or R 20 and R 21 are combined to represent a single divalent cation Zn 2+ , Ca 2+ , or Mg 2+ and can be represented as, R 24 and R 25 each independently is selected from hydrogen or C 1-6 alkyl, or they combine with the nitrogen to which they are attached to form a heterocyclic ring), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof is provided.

[0009] In at least one embodiment of the compound of structural formula (I), R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 each is H.

[0010] In at least one embodiment of the compound of structural formula (I), X 1 is CR 3 , X 2 is CR 4 , X 3 is CR 6 . In at least one embodiment of the compound of structural formula (I), X 1 is N, X 2 is CR 4 , X 3 is CR 6 . In at least one embodiment of the compound of structural formula (I), X 1 is CR 3 and X2 is N, and X 3 is CR 6 is. In at least one embodiment of the compound of structural formula (I), X 1 is CR 3 is, and X 2 is CR 4 is, and X 3 is N.

[0011] In at least one embodiment of the compound of structural formula (I), X 4 is CR 10 is, and X 5 is CR 10 is. In at least one embodiment of the compound of structural formula (I), X 4 is CR 10 is and X 5 is N. In at least one embodiment of the compound of structural formula (I), X 4 is N, and X 5 is N.

[0012] In at least one embodiment of the compound of structural formula (I), R 2 is selected from H, Cl, F, or CH3.

[0013] In at least one embodiment of the compound of structural formula (I), R 3 is selected from H, Cl, F, and CH3.

[0014] In at least one embodiment of the compound of structural formula (I), R 5 is selected from H, Cl, F, and CH3.

[0015] In at least one embodiment of the compound of structural formula (I), R 6 is selected from H, Cl, F, and CF3.

[0016] In at least one embodiment of the compound of structural formula (I), R 11 is selected from H and halogen. Selected from. In at least one embodiment, R 11 is 3-fluoro.

[0017] In at least one embodiment, the present disclosure provides a compound of formula (II):

Chem.

Chem.

[0018] In at least one embodiment of the compound of structural formula (II), X 2 and X 3 are CH.

[0019] In at least one embodiment of the compound of structural formula (II), X 2 is CH, and X 3 is N.

[0020] In at least one embodiment of the compound of structural formula (II), R 11 is H. In at least one embodiment, R 11 is 3-fluoro.

[0021] In at least one embodiment of the compound of structural formula (II), R 3 , R 4 , and R 5 are H. In at least one embodiment, R 3 , R 4 , and R 5 are independently H, Cl, F, CH3, or CF3.

[0022] In at least one embodiment of the compound of structural formula (II), R 2 is H, Cl, F, or CH3.

[0023] In at least one embodiment of the compound of structural formula (II), R 6 is H, Br, Cl, F, or CF3.

[0024] In at least one embodiment of the compound of structural formula (II), R 1 is as follows: [Chemical formula] selected from.

[0025] In at least one embodiment, the compound of structural formula (I) or structural formula (II) of the present disclosure is selected from compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), and (1n), the structures of which are described in Table 1 below (including its pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers).

[0026] [Table 1-1] [Table 1-2] [Table 1-3]

[0027] In at least one embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0028] In at least one embodiment, the present disclosure is a method of treating chemical dependence on a substance, or a state of addiction or abuse, comprising administering a compound of structural formula (I) or formula (II) (e.g., a compound of Table 1), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof. In at least one embodiment, the substance or state of addiction or abuse is selected from the group consisting of alcohol, nicotine, cocaine, opiates, amphetamines, and compulsive eating, individually or simultaneously.

[0029] In at least one embodiment, the present disclosure provides a method for treating compulsive eating, comprising administering to a human patient a compound of structural formula (I) or formula (II), or a tautomer, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0030] In at least one embodiment, the present disclosure provides a method for treating compulsive eating disorder, comprising administering to a human patient a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof. In at least one embodiment, the present disclosure provides a method for treating anxiety, comprising administering to a human patient a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0031] In at least one embodiment, the present disclosure provides an ALDH-2 inhibitor comprising a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, for use in therapy, for use as a medicament, for use in the treatment of chemical dependence on a substance, for use in the treatment of a disorder of addiction or abuse, for use in the treatment of compulsive eating disorder, or for use in the treatment of an anxiety disorder.

[0032] In at least one embodiment, the present disclosure provides an ALDH-2 inhibitor comprising a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof for use in the manufacture of a pharmaceutical composition or medicament for the treatment of chemical dependence on a substance, for use in the treatment of a disorder of addiction or abuse, for use in the treatment of binge eating disorder, or for use in the treatment of an anxiety disorder.

Embodiments for Carrying Out the Invention

[0033] It should be understood that the detailed description provided herein, including the drawings, is by way of example and illustration only and is not intended to limit the present disclosure. This description is not limited to the specific compounds, compositions, methods, techniques, protocols, cell lines, assays, and reagents disclosed herein, which may vary widely, and is also intended to encompass known variations of these particular embodiments.

[0034] Also, it should be understood that the terms used in this specification are intended to merely describe particular embodiments and are not intended to limit the scope set forth in the appended claims. In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to “a protein” includes a plurality of proteins, and a reference to “a compound” refers to a plurality of compounds. The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” and “including” is interchangeable and not intended to be limiting. When the description of various embodiments uses the term “comprising,” those skilled in the art will understand that in some specific examples, an embodiment may alternatively be described using the language “consisting essentially of” or “consisting of.”

[0035] Furthermore, unless the context clearly indicates otherwise, when a range of values is provided, each intervening integer value between the upper and lower limits of that range, as well as each tenth of an intervening integer value, and any other described value or intervening value within the described range are understood to be included in the present invention. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and are also included in this specification, subject to any specific exclusion limits described within the described range. When the described range includes one or both of its upper and lower limits, ranges excluding (i) either one or (ii) both of the included upper and lower limits are also included in the present invention. For example, “1 to 50” includes “2 to 25,” “5 to 20,” “25 to 50,” “1 to 10,” and the like.

[0036] Abbreviations, Definitions, and General Parameters

[0037] As used herein, the following terms generally are intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0038] As used herein, the term "ALDH-2 inhibitor" includes any compound that selectively inhibits the enzyme aldehyde dehydrogenase 2. Exemplary ALDH-2 inhibitory compounds include isoflavone compounds, daidzein (see, e.g., U.S. Pat. Nos. 5,624,910 and 6,121,010), and structurally related isoflavone-derived compounds (see, e.g., U.S. Pat. Nos. 7,951,813, 8,158,810, and 8,673,966; International Patent Publication Nos. WO2008 / 014497, WO2008 / 124532, WO2009 / 061924, WO2009 / 094028, and WO2013 / 033377), and compounds of formula (I) that are structurally unrelated to isoflavones, such as 2,6-dichloro-N-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide (see, e.g., U.S. Pat. Nos. 8,558,001, 8,575,353, 9,000,015, 9,610,299; International Patent Publication WO2013 / 006400).

[0039] As used herein, the term "addiction" includes any substance use disorder, including, but not limited to, substance misuse, substance dependence, drug dependence, and / or addictive conditions, such as compulsive or binge eating disorders, and / or anxiety disorders, individually or simultaneously. Exemplary substances of misuse, dependence, and / or addiction include, but are not limited to, alcohol, nicotine, cocaine, opiates, and amphetamines.

[0040] As used herein, the term "alcohol" in the context of dopamine-generating agents that are consumable by a human refers to ethanol ("EtOH").

[0041] As used herein, the term "anxiety disorder" refers to anxiety that does not go away and worsens over time, resulting in symptoms that can interfere with daily activities such as work performance, schoolwork, and human relationships. Exemplary anxiety disorders include, but are not limited to, generalized anxiety disorder, panic disorder, social anxiety disorder, and various phobia-related disorders.

[0042] As used herein, the term "compulsive eating disorder" or "hyperphagic disorder" refers to a disorder characterized by recurrent episodes of overeating, during which a person becomes uncontrollable and experiences significant distress related to food, resulting in overweight or obesity.

[0043] The term "therapeutically effective amount" refers to an amount sufficient to produce a therapeutic effect when administered to a mammal in need of such treatment, as defined below. The therapeutically effective amount will vary depending on the subject being treated and the state of the disease, the subject's weight and age, the severity of the condition, the mode of administration, etc., and these can be readily determined by one of ordinary skill in the art.

[0044] The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of an active ingredient that, in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, or ampule), produces the desired therapeutic effect.

[0045] The term "active ingredient" refers to a compound in a pharmaceutical composition that has a pharmacological effect when administered to a living organism (e.g., a mammal), and is intended to include not only the compound, but also pharmaceutically acceptable salts, pharmaceutically acceptable esters, hydrates, polymorphs, and prodrugs of such compounds.

[0046] The term "prodrug" refers to a compound that contains a chemical group and can be converted and / or cleaved in vivo from the remaining part of the molecule to provide an active drug, its pharmaceutically acceptable salt, or its biologically active metabolite.

[0047] The term "treatment" or "treating" means any administration of a compound of the present disclosure to a mammal having a disease or disorder or a mammal susceptible to a disease or disorder, which is done for the purpose of including the following: (i) Preventing a disease, i.e., not developing the clinical symptoms of the disease, (ii) Suppressing a disease, i.e., stopping the development of clinical symptoms, and / or (iii) Alleviating a disease, i.e., regressing the clinical symptoms.

[0048] As used herein, the term "during treatment" refers to the period after administering a therapeutically effective amount of a compound to a subject for the treatment of a disease or disorder until the amount of the compound in the subject decreases to a level below the level at which it is therapeutically effective.

[0049] The term "alkyl" refers to a branched or unbranched saturated hydrocarbon chain of a monoradical having 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, etc.

[0050] The term "substituted alkyl" refers to the following: (i) An alkyl group as defined above having 1, 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by definition, all substituents are optionally alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2) may be further substituted by 1, 2, or 3 substituents selected from, or (ii) Oxygen, sulfur, and NR a (wherein R a is independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl) and is interrupted by 1 to 10 atoms (e.g., 1, 2, 3, 4, or 5 atoms) of an alkyl group as defined above. All substituents are optionally alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O) n R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2) may be further substituted by, or (iii) having one, two, three, four or five substituents as defined above and interrupted by from 1 to 10 atoms (e.g., 1, 2, 3, 4, or 5 atoms) of the alkyl group as defined above.

[0051] The term "lower alkyl" refers to a branched or unbranched saturated hydrocarbon chain of a monoradical having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl and the like.

[0052] The term "substituted lower alkyl" refers to a lower alkyl as defined above having from 1 to 5 substituents (typically 1, 2, or 3 substituents) as defined for substituted alkyl, or a lower alkyl as defined above interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl as defined above having one, two, three, four or five substituents as defined above and interrupted by 1, 2, 3, 4, or 5 atoms as defined above.

[0053] The term "alkylene" typically refers to a diradical of a branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms (e.g., from 1 to 10 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms). This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH 2- -).

[0054] The term "lower alkyl" typically refers to a diradical of a branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0055] The term "substituted alkylene" refers to the following: (i) An alkylene group as defined above having 1, 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by definition, all substituents are optionally alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2), which may be further substituted by 1, 2, or 3 substituents selected therefrom, or (ii) -O-, -S-, sulfonyl, -C(O)-, -C(O)O-, -C(O)N-, and -NR a (wherein R a is independently selected from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl), an alkylene group as defined above interrupted by 1 to 10 groups (e.g., 1, 2, 3, 4, or 5 groups), or (iii) An alkylene group as defined above, having from 1, 2, 3, 4 or 5 substituents as defined above and interrupted by from 1 to 10 groups as defined above. Examples of substituted alkylene groups are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH2)CH2-), methylaminoethylene (-CH(NHMe)CH2-), 2-carboxypropylene isomers (-CH2CH(CO2H)CH2-), ethoxyethyl (-CH2CH2O-CH2CH2-), ethylmethylaminoethyl (-CH2CH2-N(CH3)-CH2CH2-), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane (-CH2CH2O-CH2CH2-OCH2CH2-OCH2CH2-), and the like.

[0056] The term "aralkyl" refers to an aryl group covalently bonded to an alkylene group, where aryl and alkylene are as defined herein. "Optionally substituted aralkyl" refers to an optionally substituted aryl group covalently bonded to an optionally substituted alkylene group. Examples of such aralkyl groups include benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.

[0057] The term "aralkyloxy" refers to an -O-aralkyl group. "Optionally substituted aralkyloxy" refers to an optionally substituted aralkyl group covalently bonded to an optionally substituted alkylene group. Examples of such aralkyl groups are illustrated by benzyloxy, phenylethyloxy, and the like.

[0058] The term "alkoxy" refers to an R-O-group, where R is an optionally substituted alkyl or an optionally substituted cycloalkyl, or R is a -Y-Z group, where Y is an optionally substituted alkylene and Z is an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are as defined herein. A typical alkoxy group is alkyl-O-, and examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.

[0059] The term "lower alkoxy" refers to an R-O-group, where R is an optionally substituted lower alkyl as defined above. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the like.

[0060] The term "alkylthio" refers to an R-S-group, where R is as defined for alkoxy.

[0061] The term "alkenyl" typically refers to a monoradical of a branched or unbranched saturated hydrocarbon chain having from 2 to 20 carbon atoms (more typically from 2 to 10 carbon atoms, such as from 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon double bonds, such as 1, 2, or 3 carbon-carbon double bonds. Typical alkenyl groups include ethenyl (or vinyl, i.e., -CH=CH2), 1-propylene (or allyl, -CH2CH=CH2), isopropylene (-C(CH3)=CH2), bicyclo[2.2.1]heptene, and the like. When alkenyl is bonded to nitrogen, the double bond cannot be alpha to the nitrogen.

[0062] The term "lower alkenyl" refers to alkenyl having 2 to 6 carbon atoms as defined above.

[0063] The term "substituted alkenyl" refers to an alkenyl group as defined above having 1, 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by definition, all substituents are optionally further substituted by 1, 2, or 3 substituents selected from R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2). n R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2).

[0064] The term "alkynyl" typically refers to a monoradical of an unsaturated hydrocarbon having 2 to 20 carbon atoms (more typically 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms) and 1 to 6 carbon-carbon triple bonds, for example, 1, 2, or 3 carbon-carbon triple bonds. Typical alkynyl groups include ethynyl (-C=CH), propargyl (or propynyl, -C=CCH3), and the like. When alkynyl is bonded to nitrogen, the triple bond cannot be alpha to the nitrogen.

[0065] The term "substituted alkynyl" refers to an alkynyl group as defined above having 1, 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by definition, all substituents are optionally further substituted by 1, 2, or 3 substituents selected from R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2). n R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2) may be further substituted by 1, 2, or 3 substituents selected therefrom.

[0066] The term "aminocarbonyl" refers to a -C(O)NRR group, wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise restricted by definition, all substituents are optionally further substituted by 1, 2, or 3 substituents selected from R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2). n R (wherein R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2) may be further substituted by 1, 2, or 3 substituents selected therefrom.

[0067] The term "ester" or "carboxyester" refers to a -C(O)OR group, where R is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which may be alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O) n R a (wherein R a is alkyl, aryl, or heteroaryl, and n is 0, 1 or 2) may be further substituted by

[0068] The term "acylamino" refers to a -NRC(O)R group, where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. All substituents may optionally be alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O) n R (wherein R is alkyl, aryl, or heteroaryl, and n is 0, 1 or 2) may be further substituted by

[0069] The term "acyloxy" refers to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-aryl, -OC(O)-heteroaryl, and -OC(O)-heterocyclyl. Unless otherwise restricted by definition, all substituents may optionally be alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R (wherein R is alkyl, aryl, or heteroaryl, and n is 0, 1 or 2) may be further substituted by 1, 2, or 3 substituents selected from

[0070] The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl), or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl, and anthryl). Typical aryls include phenyl, fluorenyl, naphthyl, anthryl, and the like.

[0071] Unless otherwise restricted by the definition of the aryl substituent, such aryl groups may optionally be substituted with 1, 2, 3, 4, or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by the definition, all substituents may optionally be alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n It may be further substituted with 1, 2, or 3 substituents selected from R (wherein R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2).

[0072] The term "aryloxy" refers to an aryl-O-group, where the aryl group is as defined above and includes an optionally substituted aryl group as defined above. The term "arylthio" refers to an R-S-group, where R is as defined for alkoxy.

[0073] The term "amino" refers to the -NH2 group.

[0074] The term "substituted amino" refers to an -NRR group (where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, provided that both R groups are not hydrogen), or a -Y-Z group (where Y is an optionally substituted alkylene and Z is an alkenyl, cycloalkenyl, or alkynyl). Unless otherwise restricted by definition, all substituents are optionally alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R (where R is alkyl, aryl, or heteroaryl and n is 0, 1, or 2) and may be further substituted by 1, 2, or 3 substituents selected therefrom.

[0075] The term "carboxyalkyl" refers to a -C(O)O-alkyl, -C(O)O-cycloalkyl group, where alkyl and cycloalkyl are as defined herein and are optionally alkyl, alkenyl, alkynyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O) n R (where R is alkyl, aryl, or heteroaryl and n is 0, 1, or 2) and may be further substituted thereby.

[0076] The term "cycloalkyl" refers to a cyclic alkyl group having a single cyclic ring or multiple fused rings, with 3 to 20 carbon atoms. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc., or polycyclic structures such as adamantanyl and bicyclo[2.2.1]heptane, or cyclic alkyl groups fused with aryl groups, such as indane, etc.

[0077] The term "cycloalkenyl" refers to a cyclic alkyl group having a single cyclic ring or multiple fused rings, with 3 to 20 carbon atoms and at least one double bond, preferably 1 to 2 double bonds.

[0078] The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer to a cycloalkyl or cycloalkenyl group having 1, 2, 3, 4, or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. The term "substituted cycloalkyl" also includes cycloalkyl groups in which one or more of the cyclic carbon atoms of the cycloalkyl group are carbonyl groups (i.e., the oxygen atom is oxo with respect to the ring). Unless otherwise restricted by definition, all substituents are optionally alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) nR (wherein R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2) may be further substituted by one, two, or three substituents selected therefrom.

[0079] The term "halogen" or "halo" refers to fluoro, bromo, chloro, and iodo.

[0080] The term "acyl" refers to a -C(O)R group, where R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0081] The term "alkoxycarbonylamino" refers to a -NHC(O)OR group, where R is optionally substituted alkyl.

[0082] The term "alkylamine" refers to R-NH2, where R is optionally substituted alkyl.

[0083] The term "dialkylamine" refers to R-NHR, where each R is independently optionally substituted alkyl.

[0084] The term "trialkylamine" refers to NR3, where R is independently optionally substituted alkyl.

[0085] The term "azide"

Chemical formula

[0086] The term "hydroxy" or "hydroxyl" refers to a -OH group.

[0087] The term "azide" refers to a -S-aryl group.

[0088] The term "heterocyclylthio" refers to an -S-heterocyclyl group.

[0089] The term "alkylthio" refers to an -S-alkyl group.

[0090] The term "aminosulfonyl" refers to a -SO2NRR group, where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. Unless otherwise restricted by definition, all substituents are optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl.

[0091] The term "aminocarbonylamino" refers to -NR c C(O)NRR group, where each R cis hydrogen or alkyl, and each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. Unless otherwise restricted by definition, all substituents are optionally further substituted with one, two, or three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl.

[0092] The term "heterocyclooxy" refers to an -O-heterocyclyl group.

[0093] The term "alkoxyamino" refers to an -NHOR group, where R is optionally substituted alkyl.

[0094] The term "hydroxyamino" refers to an -NHOH group.

[0095] The term "heteroaryl" refers to a group containing one or more rings having from 1 to 15 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur in at least one ring. The term "heteroaryl" is a general term for the terms "aromatic heteroaryl" and "partially saturated heteroaryl". The term "aromatic heteroaryl" refers to a heteroaryl in which at least one ring is aromatic. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline, and pteridine. The term "partially saturated heteroaryl" refers to a heteroaryl having a structure corresponding to the underlying aromatic heteroaryl and having one or more double bonds in the aromatic ring of the underlying saturated aromatic heteroaryl. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, and chroman.

[0096] Unless otherwise restricted by the definition of the heteroaryl substituent, such a heteroaryl group may optionally be substituted with 1 to 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl (alkyl ester), arylthio, heteroaryl, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, aralkyl, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by the definition, all substituents may optionally be alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) nR (wherein R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2) may be further substituted by one, two, or three substituents selected therefrom. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl, benzothiazole, or benzothienyl). Examples of nitrogen heterocyclyl and heteroaryl include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, etc., and N-alkoxy-nitrogen-containing heteroaryl compounds, but are not limited thereto.

[0097] The term "heteroaryloxy" refers to a heteroaryl-O-group.

[0098] The term "heterocyclyl", "heterocyclic", or "heterocyclic ring" refers to a monoradical saturated group having a single ring or multiple fused rings, having 1 to 40 carbon atoms in the ring and 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and / or oxygen.

[0099] Unless otherwise restricted by the definition of the complex ring substituent, such a heterocyclic group may optionally be substituted with 1 to 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl, and -SO2-heteroaryl. Unless otherwise restricted by the definition, all substituents may optionally be alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R (wherein R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2) may be further substituted with 1, 2, or 3 substituents selected therefrom. Preferred heterocycles include tetrahydrofuranyl, morpholino, piperidinyl, and the like.

[0100] The term "thiol" refers to the -SH group.

[0101] The term "substituted alkylthio" refers to an -S-substituted alkyl group.

[0102] The term "heteroarylthiol" refers to an -S-heteroaryl group, where the heteroaryl group is as defined above and includes optionally substituted heteroaryl groups as defined above.

[0103] The term "sulfoxide" refers to an -S(O)R group, where R is alkyl, aryl, or heteroaryl. "Substituted sulfoxide" refers to an -S(O)R group, where R is a substituted alkyl, substituted aryl, or substituted heteroaryl as defined herein.

[0104] The term "sulfone" refers to an -S(O)2R group, where R is alkyl, aryl, or heteroaryl. "Substituted sulfone" refers to an -S(O)2R group, where R is a substituted alkyl, substituted aryl, or substituted heteroaryl as defined herein.

[0105] The term "keto" or "oxo" refers to a -C(O)- group.

[0106] The term "thiocarbonyl" refers to a -C(S)- group.

[0107] The term "carboxy" refers to a -C(O)-OH group.

[0108] The term "optional" or "optionally" means that the event or circumstance described thereafter may or may not occur and that the description includes both the case where the event or circumstance occurs and the case where it does not occur.

[0109] The term "substituted" includes embodiments in which a monoradical substituent is attached to a single atom of the substituent (e.g., to form a branch), and also includes embodiments in which the substituent is a diradical bridging group that is attached to two adjacent atoms of the substituent, thereby forming a fused ring in the substituent.

[0110] When a given group (moiety) is described as being attached to a second group and the point of attachment is not specified, the given group may be attached to any available site of the second group at any available site of the given group. For example, "lower alkyl-substituted phenyl" may have any available site of a lower alkyl group attached to any available site of the phenyl group when the point of attachment is not specified. In this regard, an "available site" is a site of the group at which a hydrogen of the group may be replaced with a substituent.

[0111] Of course, in all substituents defined above, polymers obtained by defining substituents that themselves have further substituents (for example, a substituted aryl having a substituted aryl group as a substituent, where the substituent is itself substituted with a substituted aryl group, etc.) are not intended to be included herein. Also, regardless of whether the substituents are the same or different, an infinite number of substituents are not included. In such cases, the maximum number of such substituents is three. Each of the above definitions is thus restricted by limitations such as, for example, a substituted aryl group being limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0112] A compound of a given formula (e.g., "a compound of structural formula (I)") is intended to include the compounds of the present disclosure, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, hydrates, polymorphs, and prodrugs of such compounds.

[0113] In addition, the compounds of the present disclosure may have one or more asymmetric centers and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given formula depends on the number of asymmetric centers present (2n possible stereoisomers are present, where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolution of a racemic or non-racemic mixture of intermediates at some appropriate stage of synthesis or by resolution of the compounds by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers), as well as racemic and non-racemic mixtures of stereoisomers, are included within the scope of the present invention and are all intended to be represented by the structures herein unless otherwise specifically described.

[0114] The term "isomer" means different compounds having the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0115] The term "stereoisomer" means isomers that differ only in the spatial arrangement of atoms.

[0116] The term "enantiomer" means a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used, where appropriate, to indicate a racemic mixture.

[0117] The term "diastereoisomer" means stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0118] Absolute stereochemistry is defined herein according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as either R or S. A resolved compound of unknown absolute configuration is designated as (+) or (-) according to the direction in which it rotates the plane of polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory).

[0119] Some of the compounds of the present disclosure exist as "tautomeric isomers" or "tautomers". "Tautomeric isomers" or "tautomers" are isomers that are in equilibrium with each other. For example, an amide-containing compound can exist in equilibrium with its imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, it is understood by those skilled in the art that the compound includes both the amido acid tautomer and the imidic acid tautomer. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers. Non-limiting examples of tautomers containing amides and tautomers containing imidic acids are shown below.

Chemical Structure

[0120] The term "polymorph" refers to different crystal structures of a crystalline compound. Different polymorphs can result from differences in crystal packing (packing polymorphs) or differences in packing between different conformations of the same molecule (conformational polymorphs).

[0121] The term "solvate" refers to a complex formed by combining a compound with a solvent.

[0122] The term "hydrate" refers to a complex formed by combining a compound with water.

[0123] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and that are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming pharmaceutically acceptable acidic and / or basic salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0124] Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Examples of salts derived from organic bases include salts of primary, secondary, and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, diallylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, di-substituted cycloalkylamines, tri-substituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, di-substituted cycloalkenylamines, tri-substituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, and mixed di- and triamines (where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, etc.). Also included are amines in which two or three substituents together with the amino nitrogen form a heterocyclic group or a heteroaryl group. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0125] Pharmaceutically acceptable acid addition salts can also be prepared from inorganic acids and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0126] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where a conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0127] Any formula or structure provided herein that includes Formula (I) and Formula (II) is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the same structure as represented by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I. Various isotopically labeled compounds of the present invention, for example, 3 H, 13 C, 14Compounds incorporating radioisotopes such as C. Such isotope-labeled compounds can be useful in metabolic studies, reaction rate studies, detection, or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays), or in the radiotherapy of patients.

[0128] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can result in certain therapeutic benefits due to greater metabolic stability, such as an increase in the half-life in vivo or a decrease in the required dose. 18 F-labeled compounds can be useful in PET or SPECT examinations. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by using readily available isotope-labeled reagents in place of non-isotope-labeled reagents and carrying out the procedures disclosed in the following schemes or examples and preparation methods. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D), can result in certain therapeutic benefits due to greater metabolic stability, such as an increase in the half-life in vivo or a decrease in the required dose or an improvement in the therapeutic index. Deuterium in this context is understood to be regarded as a substituent in the compound of formula (I).

[0129] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotope enrichment factor. In the compounds of the present invention, atoms not specifically designated as a particular isotope represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its naturally occurring isotope composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) means deuterium.

[0130] In the description including examples, unless otherwise specified, all temperatures are in degrees Celsius (°C), and the abbreviations and acronyms have the following meanings listed in Table 2 (below).

[0131] [Table 2-1] [Table 2-2] [Table 2-3]

[0132] ALDH-2 inhibitor compound

[0133] Compounds that act as selective inhibitors of ALDH-2 have been shown to reduce pathophysiological dopamine surges. See, for example, Yao et al., “Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis,” Nature Medicine (2010), Vol. 16, No. 9, Diamond and Yao, “From Ancient Chinese Medicine to a Novel Approach to Treat Cocaine Addiction,” CNS & Neurological Disorders - Drug Targets (2015) Vol. 14, No. 6. Selective inhibitors of ALDH-2 have also been shown to have the ability to suppress nicotine self-administration in rats. See, for example, Rezvani et al., “Inhibition of Aldehyde Dehydrogenase-2 (ALDH-2) Suppresses Nicotine Self-Administration in Rats,” (2015) Journal of Drug and Alcohol Research, vol. 4:1-6, Kim et al. “Brain Microdialysis Coupled to LC-MS / MS Revealed That CVT-10216, a Selective Inhibitor of Aldehyde Dehydrogenase 2, Alters the Neurochemical and Behavioral Effects of Methamphetamine,” (2021) ACS Chem Neurosci, Vol. 12:1552-1562, and U.S. Patent Nos. 8,558,001, 8,575,353, 9,000,015, 9,610,299, International Patent Publication WO2013 / 006400.The novel ALDH-2 inhibitory compounds provided by the present disclosure have been shown to selectively inhibit ALDH-2 in preclinical assays and exhibit the property of reduced hepatotoxicity. Accordingly, the compounds of the present disclosure may be useful for the treatment of conditions responsive to the selective inhibition of ALDH-2 and the reduction of pathophysiological dopamine surges. Such uses may include the individual or simultaneous reduction and / or prevention of substance dependence or abuse or states of dependence in mammals, including alcohol, nicotine, cocaine, methamphetamine, opioids, compulsive eating disorders, and / or anxiety disorders.

[0134] In at least one embodiment, the present disclosure provides an ALDH-2 inhibitory compound of structural formula (I):

Chemical formula

[0135] As exemplified by the exemplary compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), and (1n), the structures of a wide range of specific ALDH-2 inhibitory compounds within the structural formula (I) are contemplated, which also include pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers of the compounds, and compounds having one or more of the following structural features: (i) each of R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , and R 11 is H, (ii) X 1 is CR 3 , X 2 is CR 4 , X 3 is CR 6 , (iii) X 1 is N, X 2 is CR 4 , X 3 is CR 6 , (iv) X 1 is CR 3 , X 2 is N, X 3 is CR 6 , (v) X 1 is CR 3 , X 2 is CR 4 , X 3 is N, (vi) X 4 is CR 10 , X 5 is CR 10 , (vii) X 4 is CR 10 , X 5 is N, (viii) X 4 is N, X5 is N, (ix) X 1 is CR 3 and X 2 is CR 10 and X 3 is CR 10 and (x) R 2 is selected from H, Cl, F, or CH3, (xi) R 3 is selected from H, Cl, F, and CH3, (xii) R 5 is selected from H, Cl, F, and CH3, (xiii) R 6 is selected from H, Cl, F, and CF3, (xiv) R 11 is selected from H and halogen, and / or (xv) R 11 is 3-fluoro.

[0136] In at least one embodiment, the present disclosure relates to an ALDH-2 inhibitory compound of structural formula (II):

Chemical formula

Chemical formula

[0137] As exemplified by the exemplary compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), and (1n), the structures of a wide range of specific ALDH-2 inhibitory compounds within the structural formula (II) are contemplated, including pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers of the compounds, and compounds having one or more of the following structural features: (i) X 2 and X 3 are CH, (ii) X 2 is CH and X 3 3 is N, (iii) R 11 is H, (ivR 11 is 3-fluoro, (v) R 3 , R 4 , and R5 is H, (vi) R 3 , R 4 , and R 5 is independently H, Cl, F, CH3 or CF3, (vii) R 2 is H, Cl, F, or CH3, (viii) R 6 is H, Br, Cl, F, or CF3, and / or (ix) R 1 is as follows:

Chemical formula

[0138] The ALDH-2 inhibitory compounds of structural formulas (I) and (II) can be prepared from readily available starting materials using methods and procedures known in the art. In particular, the present disclosure provides a general synthetic strategy for preparing the compounds of structural formulas (I) and (II), and also exemplifies specific synthetic protocols that can be used to prepare the exemplary compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), (1n), and (1o) described herein and listed in Table 1.

[0139] Briefly stated, the compounds of formula (I) or (II) can be prepared according to the synthetic procedures shown in Scheme A. Scheme A

Chemical formula

[0140] The reactants (a) and (b) of Scheme A are commercially available or can be prepared as described in the following examples or by means well known in the art. Generally, as shown in Scheme A, reactant (a) and at least 1 molar equivalent, preferably a slight excess (e.g., 1.2 to 1.5 molar equivalents) of (b) are combined under standard reaction conditions until the reaction is complete, generally for about 30 minutes to about 2 hours, at a temperature of about 0 °C to about 25 °C, in an inert solvent such as dichloromethane (DCM) or dimethylformamide (DMF). Standard reaction conditions further include the use of a molar excess of a suitable base such as triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), sodium hydroxide or potassium hydroxide, or pyridine, or, when LG is hydroxyl, a peptide coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) can be used. Once the reaction to form intermediate (c) is substantially complete, it is subjected to standard conditions (e.g., heat and acid) to convert the methoxy group of (c) to the oxo product (d). If necessary, the product can be further subjected to a deprotection procedure under standard reaction conditions (e.g., THF, CH2Cl2, etc., a molar excess of an acid such as acetic acid, formic acid, trifluoroacetic acid described herein) to obtain an isolate by conventional means.

[0141] R 11 The phosphate ester derivative of the compound of formula (I) or formula (II) in the substituent may be prepared as shown below in the synthetic procedure of Scheme B. Scheme B

Chemical formula

[0142] For example, the phosphate ester derivative (i) is prepared according to the synthetic procedure of Scheme B by reacting pyridin-2(1H)-one (d) with at least 1 equivalent, preferably a slight excess (e.g., 1.2 to 1.5 molar equivalents) of linker (e) (wherein R 12is an alkylene moiety optionally substituted with 1 to 6 carbon atoms), and at least 1 equivalent, preferably slightly in excess (e.g., 1.2 to 2 molar equivalents) of a suitable base such as triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), or pyridine, and alkylated under standard reaction conditions to obtain an alkylated derivative (f). This derivative (f) can then be used to O-alkylate a molar excess (e.g., 1.2 to 5 molar equivalents) of a phosphoric acid diester (g) to obtain the corresponding triester of phosphoric acid (h). Deprotection of the triester of phosphoric acid (h) under standard conditions (e.g., heating in CH3CN / H2O, etc., a molar excess of an acid such as acetic acid described herein) gives a phosphoric acid ester (i). The phosphoric acid esters of ALDH-2 inhibitory compounds have been shown to be useful as prodrugs via in vivo hydrolysis of the phosphoric acid esters. See, for example, U.S. Patent No. 8,558,001, which is incorporated herein by reference.

[0143] Of course, typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) in the examples herein, as well as other process conditions, can be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by conventional methods of optimization. Further, as will be apparent to one of ordinary skill in the art, conventional protecting groups may be necessary to protect certain functional groups from undergoing undesirable reactions. For example, protecting groups can be used to temporarily block functional groups (such as O, S, or N) so that the reaction occurs selectively at another reaction site in a polyfunctional compound. Protecting groups useful in the synthesis of the present disclosure are well known in the art and include those described in Protective Groups in Organic Synthesis, Fourth Ed., Greene, TW and Wuts, PG, Eds., John Wiley & Sons New York: 2007, the entire contents of which and the references cited therein are incorporated herein by reference.

[0144] As described above, the starting materials for Synthetic Reaction Scheme A are generally known compounds that can be disclosed in the examples of this specification, commercially available, or prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from vendors such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA). Others can be prepared by the procedures described in standard reference books such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) or obvious modifications thereof.

[0145] Methods of Use and Treatment

[0146] The present disclosure also provides the use of an ALDH-2 inhibitory compound of structural formula (I) or (II) of the present disclosure, including use in pharmaceutical compositions, which compositions can be used in methods for the individual or simultaneous treatment and / or prevention of addiction or substance abuse in mammals, including addiction or abuse to alcohol, nicotine, cocaine, methamphetamine, and / or opioids, and / or binge eating disorder, and / or anxiety disorders. The main factor in the development of an abuse or addiction state is neurophysiological reinforcement (reward). Animal experiments have suggested that there is at least one central reward reinforcement pathway for drug self-administration in the human brain (Volkow 2016). This pathway involves dopaminergic neurons that originate in the ventral tegmental area (VTA) and project to the nucleus accumbens (NAc) and the forebrain. The release of dopamine from these neurons to dopamine receptors in the Nac results in positive reinforcement.

[0147] All known addictive drugs activate the reward regions in the brain by causing a rapid increase in the release of dopamine (DA), thereby inducing a reward signal that causes associative learning or conditioning. In this type of Pavlovian learning, repeated experiences of reward are associated with the environmental stimuli that precede them. With repeated exposure to the same reward, dopamine cells stop firing in response to the reward itself and instead fire in response to a conditioned stimulus (referred to as a "cue") that, in a sense, predicts the delivery of the reward. Addictive drugs avoid the natural satiation of "natural rewards" such as food or sex by directly increasing dopamine - this factor may explain why compulsive behavior is more likely to occur when using drugs than when seeking natural rewards.

[0148] It is well established that cocaine and other addictive substances or states stimulate an increase in DA levels in the Nac, which is thought to mediate reward or reinforcement processes in the brain (DiChiara 1988) (Bileau 2003) (Tizabi 2002). Volkow and Koob (Volkow 2016) have provided evidence that surges in dopamine (DA) drive craving and addictive behaviors via reward system circuits (Feltenstein and See 2008). Conditioned responses that elicit craving for addictive substances often lead to behaviors associated with heavy substance use, and these strong cravings can persist long after use has ceased (Volkow 2016).

[0149] While not wishing to be bound by theory, ALDH-2 inhibitors such as the compounds of structural formulas (I) and (II) of the present disclosure are effective in reducing or preventing surges in dopamine levels caused by the administration or abuse of substances including alcohol, nicotine, cocaine, methamphetamine, opioids, compulsive eating disorders, and / or anxiety disorders. Accordingly, the ALDH-2 inhibitors of the present disclosure can be administered to a mammal as a method of treating, reducing, and / or preventing addiction in the treated mammal.

[0150] Accordingly, it is contemplated that an ALDH-2 inhibitor comprising a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound can be used in therapy. For example, the inhibitory compounds of the present disclosure can be used as a pharmaceutical composition or medicament, and these compositions can be used in the treatment of conditions affected by inhibition of ALDH-2. For example, use in the treatment of chemical dependence on a substance, use in the treatment of addiction or abuse conditions, use in the treatment of compulsive eating disorders, or use in the treatment of anxiety disorders.

[0151] Furthermore, the present disclosure also contemplates the use of a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound, as an ALDH-2 inhibitor in the manufacture of a pharmaceutical composition or a medicament. For example, a pharmaceutical composition or a medicament for use in the treatment of a condition of chemical dependence on a substance, for use in the treatment of a condition of addiction or abuse, for use in the treatment of binge eating disorder, or for use in the treatment of an anxiety disorder.

[0152] In at least one embodiment, it is contemplated that the method can be used to treat any mammal in need of therapy for a condition such as addiction. In particular, it is contemplated that the method can be used when the mammal is a human. Thus, in at least one embodiment, the present disclosure provides a method for the treatment or prevention of acquisition of a substance addiction or abuse condition in a mammal, the method comprising administering to the mammal a therapeutically effective amount of an ALDH-2 inhibitor, wherein the ALDH-2 inhibitor is a compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound. In at least one embodiment, the compound administered can be a compound selected from compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), and (1n), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0153] In at least one embodiment of the method, the step of administering the ALDH-2 inhibitor can comprise administering a pharmaceutical composition, the pharmaceutical composition comprising a drug, the ALDH-2 inhibitor, and a pharmaceutically acceptable carrier.

[0154] In some embodiments of such a treatment method, the method comprises self-administering a therapeutically effective dose of an ALDH-2 inhibitor to reduce the urge to use substances of abuse such as alcohol, nicotine, cocaine, methamphetamine, opioids, or food. In some embodiments, the ALDH-2 inhibitory compound in the form of a pharmaceutical composition is contemplated to be administered (including self-administration) as a dose once or twice a day. In some embodiments, the once-daily dose is a formulation (e.g., a tablet) self-administered by the subject or patient.

[0155] In some embodiments for the treatment of addiction, it is contemplated that the administration of the ALDH-2 inhibitory compound to the subject can be continued for at least 1 month, at least 3 months, at least 6 months, at least 1 year, or permanently.

[0156] In various embodiments of the methods disclosed herein for the safe treatment or prevention of acquisition of substance dependence or abuse conditions in mammals, the ALDH-2 inhibitor has low hepatotoxicity and / or is not hepatotoxic. It has been reported that an assay using HepaRG® spheroids can be used to determine the potential or tendency for hepatotoxicity of a drug candidate. See, for example, Walker et al., “The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development,” (2020) Archives of Toxicology, Vol. 94:2559-2585, which is incorporated herein by reference in its entirety. Walker et al. reported that when applying a cut-off minimum effective concentration (MEC) < 25×C max.tot the results of the HepaRG spheroid assay correlated with drugs known to cause hepatotoxicity in humans with high sensitivity, specificity, and accuracy of 84%, 100%, and 89%, respectively (C max.totis the maximum total plasma concentration of the drug, and MEC is the concentration that significantly exceeds the vehicle control threshold of the cell health marker). When applying the HepaRG spheroid assay analysis to determine the hepatotoxicity of an ALDH-2 inhibitory compound, consider the binding to plasma proteins and the limitation of CNS permeability by the blood-brain barrier. Therefore, for an ALDH-2 inhibitory compound showing low hepatotoxicity, it is reasonable to assume a multiple of 100 when determining the most preferred ratio of MEC to 50 (ALDH-2). Thus, for an assay of an ALDH-2 inhibitor showing low hepatotoxicity, an exemplary ratio of the HepaRG spheroid assay MEC to 50 is most preferably greater than 2500, next greater than 250, and next preferably not greater than 25.

[0157] Pharmaceutical composition

[0158] In some embodiments of the methods of the present disclosure, the ALDH-2 inhibitor is contemplated to be administered in the form of a pharmaceutical composition. A pharmaceutical composition comprising an ALDH-2 inhibitor comprises a therapeutically effective amount of an active ingredient, for example, an ALDH-2 inhibitory compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, and a carrier comprising one or more pharmaceutically acceptable excipients, inert solid diluents and fillers, a diluent comprising sterile aqueous solutions and various organic solvents, a penetration enhancer, a solubilizer, and an adjuvant in a dosage amount.

[0159] As disclosed elsewhere in this specification, in some embodiments of the method, the administering step may include administering a pharmaceutical composition, the pharmaceutical composition comprising an ALDH-2 inhibitor of structural formula (I) or (II) (e.g., compound (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), (1n)), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound, and a pharmaceutically acceptable carrier. Thus, in some embodiments, the present disclosure also provides a pharmaceutical composition, the composition comprising a therapeutically effective amount of an ALDH-2 inhibitor and a pharmaceutically acceptable carrier.

[0160] In some embodiments, the pharmaceutical composition useful in the methods of the present disclosure is in a unit dosage form, such as a dosage form containing the active ingredient (e.g., compound (1a)) in a single dosage form.

[0161] In some embodiments, the present disclosure provides a dosage form comprising a pharmaceutical composition of an ALDH-2 inhibitor (e.g., compound (1a)) and a pharmaceutically acceptable carrier, the dosage form comprising a therapeutically effective amount of the ALDH-2 inhibitor.

[0162] In some embodiments, the pharmaceutical composition comprises a dosage amount of the ALDH-2 inhibitor of formula (I) in an amount of about 25 mg to about 1200 mg, about 50 mg to about 600 mg, about 25 mg to about 400 mg, or about 25 mg to about 200 mg. In some embodiments, the pharmaceutical composition comprises a dosage amount of the ALDH-2 inhibitor of formula (I) in an amount of about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg.

[0163] Such pharmaceutical compositions can be prepared using methods well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)). Methods for preparing pharmaceutical compositions of ALDH-2 inhibitory compounds are described in this disclosure, including the examples disclosed herein. Useful synthetic methods of ALDH-2 inhibitory compounds are also described, for example, in U.S. Patent Nos. 7,951,813, 8,158,810, 8,673,966, 8,558,001, 8,575,353, 9,000,015, and 9,610,299, each of which is incorporated herein by reference.

[0164] Mode of Administration of ALDH-2 Inhibitor

[0165] In the methods of the present disclosure, a pharmaceutical composition(s) comprising an ALDH-2 inhibitory compound such as a compound of formula (I) or formula (II) (e.g., compound (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), (1n)), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound can be administered by any of the acceptable modes of administration of the active ingredient having similar utility, either as a single dose or as multiple doses. For example, as described in U.S. Patent No. 8,558,001, a pharmaceutical composition comprising an ALDH-2 inhibitor can be administered by rectal, buccal, intranasal, and transdermal routes, by intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, inhalation, or by using various different methods including via an impregnated or coated device such as a stent, or via a cylindrical polymer inserted into an artery.

[0166] One exemplary route of administration useful in the methods of the present disclosure is oral. Oral administration can be effected via capsules, enteric-coated tablets, and the like. Typically, when preparing a pharmaceutical composition comprising a drug containing an ALDH-2 inhibitor, e.g., a compound of formula (I) or formula (II), the active ingredient(s) is diluted by an excipient and / or enclosed within a carrier in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, suitable pharmaceutical composition(s) for administration in the methods of the present disclosure can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0167] Excipients suitable for use in the pharmaceutical compositions comprising the ALDH-2 inhibitors of the present disclosure are well known in the art and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The pharmaceutical compositions can additionally include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweetening agents, and flavoring agents.

[0168] Exemplary methods for preparing pharmaceutical compositions of ALDH-2 inhibitors suitable for use in the methods of the present disclosure are provided in the Examples.

[0169] A pharmaceutical composition containing an ALDH-2 inhibitor useful in the methods of the present disclosure can be formulated by using procedures known in the art to provide rapid release, sustained release, or delayed release of the relevant active ingredient after administration. Sustained-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that contain polymer-coated reservoirs or drug-polymer matrix formulations. Examples of sustained-release systems are shown, for example, in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345.

[0170] A pharmaceutical composition containing an ALDH-2 inhibitor useful in the methods of the present disclosure can also be formulated for administration via a transdermal delivery device (e.g., a "patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the pharmaceutical composition in a controlled amount. The construction and use of transdermal patches for delivering pharmaceutical compositions are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be configured for continuous, pulsatile, or demand-responsive delivery of the pharmaceutical composition(s). In some embodiments, the pharmaceutical composition(s) useful in the methods of the present disclosure are formulated in unit dosage forms.

[0171] Generally, ALDH-2 inhibitory compounds such as the compounds of structural formula (I) or (II) of the present disclosure are known to be effective over a wide range of dosages and are administered in a pharmaceutically effective amount as a pharmaceutical composition. In some embodiments, for oral administration, each dosage unit contains from about 10 mg to 1 g of the ALDH-2 inhibitory compound of structural formula (I) or formula (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound; in some embodiments, from 25 mg to 1200 mg. In some embodiments, for parenteral administration, the ALDH-2 inhibitory compound such as the compound of structural formula (I) or (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound is from 10 to 700 mg; in some embodiments, about 50 mg to 300 mg.

[0172] Generally, in the methods of the present disclosure, the amount of the ALDH-2 inhibitory compound such as the compound of structural formula (I) or (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound to be administered is determined by a physician taking into account the relevant circumstances of the subject being treated thereby, the route of administration selected, and of course, age, body weight, severity of symptoms, response of the individual subject to treatment, and the like.

[0173] To prepare a solid pharmaceutical composition useful in the methods of the present disclosure, the active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the active ingredient and the excipient. When these preformulation compositions are referred to as being homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition, whereby the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Tablets or pills may be coated or otherwise compounded to provide dosage forms that afford the advantages of prolonged action or that protect from the acidic conditions of the stomach. For example, a tablet or pill may comprise an inner administration component and an outer administration component, the latter being in the form of a coating that covers the former. The two components may be separated by an enteric layer that functions to withstand degradation in the stomach and to permit the inner component to enter the duodenum intact or to be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, such materials including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetates.

[0174] Another exemplary mode of administration useful in the methods of the present disclosure is parenteral, particularly by injection. The pharmaceutical compositions of the present disclosure can be incorporated for administration by injection, which includes aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in physiological saline can also be conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be utilized. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Inhibition of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0175] Sterile injectable solutions are prepared by incorporating the active ingredient of the present disclosure in the required amounts in a suitable solvent, along with the various other ingredients described above, and then, if necessary, filtering and sterilizing. Generally, dispersions are prepared by incorporating the sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other ingredients required from among the above ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, known methods of preparation include vacuum drying and lyophilization techniques, by which a powder obtained by combining the active ingredient and any desired additional ingredients from a pre-sterile filtered solution is obtained.

[0176] Pharmaceutical compositions that can be administered by inhalation or insufflation include solutions and suspensions, and powders, in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein and known in the art. In some embodiments, pharmaceutical compositions of an ALDH-2 inhibitory compound of structural formula (I) or (II) (e.g., compound (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), (1n)), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof can be administered via the oral or nasal respiratory route for local or systemic effects. In some embodiments, the pharmaceutical composition is prepared in a pharmaceutically acceptable solvent that can be nebulized by the use of an inert gas. These nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing apparatus. In some embodiments, the pharmaceutical compositions useful in the methods can be solution, suspension, or powder compositions and can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

Examples

[0177] The various features and embodiments of the present disclosure are illustrated by the following representative examples, which are intended to be illustrative and not limiting. As will be readily understood by those skilled in the art, the specific examples are merely illustrative of the invention, which is more fully described in the claims that follow. It should be understood that any embodiment and feature described in this application are interchangeable and combinable with any embodiment included herein.

[0178] In the following Examples 1 to 15, methods for synthesizing exemplary ALDH-2 inhibitory compounds of Structural Formulas (I) and (II) shown in Table 1 (above) are described.

[0179] The reagents used in the syntheses of Examples 1 to 15 were purchased from commercial sources and used as received. Other general methods and equipment used in the syntheses of Examples 1 to 15 were as follows. 1 1H NMR spectra were obtained at 300 MHz on a Bruker AVANCE 300 spectrometer and at 400 MHz on a Bruker AVANCE 400 spectrometer using tetramethylsilane as an internal reference. Thin-layer chromatography (TLC) was performed using Whatman No. 4500-101 (Diamond No. MK6F silica gel 60 Å) plates. Mass spectrometry was obtained using a Waters Acquity UPLC-MS spectrometer with electrospray ionization, detector - SQD, column - Acquity BEH - C18, 1.7 μm, 2.1×50 mm, mobile phase - acetonitrile: 10 mM ammonium formate. HPLC analysis was performed on an Agilent 1200 series equipped with a PDA detector and a column Polaris C18 - A, 100×3.0 mm and 2.6 μm. Chemical abbreviations used in the examples are provided in Table 2 (above).

[0180] Example 1: Synthesis of 2-chloro-6-methyl-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1a)

Chemical formula

[0181] Compound 1a was prepared via the synthesis summarized in Scheme 1 (below). Scheme 1

Chemical formula

[0182] Step 2: Synthesis of (4-(6-methoxypyridin-2-yl)phenyl)methanamine hydrochloride (3): To a stirred solution of tert-butyl (4-(6-methoxypyridin-2-yl)benzyl)carbamate (2) (0.9 g, 2.86 mmol) in 2,2,2-trifluoroethanol (15 mL) was added TMSCl (1.55 g, 14.33 mmol) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and MTBE was added. The solid was filtered and washed with MTBE to give (4-(6-methoxypyridin-2-yl)phenyl)methanamine hydrochloride (3) (650 mg, 90% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 8.62 (brs, 2H), 8.13 (d, J = 8.4 Hz, 2H), 7.8 (t, J = 7.2 Hz, 1H), 7.63 - 7.56 (m, 3H), 6.80 (d, J = 8.0 Hz, 1H), 4.07 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H).

[0183] Step 3: Synthesis of 2-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)-6-methylbenzamide (4): To a stirred solution of (4-(6-methoxypyridin-2-yl)phenyl)methanamine hydrochloride (3) (265 mg, 1.06 mmol) in CH2Cl2 (5.0 mL) were added Et3N (321 mg, 3.18 mmol) and 2-chloro-6-methylbenzoyl chloride (II) (200 mg, 1.06 mmol) at 0 °C, and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water, basified with saturated aqueous sodium bicarbonate, and extracted with EtOAc (2 × 50 mL). The organic layer was separated, washed with water and brine (1 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give 2-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)-6-methylbenzamide (4) (200 mg, 51% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.07 (t, J = 6.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.31 - 7.30 (m, 2H), 7.23 - 7.21 (m, 1H), 6.77 (d, J = 6.0 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H), 2.25 (s, 3H). MS (ESI + APCI; multi-mode): 367 [M + H] + , HPLC: 96.9 (AUC%).

[0184] Step 4: Synthesis of 2-chloro-6-methyl-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1a): A stirred solution of 2-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)-6-methylbenzamide (4) (160 mg, 0.43 mmol) in 33% HBr / CH3COOH (3 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and basified to pH 9 - 10 with saturated aqueous NaHCO3. The reaction mixture was extracted with 10% CH3OH in CH2Cl2 (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (10% CH3OH in CH2Cl2) to give 2-chloro-6-methyl-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1a) (100 mg, 65% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): 11.66 (brs, 1H), δ 9.08 (t, J = 6.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.55 - 7.46 (m, 3H), 7.31 -7.21 (m, 3H), 6.67 (s, 1H), 6.36 (d, J = 8.8 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 2.24 (s, 3H). MS (ESI + APCI; Multi-mode): 353 [M + H] + , HPLC: 95.2 (AUC %).

[0185] Example 2: Synthesis of 2-chloro-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1b)

Chemical Structure

[0186] Compound 1b was prepared via the synthesis summarized in Scheme 2 (below). Scheme 2

Chemical Structure

[0187] Step - 5: Synthesis of 2-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)benzamide (5): Prepared as in Example 1 (Step - 3 of Scheme 1). The residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give 2-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)benzamide (5) (200 mg, 71% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.04 (t, J = 6.0 Hz, 1H), 8.08 (d, J = 4.4 Hz, 2H), 7.77 (t, J = 3.6 Hz, 1H), 7.75 - 7.39 (m, 7H), 6.77 (d, J = 8.0 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H). MS (ESI + APCI; multi-mode): 353 [M + H] + ; HPLC: 98.0 (AUC %).

[0188] Step 6: Synthesis of 2-chloro-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1b): Prepared as in Example 1 (Step 4 of Scheme 1). The residue was purified by silica gel chromatography (10% CH3OH in CH2Cl2) to give 2-chloro-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1b) (70.0 mg, yield 46%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.58 (brs, 1H), 9.03 (t, J = 5.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.55 - 7.41 (m, 7H), 6.67 (s, 1H), 6.36 (d, J = 5.6 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H). MS (ESI + APCI; multi-mode): 338 [M + H] + , HPLC: 95.6 (AUC %).

[0189] Example 3: Synthesis of 4-chloro-2-methyl-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)nicotinamide (1c) [Chemical formula]

[0190] Compound 1c was prepared via the synthesis summarized in Scheme 3 (below). Scheme 3

Chemical Structure

[0191] Step 7: Synthesis of 4-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)-2-methylnicotinamide (6): To a stirred solution of (4-(6-methoxypyridin-2-yl)phenyl)methanamine hydrochloride (3) (600 mg, 2.40 mmol) in CH2Cl2 (20 mL) was added i-Pr2EtN (936 mg, 7.20 mmol) and 4-chloro-2-methylnicotinoyl chloride (IV) (541 mg, 2.88 mmol) at 0 °C, and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water, basified with saturated aqueous sodium bicarbonate, and extracted with CH2Cl2 (2 × 50 mL). The organic layer was separated, washed with water and brine (1 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc in hexane) to give 4-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)-2-methylnicotinamide (6) (330 mg, 38% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.21 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 0.4 Hz, J = 5.4, 6 Hz, 1H), 6.77 (dd, J = 0.4 Hz, J = 8.4 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H), 2.44 (s, 3H); MS (ESI + APCI; multimode): 368 [M + H] + ; HPLC: 98.7 (AUC %).

[0192] Step 8: Synthesis of 4-chloro-2-methyl-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)nicotinamide (1c): A stirred solution of 4-chloro-N-(4-(6-methoxypyridin-2-yl)benzyl)-2-methylnicotinamide (6) (160 mg, 0.43 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was irradiated with microwave at 120 °C for 50 min. The reaction mixture was concentrated under reduced pressure and basified to pH 9 - 10 with saturated aqueous NaHCO3. The reaction mixture was extracted with 10% CH3 in CH2Cl2 (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (15% CH3OH in CH2Cl2) to give 4-chloro-2-methyl-N-(4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)nicotinamide (1c) (110 mg, 70% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.70 - 11.43 (m, 1H), 9.22 (t, J = 5.6 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.55 - 7.44 (m, 4H), 6.68 (brs, 1H), 6.36 (d, J = 9.2 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 2.43 (s, 3H): MS (ESI + APCI; multimode): 354 [M + H] + ; HPLC: 98.2 (AUC %).

[0193] Example 4: Synthesis of 2,6-dichloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1d)

Chemical Structure

[0194] Compound 1d was prepared via the synthesis summarized in Scheme 4 (below). Scheme 4 [Chemical formula]

[0195] Synthesis of 2,4-dichlorobenzoyl chloride (V): To a stirred solution of 2,4-dichlorobenzoic acid (20 g, 116 mmol) in anhydrous CH2Cl2 (500 mL), SOCl2 (27.6 mL, 1570 mmol) and DMF (5 mL) were added at 0 °C under a N2 atmosphere. The mixture was stirred at 55 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give crude 2,4-dichlorobenzoyl chloride (I) (18 g, 86.12 mmol) as a colorless liquid. The crude compound was used directly in the next step.

[0196] Step 9: Synthesis of N-(4-bromobenzyl)-2,6-dichlorobenzamide (8): To a stirred solution of (4-bromophenyl)methanamine (7) (18.0 g, 86.12 mmol) in CH2Cl2 (150 mL), Et3N (24.1 mL, 17.22 mmol) and 2,6-dichlorobenzoyl chloride (V) (16.0 g, 86.12 mmol) were added at 0 °C and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water and extracted with CH2Cl2 (2 × 500 mL). The organic layer was separated, washed with water and brine (2 × 500 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (50% EtOAc in hexane) to give N-(4-bromobenzyl)-2,6-dichlorobenzamide (8) (17.6 g, 53% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.23 (t, J = 6.0 Hz, 1H), 7.56 - 7.42 (m, 5H), 7.36 (d, J = 8.4 Hz, 2H), 4.44 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multimode): 358.0 [M + H] + .

[0197] Step - 10: 2,6 - Dichloro - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)benzamide (9): To a stirred solution of N-(4 - bromobenzyl)-2,6 - dichlorobenzamide (8) (5.00 g, 13.92 mmol) in 1,4 - dioxane (50 mL) was added bis(pinacolato)diboron (4.59 g, 18.10 mmol) and KOAc (3.14 g, 34.81 mmol) at room temperature. The mixture was degassed with Ar(g) for 10 minutes. Pd(dppf)Cl2 (512 mg, 0.696 mmol) was added to the reaction mixture all at once under an N2 atmosphere. The reaction mixture was stirred at 110 °C for 6 hours. The solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 × 50 mL). The organic layer was separated, washed with water and brine (2 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (5% CH3OH in CH2Cl2) to give 2,6 - dichloro - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)benzamide (9) (4.00 g, 70% yield) as an off - white solid. 1 H NMR (400 MHz, DMSO - d6): δ 9.20 (t, J = 6.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.52 - 7.50 (m, 2H), 7.45 - 7.40 (m, 3H) 4.48 (d, J = 6.0 Hz, 2H), 1.29 (s, 12H). MS (ESI + APCI; multi - mode): 406.0 [M + H] + .

[0198] Step 11: Synthesis of 2-bromo-6-(tert-butoxy)-3-fluoropyridine (11): To a stirred solution of 2-bromo-3,6-difluoropyridine (10) (300 mg, 1.55 mmol) in THF (5.0 mL) was added potassium tert-butoxide (3.10 mL, 3.10 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2 × 50 mL). The organic layer was separated, washed with water and brine (1 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure to afford 2-bromo-6-(tert-butoxy)-3-fluoropyridine (11) (300 mg, 78% yield) as a colorless liquid. 1 H NMR (400 MHz, DMSO-d6): δ 7.76 (dd, J = 8.0 Hz, 8.8 Hz, 1H), 6.76 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 1.51(s, 9H).

[0199] Step - 12: Synthesis of N-(4-(6-(tert - butoxy)-3 - fluoropyridin - 2 - yl)benzyl)-2,6 - dichlorobenzamide (12): To a degassed solution of 2 - bromo - 6-(tert - butoxy)-3 - fluoropyridine (11) (300 mg, 1.21 mmol) in 1,4 - dioxane:water (4:1) (10 mL), 2,6 - dichloro - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)benzamide (9) (491 mg, 1.21 mmol), Cs2CO3 (789 mg, 2.42 mmol), and Pd(dppf)Cl2·CH2Cl2 (99 mg, 0.21 mmol) were added at room temperature. The mixture was degassed again with Ar(g) for 5 minutes and irradiated in a microwave at 110 °C for 30 minutes. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 × 50 mL). The organic layer was separated, washed with water and brine (1 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in hexane) to give N-(4-(6-(tert - butoxy)-3 - fluoropyridin - 2 - yl)benzyl)-2,6 - dichlorobenzamide (12) (160 mg, yield 29%) as an off - white solid. 1 H NMR (400 MHz, DMSO - d6): δ 9.22 (t, J = 6.0 Hz, 1H), 7.87 (d, J = 6.82 Hz, 2H), 7.71 -7.66 (m, 1H), 7.66 - 7.51 (m, 4H), 7.76 - 7.42 (m, 1H), 6.71 (dd J = 2.4 Hz, 8.8 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 1.58 (s, 9H).

[0200] Step 13: Synthesis of 2,6-dichloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (Compound (1d)): To a stirred solution of N-(4-(6-(tert-butoxy)-3-fluoropyridin-2-yl)benzyl)-2,6-dichlorobenzamide (12) (150 mg, 0.33 mmol) in 2,2,2-trifluoroethanol (3.0 mL), TMSCl (105 mg, 1.00 mmol) was added at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and MTBE was added. The solid was filtered and washed with MTBE to afford 2,6-dichloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1d) (50.0 mg, 38% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 9.25 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.68 - 7.63 (m, 1H), 7.53 - 7.50 (m, 4H), 7.46 -7.42 (m, 1H), 6.61 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multimode): 391 [M + H] + ; HPLC: 98.2 (AUC %).

[0201] Example 5: Synthesis of 2-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-6-methylbenzamide (1e)

Chemical Structure

[0202] Compound 1e was prepared via the synthesis summarized in Scheme 5 (below). Scheme 5

Chemical Structure

[0203] Step - 15: Synthesis of 2 - chloro - 6 - methyl - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)benzamide (14): To a degassed solution of N-(4 - bromobenzyl)-2 - chloro - 6 - methylbenzamide (13) (1.00 g, 2.96 mmol) in 1,4 - dioxane (20 mL), 4,4,4’,4’,5,5,5’,5’ - octamethyl - 2,2’ - bi(1,3,2 - dioxaborolane (1.12 g, 4.45 mmol), KOAc (870 mg, 8.88 mmol) and Pd(dppf)Cl2·CH2Cl2 (241 mg, 0.296 mmol) were added at room temperature. The mixture was degassed again with Ar(g) for 5 minutes and heated at 110 °C for 5 hours. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (2×100 mL). The organic layer was separated, washed with water and brine (1×50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (60% ethyl acetate in hexane) to give 2 - chloro - 6 - methyl - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)benzamide (14) (600 mg, 53% yield) as an off - white solid. 1 H NMR (400 MHz, DMSO - d6): δ 9.02 (t, J = 6.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 2.8 Hz, 2H), 7.22 - 7.20 (m, 1H), 4.46 (d, J = 6.0 Hz, 2H), 2.22 (s, 3H), 1.29 (s, 12H). MS (ESI + APCI; multimode): 386 [M + H] + .

[0204] Step 16: Synthesis of 2-chloro-N-(4-(3-fluoro-6-methoxypyridin-2-yl)benzyl)-6-methylbenzamide (19): To a degassed solution of 2-chloro-6-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (17) (300 mg, 0.77 mmol) in 1,4-dioxane:water (4:1) (10 mL) was added 2-bromo-3-fluoro-6-methoxypyridine (18) (158 mg, 0.77 mmol), Cs2CO3 (506 mg, 1.55 mmol), and Pd(dppf)Cl2·CH2Cl2 (63.0 mg, 0.077 mmol) at room temperature. The mixture was degassed again with Ar(g) for 5 minutes and irradiated in a microwave at 100 °C for 50 minutes. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 × 50 mL). The organic layer was separated, washed with water and brine (1 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 2-chloro-N-(4-(3-fluoro-6-methoxypyridin-2-yl)benzyl)-6-methylbenzamide (19) (200 mg, 66% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 9.08 (t, J = 6.0 Hz, 1H), 7.95 (d, J = 6.8 Hz, 2H), 7.79 - 7.74 (m, 1H), 7.53 - 7.51 (m, 2H), 7.31 -7.30 (m, 2H), 7.23 - 7.21 (m, 1H), 6.85 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 2.25 (s, 3H). MS (ESI + APCI; multimode): 385 [M + H] +.

[0205] Step 17: Synthesis of 2-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-6-methylbenzamide (Compound (1e)): Prepared as in Example 1 (Step 4 of Scheme 1). The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2) to give 2-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-6-methylbenzamide (1e) (70.0 mg, yield 47%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 10.9 (s, 1H), 9.06 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.67 - 7.62 (m, 1H), 7.51 - 7.48 (m, 2H), 7.31 - 7.29 (m, 2H), 7.23 - 7.21 (m, 1H), 6.60 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 2.24 (s, 3H). MS (ESI + APCI; multimode): 371 [M + H] + ; HPLC: 95.7 (AUC %).

[0206] Example 6: Synthesis of 2-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1f)

Chemical formula

[0207] Compound 1f was prepared via the synthesis summarized in Scheme 6 (below). Scheme 6

Chemical formula

[0208] Step - 18: Synthesis of N-(4-bromobenzyl)-2-chlorobenzamide (17): Prepared as in Example 5 (Step - 14 of Scheme 5). The residue was purified by silica gel chromatography (40% EtOAc in hexane), and N-(4-bromobenzyl)-2-chlorobenzamide (17) (2.50 g, yield 67%) was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (t, J = 6.0 Hz, 1H), 7.55 - 7.40 (m, 6H), 7.39 - 7.31 (m, 2H), 4.41 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multi-mode): 324 [M + H] + .

[0209] Step 19: Synthesis of 2-chloro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (18): Prepared as in Example 5 (Step 15 of Scheme 5). The residue was purified by silica gel chromatography (60% EtOAc in hexane), and 2-chloro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (18) (500 mg, yield 43%) was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (t, J = 6.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.51 - 7.36 (m, 6H), 4.46 (d, J = 6.0 Hz, 2H), 1.29 (s, 12H). MS (ESI + APCI; multi-mode): 372 [M + H] + .

[0210] Step 20: Synthesis of 2-chloro-N-(4-(3-fluoro-6-methoxypyridin-2-yl)benzyl)benzamide (20): Prepared as in Example 5 (Step 16 of Scheme 5). The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 2-chloro-N-(4-(3-fluoro-6-methoxypyridin-2-yl)benzyl)benzamide (20) (180 mg, 60% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.06 (t, J = 5.6 Hz, 1H), 7.96 - 7.94 (m, 2H), 7.79 - 7.74 (m, 1H), 7.53 -7.39 (m, 6H), 6.85 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H). MS (ESI + APCI; multi-mode): 371 [M + H] +.

[0211] Step 21: Synthesis of 2-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (Compound (1f)): Prepared as in Example 1 (Step 4 of Scheme 1). The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2) to give 2-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)benzamide (1f) (20.0 mg, 16% yield) as an off-white solid 1 H NMR (400 MHz, DMSO-d6): δ 11.06 (brs, 1H), 9.03 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.67 - 7.65 (m, 1H), 7.52 - 7.41 (m, 6H), 6.59 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multi-mode): 357 [M + H] + ; HPLC: 95.3 (AUC %).

[0212] Example 7: Synthesis of 4-bromo-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-2-methylnicotinamide (1 g)

Chemical formula

[0213] Compound 1 g was prepared via the synthesis summarized in Scheme 7 (below). Scheme 7

Chemical formula

[0214] Step 22: Synthesis of N-(4-bromobenzyl)-4-chloro-2-methylnicotinamide (21): Prepared as in Example 5 (Step 14 of Scheme 5). The residue was purified by silica gel chromatography (70% EtOAc in hexane) to afford N-(4-bromobenzyl)-4-chloro-2-methylnicotinamide (21) (550 mg, 61% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.19 (t, J = 6.0 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.57 - 7.54 (m, 2H), 7.44 (dd, J = 0.8 Hz, J = 5.6 Hz, 1H), 7.35 - 7.32 (m, 2H), 4.44 (d, J = 6.0 Hz, 2H), 2.40 (s, 3H). MS (ESI + APCI; multimode): 339 [M + H] + .

[0215] Step - 23: Synthesis of 4 - chloro - 2 - methyl - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)nicotinamide (22): Prepared as in Example 5 (Step - 15 of Scheme 5). The residue was purified by silica gel chromatography (70% EtOAc in hexane) to give 4 - chloro - 2 - methyl - N-(4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)benzyl)nicotinamide (22) (200 mg, yield 58%) as a semi - solid. 1 H NMR (400 MHz, DMSO - d6): δ 9.21 (t, J = 6.0 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.44 (dd, J = 0.4 Hz, J = 5.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 4.44 (d, J = 6.0 Hz, 2H), 2.40 (s, 3H), 1.29 (s, 12H). MS (ESI + APCI; multi - mode): 387 [M + H] + .

[0216] Step - 24: Synthesis of 4 - chloro - N-(4-(3 - fluoro - 6 - methoxypyridin - 2 - yl)benzyl)-2 - methylnicotinamide (23): Prepared as in Example 1 (Step - 3 of Scheme 1). The residue was purified by silica gel chromatography (80% EtOAc in hexane) to give 4 - chloro - N-(4-(3 - fluoro - 6 - methoxypyridin - 2 - yl)benzyl)-2 - methylnicotinamide (23) (100 mg, yield 50%) as an off - white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.24 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 1.2 Hz, J = 8.4 Hz, 2H), 7.79 - 7.74 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 0.4 Hz, J = 5.2 Hz, 1H), 6.86 (d, J = 2.8 Hz, J = 8.8 Hz, 2H), 4.55 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 2.5 (s, 3H). MS (ESI + APCI; multi-mode): 386 [M + H]+ + .

[0217] Step - 25: 4-Bromo-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-2-methylnicotinamide (1g): Prepared as in Example 1 (Step - 4 of Scheme 1). The residue was purified by silica gel chromatography (12% MeOH in CH2Cl2) to give 2-bromo-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-2-methylnicotinamide (1g) (25.0 mg, yield 23%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.01 (brs, 1H), 9.22 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.68 - 7.50 (m, 4H), 6.60 (d, J = 7.2 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 2.43 (s, 3H) MS (ESI + APCI; multi-mode): 416 [M + H]+; HPLC: 96.8 (AUC %).

[0218] Example 8: Synthesis of 4-Chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-2-methylnicotinamide (1h) [Chem.]

[0219] Compound 1h was prepared via the synthesis summarized in Scheme 8 (below). Scheme 8 [Chem.]

[0220] Step 26: Synthesis of 4-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-2-methylnicotinamide (1h): Prepared as in Example 3 (Step 8 of Scheme 3). The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2) to give 4-chloro-N-(4-(3-fluoro-6-oxo-1,6-dihydropyridin-2-yl)benzyl)-2-methylnicotinamide (1h) (45.0 mg, 31% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.9 (brs, 1H), 9.22 (t, J = 6.0 Hz, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.67 - 7.63 (m, 1H), 7.50 - 7.44 (m, 3H), 6.60 (dd, J = 6.8 Hz, 9.2 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 2.43 (s, 3H). MS (ESI + APCI; multimode): 372 [M + H] + ; HPLC: 95.8 (AUC %).

[0221] Example 9: Synthesis of 2,6-dichloro-N-((3'-fluoro-6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1i) [Chem.]

[0222] Compound 1i was prepared via the synthesis summarized in Scheme 9 (below). Scheme 9:

Chemical Structure

[0223] Step 27: Synthesis of 3'-fluoro-6'-methoxy-[2,2'-bipyridine]-5-carbonitrile (25): Prepared as in Example 1 (Step 1 of Scheme 1). The residue was purified by silica gel chromatography (10% EtOAc in hexanes) to give 3'-fluoro-6'-methoxy-[2,2'-bipyridine]-5-carbonitrile (25) (120 mg, 15% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.14 (d, J = 2.0 Hz, 1H), 8.47 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.06 (dd, J = 2.8 Hz, J = 8.8 Hz, 1H), 3.94 (s, 3H). MS (ESI + APCI; multimode): 230 [M + H] + .

[0224] Step - 28: Synthesis of tert - butyl ((3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methyl)carbamate (26): To a stirred solution of 3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - carbonitrile (25) (120 mg, 0.52 mmol) in MeOH:THF (ratio 1:3, 18 mL), NiCl2·6H2O (147 mg, 0.62 mmol), (Boc)2O (340 mg, 1.56 mmol), and NaBH4 (59 mg, 1.56 mmol) were added at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. The residue was diluted with water and extracted with EtOAc (2 × 50 mL). The organic extracts were separated, washed with water, brine (1 × 50 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel chromatography (20% EtOAc in hexane) to give tert - butyl ((3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methyl)carbamate (26) (120 mg, 44% yield) as an off - white solid. 1 H NMR (400 MHz, DMSO - d6): δ 8.55 (d, J = 1.6Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.81 - 7.77 (m, 2H), 7.51 (t, J = 5.2 Hz, 1H), 6.95 - 6.92 (m, 1H), 4.21 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 1.40 (s, 9H). MS (ESI + APCI; multimode): 334 [M + H] + .

[0225] Step - 29: Synthesis of (3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methanamine hydrochloride (27): TMSCl (80.0 mg, 0.720 mmol) was added to a stirred solution of tert - butyl ((3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methyl)carbamate (26) (80.0 mg, 0.24 mmol) in 2,2,2 - trifluoroethanol (1.0 mL) at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure and MTBE was added. The solid was filtered and washed with MTBE to afford (3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methanamine hydrochloride (27) (50.0 mg, 89% yield) as an off - white solid. 1 H NMR (400 MHz, DMSO - d6): δ 8.78 (s, 1H), 8.41 (brs, 2H), 8.10 (d, J = 1.20 Hz, 2H), 7.84 - 7.80 (m, 1H), 6.99 (dd, J = 2.8 Hz, J = 8.8 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H).

[0226] Step - 30: Synthesis of 2,6 - dichloro - N - ((3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methyl)benzamide (28): Prepared as in Example 1 (Step - 3 of Scheme 1). The residue was purified by silica gel chromatography (50% EtOAc in hexane) to afford 2,6 - dichloro - N - ((3’ - fluoro - 6’ - methoxy - [2,2’ - bipyridin] - 5 - yl)methyl)benzamide (28) (40.0 mg, 53% yield) as an off - white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.33 (t, J = 5.6 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 7.95 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.53 (dd,J = 1.6 Hz, J = 8.8 Hz, 2H), 7.47 - 7.43 (m, 1H), 6.95 (dd, J = 2.8 Hz, J = 8.8 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H). MS (ESI + APCI; multi-mode): 406 [M + H] + .

[0227] Step 31: Synthesis of 2,6-dichloro-N-((3'-fluoro-6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1i): Prepared as in Example 1 (Step 4 of Scheme 1). The residue was purified by silica gel chromatography (7% MeOH in CH2Cl2) to give 2,6-dichloro-N-((3'-fluoro-6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1i) (25.0 mg, 65% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.00 (brs, 1H), 9.32 (t, J = 6.0 Hz, 1H), 8.71 (s, 1H), 7.96 - 7.89 (m, 2H), 7.69 (t, J = 9.6 Hz, 1H), 7.54 - 7.43 (m, 3H), 6.64 (t, J = 2.8 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H). MS (ESI + APCI; multi-mode): 392 [M + H] + ; HPLC: 98.0 (AUC %).

[0228] Example 10: Synthesis of 2,6-dichloro-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1j)

Chem.

[0229] Compound 1j was prepared via the synthesis summarized in Scheme 10 (below). Scheme 10

Chem.

[0230] Step 32: Synthesis of tert-butyl ((6-chloropyridin-3-yl)methyl)carbamate (30): To a stirred solution of (6-chloropyridin-3-yl)methanamine (29) (300 mg, 2.11 mmol) in CH2Cl2 (5.0 mL) were added Et3N (0.94 mL, 6.34 mmol) and Boc-anhydride (0.58 mL, 2.53 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 h. The residue was diluted with water and extracted with EtOAc (2 × 50 mL). The organic extracts were separated, washed with water, brine (1 × 50 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel chromatography (20% EtOAc in hexane) to give tert-butyl ((6-chloropyridin-3-yl)methyl)carbamate (30) (305 mg, 60% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.72 - 7.69 (m, 1H), 7.48 (d, J = 8.0 Hz, 2H), 4.14 (d, J = 6.0 Hz, 2H), 1.38 (s, 9H).

[0231] Step-33: Synthesis of tert-butyl ((6’-methoxy-[2,2’-bipyridin]-5-yl)methyl)carbamate (31): Prepared as in Example 1 (Step-1 of Scheme 1). The residue was purified by silica gel chromatography (10% EtOAc in hexane) to give tert-butyl ((6’-methoxy-[2,2’-bipyridin]-5-yl)methyl)carbamate (31) (1.40 g, yield 54%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J = 2.0, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.85 - 7.52 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 4.20 (d, J = 6.0 Hz, 1H), 3.98 (s, 3H), 1.40 (s, 9H). MS (ESI + APCI; multimode): 316.0 [M + H] +.

[0232] Step-34: Synthesis of (6’-methoxy-[2,2’-bipyridin]-5-yl)methanamine hydrochloride (33): Prepared as in Example 9 (Step-29 of Scheme 9). The solvent was removed under reduced pressure and MTBE was added. The solid was filtered and washed with MTBE to give (6’-methoxy-[2,2’-bipyridin]-5-yl)methanamine hydrochloride (33) (680 mg, yield 77%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.46 - 7.85 (m 7H), 6.93 - 6.91 (m, 1H), 4.15 (d, J = 6.0 Hz, 2H), 3.99 (s, 3H).

[0233] Step-35: Synthesis of 2,6-dichloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)benzamide (33): Prepared as in Example 1 (Step-3 of Scheme 1). The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 2,6-dichloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)benzamide (33): 160 mg, 52% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.32 (t, J = 6.0 Hz, 1H), 8.68 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.99 - 7.82 (m, 3H), 7.54 - 7.43 (m, 3H), 6.88 (d, J = 8.0 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H). MS (ESI + APCI; multi-mode): 387.9 [M + H] + . HPLC: 97.2 (AUC %).

[0234] Step-36: Synthesis of 2,6-dichloro-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1j): Prepared as in Example 1 (Step-4 of Scheme 1). The residue was purified by silica gel chromatography (15% MeOH in CH2Cl2) to give 2,6-dichloro-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1j) (58.0 mg, 60% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 11.01 (brs, 1H), 9.32 (t, J = 6.0 Hz, 1H), 8.70 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.95 - 7.43 (m, 5H), 7.20 (s, 1H), 6.550 (d, J = 8.8 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multi-mode): 373.9 [M + H] + . HPLC: 98.2 (AUC %).

[0235] Example 11: Synthesis of 2-chloro-6-methyl-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1k)

Chemical Structure

[0236] Compound 1k was prepared via the synthesis summarized in Scheme 11 (below). Scheme 11

Chemical Structure

[0237] Step 37: Synthesis of 2-chloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)-6-methylbenzamide (33): Prepared as in Example 1 (Step 3 of Scheme 1). The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 2-chloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)-6-methylbenzamide (33) (150 mg, 54% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.12 (t, J = 6.0 Hz, 1H), 8.67 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.99 - 7.82 (m, 3H), 7.32 - 7.21 (m, 3H), 6.87 (d, J = 8.0 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H), 2.23 (s, 3H). MS (ESI + APCI; multi-mode): 368.0 [M + H] + . HPLC: 95.6 (AUC %).

[0238] Step 38: Synthesis of 2-chloro-6-methyl-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1k): Prepared as in Example 1 (Step 4 of Scheme 1). The residue was purified by silica gel chromatography (15% MeOH in CH2Cl2) to give 2-chloro-6-methyl-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1k) (58.0 mg, 60% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.01 (brs, 1H), 9.32 (t, J = 6.0 Hz, 1H), 8.70 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.95 - 7.43 (m, 5H), 7.20 (s, 1H), 6.550 (d, J = 8.8 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multi-mode): 373.9 [M + H] + . HPLC: 98.2 (AUC %).

[0239] Example 12: Synthesis of 2-chloro-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1l) [Chemical formula]

[0240] Compound 1l was prepared via the synthesis summarized in Scheme 12 (below). Scheme 12

Chemical Structure

[0241] Step 39: Synthesis of 2-chloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)benzamide (34): Prepared as in Example 1 (Step 3 of Scheme 1). The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 2-chloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)benzamide (34) (170 mg, 61% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.14 (t, J = 6.0 Hz, 1H), 8.66 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.99 - 7.82 (m, 3H), 7.53 - 7.39 (m, 4H), 6.88 (d, J = 8.0 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H). MS (ESI + APCI; multi-mode): 354.0 [M + H] + . HPLC: 97.3 (%).

[0242] Step - 40: Synthesis of 2-chloro-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1l): Prepared as in Example 1 (Step - 4 of Scheme 1). The residue was purified by silica gel chromatography (15% MeOH in CH2Cl2) to give 2-chloro-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)benzamide (1l) (65.0 mg, 68% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 9.12 (t, J = 6.0 Hz, 1H), 8.68 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.63 - 7.39 (m, 5H), 7.39 (s, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H). MS (ESI + APCI; multi-mode): 340.0 [M + H] + . HPLC: 99.9 (AUC %).

[0243] Example 13: Synthesis of 4-chloro-2-methyl-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)nicotinamide (1m):

Chem.

[0244] Compound 1m was prepared via the synthesis summarized in Scheme 13 (below). Scheme 13

Chem.

[0245] Step 41: Synthesis of 4-chloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)-2-methylnicotinamide (33): Prepared as in Example 1 (Step 3 of Scheme 1). The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2) to give 4-chloro-N-((6'-methoxy-[2,2'-bipyridin]-5-yl)methyl)-2-methylnicotinamide (33) (170 mg, 46% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.28 (t, J = 6.0 Hz, 1H), 8.67 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.98 (dd, J = 0.8 Hz, J = 7.6 Hz, 1H), 7.93 (dd, J = 2.4, Hz, J = 8.4 Hz, 1H), 7.84 (t, J = 0.8 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 6.88 (dd, J = 0.8, Hz, J = 8.0 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H), 2.42 (s, 3H); MS (ESI + APCI; multi-mode): 369 [M + H] + ; HPLC: 96.7 (AUC %).

[0246] Step - 45: Synthesis of 4-chloro-2-methyl-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)nicotinamide (1m): Prepared as in Example 1 (Step - 4 of Scheme 1). The residue was purified by silica gel chromatography (16% MeOH in CH2Cl2) to give 4-chloro-2-methyl-N-((6'-oxo-1',6'-dihydro-[2,2'-bipyridin]-5-yl)methyl)nicotinamide (1m) (70.0 mg, 56% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.31 (t, J = 5.2 Hz, 1H), 8.69 (S, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.19-7.10 (m, 1H), 6.50 (brs, 1H), 4.57 (d, J = 5.6 Hz, 2H), 2.41 (s, 3H): MS (ESI + APCI; multi-mode): 355 [M + H]+ ; HPLC: >99 (AUC %).

[0247] Example 14: Synthesis of 2-chloro-6-methyl-N-((2-(6-oxo-1,6-dihydropyridin-2-yl)pyrimidin-5-yl)methyl)benzamide (1n)

Chemical Structure

[0248] Compound 1n was prepared via the synthesis summarized in Scheme 14 (below). Scheme 14:

Chemical Structure

[0249] Step 43: 2-(6-Methoxypyridin-2-yl)pyrimidine-5-carbonitrile (35): To a degassed solution of 2-chloropyrimidine-5-carbonitrile (34) (1.00 g, 7.24 mmol) in 1,4-dioxane:water (4:1) (36 mL), 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (I) (2.2 g, 9.42 mmol), Cs2CO3 (7.06 g, 21.7 mmol) and Pd(dppf)Cl2·CH2Cl2 (591 mg, 0.72 mmol) were added at room temperature. The mixture was degassed again with Ar(g) for 5 min and heated at 100 °C for 5 h. The residue was diluted with water and extracted with EtOAc (2 × 100 mL). The organic extracts were separated, washed with water, brine (1 × 100 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 2-(6-methoxypyridin-2-yl)pyrimidine-5-carbonitrile (35) (600 mg, 40% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 2H), 8.17 - 8.09 (m, 1H), 7.98 - 7.90 (m, 1H), 7.06 (dd, J = 8.3 Hz, J = 8.3 Hz, 1H), 3.97 (s, 3H); MS (ESI + APCI; multimode): 213 [M + H] + .

[0250] Step - 44: Synthesis of (2-(6 - methoxypyridin - 2 - yl)pyrimidin - 5 - yl)methanamine (36): To a stirred solution of 2-(6 - methoxypyridin - 2 - yl)pyrimidine - 5 - carbonitrile (35) (400 mg, 1.88 mmol) in EtOH (40 mL), Raney nickel (837 mg, 9.43 mmol) and NH4OH (30 mL) were added under an inert atmosphere. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (16% in CH2Cl2 (10% NH4OH in MeOH)), and (2-(6 - methoxypyridin - 2 - yl)pyrimidin - 5 - yl)methanamine (36) (280 mg, 68% yield) was obtained as an off - white solid. 1 H NMR (400 MHz, DMSO - d6): δ 8.89 (s, 2H), 7.98 (dd, J = 0.8 Hz, J = 7.2 Hz, 1H), 7.88 - 7.84 (m, 1H), 6.94 (dd, J = 0.8 Hz, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.81 (s, 2H): MS (ESI + APCI; multimode): 217 [M + H] + .

[0251] Step - 45: Synthesis of 2 - chloro - N - ((2-(6 - methoxypyridin - 2 - yl)pyrimidin - 5 - yl)methyl)-6 - methylbenzamide (37): Prepared as in Example 1 (Step - 3 of Scheme 1). The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2), and 2 - chloro - N - ((2-(6 - methoxypyridin - 2 - yl)pyrimidin - 5 - yl)methyl)-6 - methylbenzamide (37) (270 mg, 61% yield) was obtained as an off - white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.17 (t, J = 5.6 Hz, 1H), 8.95 (s, 2H), 8.01 (dd, J = 0.4 Hz, J = 7.2 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.32 - 7.29 (m, 2H), 7.24 - 7.22 (m, 1H), 6.97 (dd, J = 0.8 Hz, J = 8.4 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H), 2.23 (s, 3H); MS (ESI + APCI; multi-mode): 369 [M + H] + ; HPLC: >99 (AUC %).

[0252] Step - 46: Synthesis of 2-chloro-6-methyl-N-((2-(6-oxo-1,6-dihydropyridin-2-yl)pyrimidin-5-yl)methyl)benzamide (1n): Prepared as in Example 1 (Step - 4 of Scheme 1). The residue was purified by silica gel chromatography (16% MeOH in CH2Cl2) to give 2-chloro-6-methyl-N-((2-(6-oxo-1,6-dihydropyridin-2-yl)pyrimidin-5-yl)methyl)benzamide (1n) (90.0 mg, 59% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 10.99 (brs, 1H), 9.20 (t, J = 6.0 Hz, 1H), 8.95 (S, 2H), 7.64 - 7.60 (m, 1H), 7.32 - 7.28 (m, 3H), 7.25 - 7.22 (m, 1H), 6.57 (dd, J = 0.4 Hz, J = 9.2 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 2.22 (s, 3H); MS (ESI + APCI; multi-mode): 355 [M + H] + ; HPLC: 95.6 (AUC %).

[0253] Example 15: ALDH-1, ALDH-2, ALDH-3, MAO-A, MAO-B, and HepaRG spheroid assays of ALDH-2 inhibitory compounds

[0254] This example describes the testing of exemplary ALDH-2 inhibitory compounds of the present disclosure in assays measuring the inhibition of ALDH-2, ALDH-1, ALDH-3, as well as MAO-A and MAO-B. The example also describes the testing of the compounds in the HepaRG 3D spheroid assay, which provides a measure of potential hepatotoxicity.

[0255] Materials and Methods

[0256] A. ALDH-2 inhibition assay: The ALDH-2 reaction mixture used in the assay contained 125 μM formaldehyde, 75 μM NAD+, 20 mM NaCl, 10 mM MgCl2, and 20 nM recombinant human ALDH-2 in 50 mM Hepes buffer (pH 7.5). Using a 384-well Corning 3820 plate, the final volume was 10 μL. The test ALDH-2 inhibitory compound was pre-incubated with ALDH-2 for 60 minutes, and then the reaction was initiated by adding NAD+ and formaldehyde, and the assay reaction mixture was allowed to proceed for 60 minutes. The activity of the ALDH-2 enzyme was measured by monitoring NADH formation using a Perkin-Elmer Envision reader, with the excitation and emission wavelengths set at 340 and 460 nm, respectively. Inhibition was determined as IC 50 This refers to the concentration of the test ALDH-2 inhibitory compound that inhibited the reaction by 50%.

[0257] B. ALDH-1 Inhibition Assay: The ALDH-1 reaction mixture used in the assay contained 100 μM formaldehyde, 2.5 mM NAD+, 20 mM NaCl, 10 mM MgCl2, 1 mM dithiothreitol (DTT, reducing agent), and 50 nM recombinant human ALDH-1 in 50 mM Hepes buffer (pH 7.5). Using a 384-well Corning 3820 plate, the final volume was 10 μL. After pre-incubating the test ALDH-2 inhibitory compound with ALDH-1 for 60 minutes, the reaction was initiated by adding NAD+ and formaldehyde, and the assay reaction mixture was allowed to proceed for 60 minutes. The activity of the ALDH-1 enzyme was measured by monitoring NADH formation using a Perkin-Elmer Envision reader with the excitation and emission wavelengths set at 340 and 460 nm, respectively. Inhibition was determined as IC 50 . This refers to the concentration of the test ALDH-2 inhibitory compound that inhibited the reaction by 50%.

[0258] C. ALDH-3 Inhibition Assay: The ALDH-3 reaction mixture used in the assay contained 200 μM benzaldehyde, 2.5 mM NAD+, 20 mM NaCl, 10 mM MgCl2, and 10 nM recombinant human ALDH-3 in 50 mM Hepes buffer (pH 7.5). Using a 384-well Corning 3820 plate, the final volume was 10 μL. After pre-incubating the test ALDH-2 inhibitory compound with ALDH-3 for 60 minutes, the reaction was initiated by adding NAD+ and benzaldehyde, and the assay reaction mixture was allowed to proceed for 60 minutes. The activity of the ALDH-3 enzyme was measured by monitoring NADH formation using a Perkin-Elmer Envision reader with the excitation and emission wavelengths set at 340 and 460 nm, respectively. Inhibition was determined as IC 50 . This refers to the concentration of the test ALDH-2 inhibitory compound that inhibited the reaction by 50%.

[0259] D.MAO-A and MAO-B Inhibition Assay: The MAO assay contained a luminescent MAO substrate, reaction buffer, luciferin detection, and a reconstitution buffer containing esterase. The MAO reaction mixture used in the assay contained microsomes containing MAO-A (2 μg) or MAO-B (10 μg), 160 μM of the MAO-A substrate or 16 μM of the MAO-B substrate, MAO-A buffer (100 mM Hepes buffer, pH 7.5, 5% glycerol) or MAO-B buffer (100 mM Hepes, pH 7.5, 5% glycerol, 10% dimethyl sulfoxide), with a final volume of 30 μL. The MAO-A or MAO-B enzyme was pre-incubated with the test ALDH-2 inhibitory compound for 20 minutes, and then the reaction was initiated by adding the enzyme substrate, and the reaction was allowed to proceed for 60 minutes. Then, the reconstituted luciferin detection reagent (30 μL) was added to stop the MAO reaction and at the same time convert the methyl ester derivative to luciferin to generate light. The amount of light generated is directly proportional to the activity of MAO. The mixture was incubated for an additional 20 minutes, and the activity of the enzyme was measured using a Perkin-Elmer Envision reader. Inhibition was determined as IC 50 and refers to the concentration of the test ALDH-2 inhibitory compound that inhibited the reaction by 50%.

[0260] E. HepaRG (registered trademark) 3D spheroid assay: The HepaRG 3D spheroid assay is described in Walker et al., “The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development,” (2020) Archives of Toxicology, Vol. 94:2559-2585. Briefly, HepaRG (registered trademark) cells were seeded into ultra-low attachment 96-well black wall clear bottom spheroid microplates. After formation, a range of concentrations of the test ALDH-2 inhibitory compound were administered to the spheroids to obtain an 8-point dose-response curve with maximum concentrations of 1, 4, 7, and 10 and 100 mM on days 1, 4, 7, and 10 (3 replicates per concentration). At the end of the incubation period, the relevant dyes / antibodies were loaded onto the spheroids for each cell health marker (number of spheroids, spheroid size, DNA structure, mitochondrial mass, mitochondrial membrane potential, oxidative stress, glutathione content, and cellular ATP). The plates were then scanned using an automated fluorescence cell imaging device, ArrayScan (registered trademark) (Thermo Scientific Cellomics). The minimum effective concentration (“MEC”) was determined as the amount of test compound that significantly exceeded the vehicle control threshold for the cell health marker.

[0261] Results

[0262] The results of the ALDH-2, ALDH-1, ALDH-3, MAO-A, MAO-B, and HepaRG 3D spheroid assays for the exemplary ALDH-2 inhibitory compounds of Table 1 are summarized in Table 3 below.

[0263] [Table 3] Example 16: Formulation of Pharmaceutical Compositions

[0264] This example describes the formulation of a pharmaceutical composition comprising ALDH-2 inhibitors of structural formula (I) and formula (II) that can be used in the method of the present disclosure for treating substance dependence or a state of dependence or abuse.

[0265] Hard gelatin capsules: Mix the ingredients listed below and fill into hard gelatin capsules. Amount Ingredient (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0

[0266] 240 mg tablets: Blend the ingredients listed below and compress to form 240 mg tablets: Amount Ingredient (mg / tablet) Active ingredient 25.0 Microcrystalline cellulose 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0267] 120 mg tablets: Blend the ingredients listed below and compress as described below to form 120 mg tablets: Amount Ingredient (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

[0268] Pass the active ingredient, starch, and cellulose through a No. 20 mesh US sieve and mix well. Mix with the solution of polyvinylpyrrolidone of the obtained powder, and then pass this through a 16 mesh US sieve. Dry the granules thus produced at 50 °C to 60 °C and pass through a 16 mesh US sieve. Then add sodium carboxymethyl starch passed through a No. 30 mesh US sieve, magnesium stearate, and talc to the granules, and after mixing, compress this with a tablet machine to obtain tablets each weighing 120 mg.

[0269] Suppositories: Suppositories containing 25 mg of the active ingredient each are prepared as follows: Ingredient Amount Active ingredient 25 mg Saturated fatty acid glyceride 2,000 mg

[0270] Pass the active ingredient through a No. 60 mesh US sieve and suspend it in the saturated fatty acid glyceride previously melted using the minimum necessary heat. Then pour the mixture into a mold for suppositories with a nominal volume of 2.0 g and cool.

[0271] Suspension: A suspension containing 50 mg of the active ingredient per 5.0 mL dose is prepared as follows: Ingredient Amount Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and coloring agent q.v. Purified water 5.0 mL

[0272] Blend the active ingredient, sucrose, and xanthan gum, pass through a No. 10 mesh US sieve, and then mix with a pre-prepared solution of microcrystalline cellulose and carboxymethyl cellulose in water. Dilute sodium benzoate, flavoring agent, and coloring agent with a portion of water and add with stirring. Next, add sufficient water to obtain the required volume.

[0273] Subcutaneous: Prepare the subcutaneous preparation as follows: Ingredient Amount Active ingredient 5.0 mg Corn oil 1.0 mL

[0274] Injectable: Prepare the injectable preparation by combining the following ingredients: Ingredient Amount Active ingredient 2.0 mg / mL Mannitol, USP 50 mg / mL Gluconic acid, USP q.s. (pH 5 - 6) Water (distilled, sterilized) q.s. ~ 1.0 mL Nitrogen gas, NF q.s.

[0275] Topical: Prepare the topical preparation by combining the following ingredients as described below: Ingredient Amount (g) Active ingredient 0.01 - 1 Span 60 2.0 Tween® 60 2.0 Mineral oil 5.0 Petrolatum 0.10 Methylparaben 0.15 Propylparaben 0.05 BHA (butylhydroxyanisole) 0.01 Water q.s. ~ 100

[0276] Combine all of the above ingredients except water and heat to 60 °C with stirring. Next, add a sufficient amount of water at 60 °C with vigorous stirring to emulsify the ingredients, and then add water to make 100 g.

[0277] All of the published documents, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual published document, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes.

[0278] Although various specific embodiments have been described and illustrated, it will be understood that various modifications may be made without departing from the spirit and scope of the invention.

Claims

1. Compound of formula (I), 【Chemistry 51】 (In the formula, X １ is N or CR ３ and X ２ is N or CR ４ and X ３ is N or CR ６ and provided that X １ X ２ and X ３ one or less of them is N X ４ and X ５ Each of these independently is N or CR １０ And, R １１ C is substituted with H, halogen, or of any choice. １－６ Alkyl or cycloalkyl, R ７ C is replaced by H, or C of any choice. １－６ It is alkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ８ , R ９ , and R １０ Each of these independently corresponds to H, halogen, and -CF ３ -OH, -CH ２ OH, -CN, optionally substituted alkyl, optionally substituted alkylene, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, aminocarbonyl, acyl, acylamino, -O-(C １ -C ６ -Alkyl)-O-(C １ -C ６ -Alkyl), -CH ２ OP(O)(OR ２０ ) ( OR ２１ ), -SO ２ NR ２４ R ２５ , or -NR ２４ R ２５ And, however, X １ CR ３ X ２ CR ４ X ３ CR ６ X ４ CR １０ X ５ CR １０ And R １１ If H, then R ２ and R ６ Neither of them is Cl. R ２０ and R ２１ Each of them independently, Na ＋ Li ＋ _K ＋ , hydrogen, C １－６ Alkyl or R ２０ and R ２１ These are combined to form a single divalent cation Zn ２＋ Ca ２＋ , or Mg ２＋ It can represent, R ２４ and R ２５ Each of them independently contains either hydrogen or C １－６ (Selected from alkyl groups, or combined with the nitrogen they are bonded to to form heterocycles.) or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

2. R ２ , R ３ , R ４ , R ５ , R ７ , R ８ , R ９ , R １０ , and R １１ The compound according to claim 1, wherein each of them is H.

3. X １ However, CR ３ X ２ However, CR ４ X ３ However, CR ６ The compound according to claim 1.

4. X １ However, N is X ２ However, CR ４ X ３ However, CR ６ The compound according to claim 1.

5. X １ is CR ３ and X ２ is N, and X ３ is CR ６ The compound according to claim 1, wherein

6. X １ However, CR ３ X ２ However, CR ４ X ３ The compound according to claim 1, wherein N is present.

7. X ４ is CR １０ and X ５ is CR １０ The compound according to claim 1

8. X ４ However, CR １０ X ５ The compound according to claim 1, wherein N is present.

9. X ４ However, N is X ５ The compound according to claim 1, wherein N is present.

10. R ２ However, H, Cl, F, or CH ３ A compound according to claim 1, selected from the following.

11. R ３ However, H, Cl, F, and CH ３ A compound according to claim 1, selected from the following.

12. R ５ However, H, Cl, F, and CH ３ A compound according to claim 1, selected from the following.

13. R ６ However, H, Cl, F, and CF ３ A compound according to claim 1, selected from the following.

14. R １１ The compound according to claim 1, wherein H and halogen are selected.

15. R １１ The compound according to claim 1, wherein it is 3-fluoro.

16. Compounds of structural formula (II): 【Chemistry 52】 (In the formula, X ２ and X ３ Each of them is independently N or CH, R １１ C is substituted with H, halogen, or of any choice. １－６ Alkyl or cycloalkyl, R １ The following can be selected: 【Chemistry 53】 R ２ , and R ６ Each of these is independently H, Br, Cl, F, CH ３ , or CF ３ And, R ３ , R ４ , and R ５ Each of these is independently H, Br, Cl, F, CH ３ CF ３ -OH, -CH ２ OH, -CN, optionally substituted alkyl, optionally substituted alkylene, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, aminocarbonyl, acyl, acylamino, -O-(C １ -C ６ -Alkyl)-O-(C １ -C ６ -Alkyl), -CH ２ OP(O)(OR ２０ ) ( OR ２１ ), -SO ２ NR ２４ R ２５ , or -NR ２４ R ２５ And, however, R １ X is an aromatic ring, ２ and X ３ CH is, R １１ If H, then R ２ and R ６ (Neither of them are Cl) or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

17. X ２ and X ３ The compound according to claim 16, wherein the compound is CH.

18. X ２ However, it is CH, and X ３ The compound according to claim 16, wherein N is present.

19. R １１ The compound according to claim 16, wherein H is present.

20. R １１ The compound according to claim 16, wherein it is 3-fluoro.

21. R ３ , R ４ , and R ５ The compound according to claim 16, wherein H is present.

22. R ３ , R ４ , and R ５ However, independently, H, Cl, F, CH ３ , or CF ３ The compound according to claim 16.

23. R ２ However, H, Cl, F, or CH ３ The compound according to claim 16.

24. R ６ However, H, Br, Cl, F, or CF ３ The compound according to claim 16.

25. R １ However, the compound according to claim 16, selected from the following: 【Chemistry 54】

26. R １ However, the compound according to claim 16, selected from the following: 【Transformation 55】

27. The compound according to claim 1, wherein the compound is selected from compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h), (1i), (1j), (1k), (1l), (1m), and (1n), or pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers thereof. 【Chemistry 56-1】 【Chemistry 56-2】 【Chemistry 56-3】

28. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

29. A composition comprising the compound according to any one of claims 1 to 27 for treating a chemical dependence or dependent state to a substance, or a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

30. The composition according to claim 29, wherein the substance or the addiction state is selected from the group consisting of alcohol, nicotine, cocaine, opiates, amphetamines, and compulsive eating.

31. A composition comprising the compound according to any one of claims 1 to 27 for treating obsessive-compulsive eating disorders in human patients, or a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

32. A composition comprising the compound according to any one of claims 1 to 27 for treating anxiety in human patients, or a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

33. A composition comprising the compound according to any one of claims 1 to 27 for treating obsessive-compulsive eating disorders in human patients, or a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

34. A composition for use in therapy, comprising a compound according to any one of claims 1 to 27.

35. A composition for use as a pharmaceutical, comprising a compound according to any one of claims 1 to 27.

36. A composition for the treatment of chemical dependence on a substance, for the treatment of an addiction or abuse state, for the treatment of an obsessive-compulsive eating disorder, or for the treatment of an anxiety disorder, comprising a compound according to any one of claims 1 to 27.

37. Use of the compound according to any one of claims 1 to 27 in the manufacture of a medicament for the treatment of chemical dependence on a substance, for the treatment of an addictive or abusive state, for the treatment of an obsessive-compulsive eating disorder, or for the treatment of an anxiety disorder.

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