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 priority of U.S. Provisional Patent Application No. 63 / 351,997, filed on June 14, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] 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 the use of such compounds or compositions in methods for safely treating chemical dependencies or dependency states to substances such as alcohol, nicotine, cocaine, opioids, amphetamines, binge - eating disorder, and / or anxiety disorder, either individually or simultaneously.

Background Art

[0003] Addiction remains a major health problem worldwide. The U.S. Surgeon General has stated that drug abuse is the medical breakdown of the country, 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, the need for treatment of 23 million people, and an economic burden of $400 billion annually. See “Facing Adplication 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 due to overdose of illegal drugs, 14,000 of which were caused by prescription opioids.

[0004] Inhibition of aldehyde dehydrogenase-2 (ALDH-2) has been shown to reduce pathophysiological dopamine surges 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 inhibitor, there is still a need for ALDH-2 inhibitory compounds that are not hepatotoxic.

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. 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

Summary of the Invention

[0007] The present disclosure generally relates to compounds that inhibit ALDH-2, pharmaceutical compositions containing these compounds, and the use of these compounds for the treatment of addiction, compulsive eating disorders, and / or anxiety disorders in mammals. This summary is intended to introduce the subject matter of the present disclosure but does not cover all embodiments, combinations, or variations 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

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

[0010] In at least one embodiment of the compound of structural formula (I), X 1 is CR 3 , X 2 is CR4, and R 3 , R 4 , and R 5 each independently is H, Cl, F, CH3, or CF3.

[0011] 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 .

[0012] In at least one embodiment of the compound of structural formula (I), R 2 is selected from H, Cl, F, or CH3. In at least one embodiment, R 6 is selected from H, Cl, F, or CF3.

[0013] In at least one embodiment, the present disclosure provides a compound of formula (II): [Chemical Formula] (wherein, R 1 is selected from the following, [Chemical Formula] R 2 and each of R 6 is independently H, Br, Cl, F, CH3, or CF3, R 10 is H, optionally substituted C 1-6 alkyl, -CH2OH, -CH2OP(O)(OR 20 )(OR 21 ), 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 3 R 4 R 5 R 8 and each of R 9 is independently H, Br, Cl, F, CH3, 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 R25 is), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0014] In at least one embodiment of the compound of structural formula (II), R 3 , R 4 , and R 5 are, independently, H, Cl, F, CH3, or CF3. In at least one embodiment, R 3 , R 4 , and R 5 are H.

[0015] In at least one embodiment of the compound of structural formula (II), R 2 is selected from H, Cl, F, or CH3. In at least one embodiment, R 6 is H, Cl, F, or CF3.

[0016] In at least one embodiment of the compound of structural formula (II), R 1 is selected from the following:

Chemical formula

[0017] In at least one embodiment of the compound of structural formula (I) or structural formula (II) of the present disclosure, the compound is selected from compounds (1a), (1b), (1c), and (1d), the structures of which are described in Table 1 below (including its pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers).

[0018]

Table 1

[0019] 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.

[0020] In at least one embodiment, the present disclosure provides 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, e.g., compounds (1a), (1b), (1c), and (1d)), 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, opioid, amphetamine, binge eating disorder, and anxiety disorder, individually or simultaneously.

[0021] In at least one embodiment, the present disclosure provides a method of treating binge eating, 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 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.

[0022] In at least one embodiment, the present disclosure provides a method for treating binge eating disorder, the method 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 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.

[0023] In at least one embodiment, the present disclosure provides a method for treating an anxiety disorder, the method 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 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.

[0024] 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 binge eating disorder, or for use in the treatment of an anxiety disorder.

[0025] 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

[0026] 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.

[0027] 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 the 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" are 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 can alternatively be described using the language "consisting essentially of" or "consisting of".

[0028] Furthermore, unless the context clearly dictates 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 in accordance with any specific exclusion limit 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.

[0029] Abbreviations, Definitions, and General Parameters

[0030] 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.

[0031] As used herein, the term "ALDH-2 inhibitor" includes any compound that selectively inhibits the enzyme aldehyde dehydrogenase 2. In addition to the compounds of structural formulas (I) and (II) of the present disclosure, exemplary ALDH-2 inhibitory compounds include isoflavone compounds, daidzein (see, e.g., U.S. Pat. Nos. 5,624,910 and 6,121,010), 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 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).

[0032] As used herein, the term "addiction" includes any substance use disorder, including, but not limited to, misuse of substances, 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, opioids, and amphetamines.

[0033] As used herein, in the context of a substance of abuse that is consumable by a human, the term "alcohol" refers to ethanol ("EtOH").

[0034] 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 interpersonal relationships. Exemplary anxiety disorders include, but are not limited to, generalized anxiety disorder, panic disorder, social anxiety disorder, and various phobia-related disorders.

[0035] 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, experiences significant distress with respect to food, and as a result becomes overweight or obese.

[0036] 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 and disorder being treated, the subject's weight and age, the severity of the condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0037] The term "unit dosage form" refers to physically discrete units suitable as unitary 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.

[0038] 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 compound.

[0039] The term "prodrug" refers to a compound that contains a chemical moiety and can be converted and / or cleaved from the remainder of the molecule in vivo to provide the active drug, its pharmaceutically acceptable salt, or its biologically active metabolite.

[0040] 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 causing the clinical symptoms of the disease, (ii) Suppressing a disease, i.e., stopping the onset of clinical symptoms, and / or (iii) Alleviating a disease, i.e., regressing the clinical symptoms.

[0041] 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.

[0042] 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.

[0043] 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 therefrom; 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 thereby; 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.

[0044] The term "lower alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain 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.

[0045] 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 from 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 from 1, 2, 3, 4, or 5 atoms as defined above.

[0046] 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- -).

[0047] 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.

[0048] 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) 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 hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl which are optionally substituted, independently selected from 1 to 10 groups (e.g., 1, 2, 3, 4, or 5 groups)) interrupted alkylene group as defined above; or (iii) An alkylene group as defined above, having 1, 2, 3, 4 or 5 substituents as defined above and interrupted by 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.

[0049] The term "aralkyl" refers to an aryl group covalently bonded to an alkylene group, where aryl and alkylene are 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.

[0050] 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.

[0051] The term "alkoxy" refers to an R-O-group, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a -Y-Z group, where Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl, or 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.

[0052] The term "lower alkoxy" refers to an R-O-group, where R is 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.

[0053] The term "alkylthio" refers to an R-S-group, where R is as defined for alkoxy.

[0054] 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.

[0055] The term "lower alkenyl" refers to an alkenyl having 2 to 6 carbon atoms as defined above.

[0056] 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).

[0057] 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, such as 2 to 6 carbon atoms) and 1 to 6 carbon-carbon triple bonds, such as 1, 2, or 3 carbon-carbon triple bonds. Typical alkynyl groups include ethynyl (-C≡CH), propargyl (or propynyl, -C≡CCH3), etc. When alkynyl is bonded to nitrogen, the triple bond cannot be alpha to the nitrogen.

[0058] 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 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 therefrom.

[0059] The term "aminocarbonyl" refers to a -C(O)NRR group, where 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 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 therefrom.

[0060] The term "ester" or "carboxyester" refers to a -C(O)OR group, where R is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which are 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

[0061] The term "acylamino" refers to a -NRC(O)R group, where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. 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

[0062] 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 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

[0063] 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, etc.

[0064] 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).

[0065] 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.

[0066] The term "amino" refers to the - NH2 group.

[0067] 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 alkenyl, cycloalkenyl, or alkynyl). Unless otherwise restricted by definition, all substituents are optionally further substituted by 1, 2, or 3 substituents selected from 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).

[0068] 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 further substituted by 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).

[0069] The term "cycloalkyl" refers to a cyclic alkyl group having a single cyclic ring or multiple fused rings and having 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.

[0070] The term "cycloalkenyl" refers to a cyclic alkyl group having a single cyclic ring or multiple fused rings and having at least one double bond, preferably 1 to 2 double bonds, and having 3 to 20 carbon atoms.

[0071] 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.

[0072] The term "halogen" or "halo" refers to fluoro, bromo, chloro, and iodo.

[0073] 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.

[0074] The term "alkoxycarbonylamino" refers to a -NHC(O)OR group, where R is optionally substituted alkyl.

[0075] The term "alkylamine" refers to R-NH2, where R is optionally substituted alkyl.

[0076] The term "dialkylamine" refers to R-NHR, where each R is independently optionally substituted alkyl.

[0077] The term "trialkylamine" refers to NR3, where each R is independently optionally substituted alkyl.

[0078] The term "azide" refers to

Chemical formula

[0079] The term "hydroxy" or "hydroxyl" refers to a -OH group.

[0080] The term "azide" refers to a -S-aryl group.

[0081] The term "heterocyclylthio" refers to an -S-heterocyclyl group.

[0082] The term "alkylthio" refers to an -S-alkyl group.

[0083] 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.

[0084] 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.

[0085] The term "heterocyclooxy" refers to an -O-heterocyclyl group.

[0086] The term "alkoxyamino" refers to an -NHOR group, where R is optionally substituted alkyl.

[0087] The term "hydroxyamino" refers to an -NHOH group.

[0088] The term "heteroaryl" refers to a group containing one or more rings, with 1 to 15 carbon atoms and 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 heteroaryl 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 heteroaryl include dihydropyrrole, dihydropyridine, and chroman.

[0089] Unless otherwise restricted by the definition of the heteroaryl substituent, such heteroaryl groups 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.

[0090] The term "heteroaryloxy" refers to a heteroaryl-O-group.

[0091] The terms "heterocyclyl", "heterocyclic", or "heterocyclic ring" refer to a monoradical saturated group having a single ring or multiple fused rings, with 1 to 40 carbon atoms and 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and / or oxygen in the ring.

[0092] 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.

[0093] The term "thiol" refers to the -SH group.

[0094] The term "substituted alkylthio" refers to an -S-substituted alkyl group.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] The term "keto" or "oxo" refers to a -C(O)- group.

[0099] The term "thiocarbonyl" refers to a -C(S)- group.

[0100] The term "carboxy" refers to a -C(O)-OH group.

[0101] 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.

[0102] The term "substituted" includes embodiments in which a monoradical substituent is bonded 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 bonded to two adjacent atoms of the substituent, thereby forming a fused ring in the substituent.

[0103] When a given group (moiety) is described as being attached to a second group and the site 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 the lower alkyl group attached to any available site of the phenyl group when the site of attachment is not specified. In this regard, an "available site" is a site of the group where a hydrogen of the group can be replaced by a substituent.

[0104] 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 in this specification. 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.

[0105] A compound of a given formula (for example, "a compound of 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.

[0106] In addition, the compounds of the present disclosure may have one or more chiral centers and can be produced as racemic mixtures or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given formula depends on the number of chiral centers present (2n possible stereoisomers are present, where n is the number of chiral 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 compound 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 invention and are all intended to be represented by the structures herein unless otherwise specifically described.

[0107] The term "isomer" means different compounds having the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0108] The term "stereoisomer" means isomers that differ only in the way the atoms are arranged in space.

[0109] 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.

[0110] The term "diastereoisomer" means stereoisomers that have at least two chiral atoms but are not mirror images of each other.

[0111] 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 either (+) or (-) according to the direction in which it rotates the plane of polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory).

[0112] 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

[0113] 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).

[0114] The term "solvate" refers to a complex formed by combining a compound with a solvent.

[0115] The term "hydrate" refers to a complex formed by combining a compound with water.

[0116] 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.

[0117] 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, 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.), but are not limited thereto. 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.

[0118] Pharmaceutically acceptable acid addition salts can also be prepared from inorganic acids and organic acids. Examples of salts derived from inorganic acids include salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and include chlorides, chlorates, bromides, bromates, nitrites, nitrates, phosphites, phosphates, sulfates, and hemisulfates, but are not limited thereto. Examples of salts derived from organic acids include salts such as 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, etc.

[0119] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated, except when conventional media or agents are incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the composition.

[0120] Any formula or structure provided herein, including 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 structure represented by the formula given herein, except that one or more atoms are replaced with atoms 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 125I is mentioned. Various isotope-labeled compounds of the present invention, for example, 3 H, 13 C, 14 C and other compounds incorporated with radioisotopes. 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.

[0121] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties regarding 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 dosage. 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 instead of non-isotope-labeled reagents and performing the procedures disclosed in the following schemes or examples and preparation methods. Furthermore, substitution with heavier isotopes, especially 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 dosage or an improvement in the therapeutic index. It is understood that deuterium in this context is regarded as a substituent in the compounds of formula (I) or formula (II).

[0122] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotope enrichment factor. In the compounds of the present invention, an atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise stated, 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.

[0123] In the description including examples, unless otherwise stated, all temperatures are in degrees Celsius (°C), and the abbreviations and acronyms have the following meanings listed in Table 2 (below).

[0124] [Table 2-1] [Table 2-2] [Table 2-3]

[0125] ALDH-2 inhibitor compound

[0126] 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. Therefore, 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 dependence states in mammals, including alcohol, nicotine, cocaine, methamphetamine, opioids, binge eating disorder, and / or anxiety disorders.

[0127] In at least one embodiment, the present disclosure provides an ALDH-2 inhibitory compound of structural formula (I):

Chemical formula

[0128] As exemplified by the exemplary compounds (1a), (1b), (1c), and (1d) (structures illustrated in Table 1), the structures of a wide range of specific ALDH-2 inhibitory compounds within 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 7 , R 8 , R 9 , R 10 , and R 11 is H, (ii) each of R 3 , R 4 , and R 5 is H, (iii) X 1 is CR 3 , X 2 is CR 4 , and R 3 , R 4 , and R 5 are independently selected from H, Cl, F, CH3, and CF3, (iv) X 1 is CR 3 , X 2 is CR 4 , X 3 is CR 6 , (vii) R 2 is selected from H, Cl, F, or CH3, and / or (viii) in at least one embodiment, R 6 is selected from H, Cl, F, or CF3.

[0129] In at least one embodiment, the present disclosure relates to an ALDH-2 inhibitory compound of structural formula (II):

Chemical formula

Chemical formula

[0130] As exemplified by the illustrative compounds (1a), (1b), (1c), and (1d) (structures illustrated in Table 1), the structures of a wide range of specific ALDH-2 inhibitory compounds within structural formula (II) 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) R 3 R 4 and R 5 are, independently, H, Cl, F, CH3, or CF3, (ii) R 3 R 4 and R 5 are H, (iii) R 2 is H, Cl, F, or CH3, (vi) R 6 is H, Cl, F, or CF3, and / or (iv) R1 is R 1 is selected from:

Chemical formula

[0131] 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 general synthetic strategies 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), and (1d) described herein and listed in Table 1.

[0132] 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

[0133] R 10 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

[0134] For example, the phosphate ester derivative (h) can be prepared by alkylating pyridin-2(1H)-one (c) with at least 1 equivalent, preferably slightly in excess (e.g., 1.2 - 1.5 molar equivalents) of a linker (d) (wherein R 12 is an optionally substituted alkylene moiety having 1 to 6 carbon atoms), and at least 1 equivalent, preferably slightly in excess (e.g., 1.2 - 2 molar equivalents) of a suitable base such as triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), or pyridine under standard reaction conditions to obtain an alkylated pyridin-2(1H)-one derivative (e). This derivative (e) can then be used to O-alkylate a molar excess (e.g., 1.2 - 5 molar equivalents) of a phosphoric acid diester (f) to obtain the corresponding phosphoric acid triester (g). The phosphoric acid ester (h) is obtained by deprotecting the phosphoric acid triester (g) under standard conditions (e.g., heating with a molar excess of an acid such as acetic acid described herein, such as CH3CN / H2O). The phosphate esters of ALDH-2 inhibitory compounds have been shown to be useful as prodrugs via in vivo hydrolysis of the phosphate ester. See, for example, U.S. Patent No. 8,558,001, which is incorporated herein by reference.

[0135] Of course, typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) in the examples of this specification, as well as other process conditions, can be used unless otherwise stated. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art using established methods of optimization. Furthermore, as will be apparent to those skilled 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.

[0136] As described above, the starting materials of 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.

[0137] A. Uses and Methods of Treatment

[0138] 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 conditions of addiction or substance abuse in mammals, including addiction or abuse of alcohol, nicotine, cocaine, methamphetamine, and / or opioids, and / or binge eating disorder, and / or anxiety disorder. The main factor in the development of a state of abuse or addiction is neurophysiological reinforcement (reward). Animal experiments suggest 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. Release of dopamine from these neurons onto dopamine receptors in the NAc results in positive reinforcement.

[0139] 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. When repeatedly exposed 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 predicts, in a sense, 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.

[0140] 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 high levels of substance use, and these strong cravings can persist long after use has ceased (Volkow 2016).

[0141] 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.

[0142] 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 a condition of addiction or abuse, use in the treatment of compulsive eating disorder, or use in the treatment of an anxiety disorder.

[0143] 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 addiction or abuse, for use in the treatment of obsessive-compulsive eating disorder, or for use in the treatment of an anxiety disorder, for the treatment of chemical dependence on a substance.

[0144] 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), and (1d), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0145] In at least one embodiment of the method, the step of administering the ALDH-2 inhibitor can include administering a pharmaceutical composition, the pharmaceutical composition comprising a drug, the ALDH-2 inhibitor, and a pharmaceutically acceptable carrier.

[0146] In some embodiments of such treatment methods, 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, and food. In some embodiments, the ALDH-2 inhibitory compound in the form of a pharmaceutical composition is contemplated to be administered as a dose once or twice a day (including self-administration). In some embodiments, the once-daily dose is a formulation (e.g., a tablet) self-administered by the subject or patient.

[0147] 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.

[0148] 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 of a drug candidate for hepatotoxicity. 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 restriction 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). Therefore, for an ALDH-2 inhibitor assay IC 50 the exemplary ratio of HepaRG spheroid assay MEC to is most preferably greater than 2500, next greater than 250, and next not preferably greater than 25.

[0149] Pharmaceutical composition

[0150] 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 one or more pharmaceutically acceptable excipients, carriers comprising inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizing agents, and adjuvants in a dosage amount.

[0151] As disclosed elsewhere herein, in some embodiments of the method, the administering step may comprise administering a pharmaceutical composition, the pharmaceutical composition comprising an ALDH-2 inhibitor of structural formula (I) or (II) (e.g., compounds (1a), (1b), (1c), and (1d)), 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.

[0152] In some embodiments, the pharmaceutical compositions useful in the methods of the present disclosure are in unit dosage forms such as dosage forms containing the active ingredient (e.g., compound (1a)) in a single dosage form.

[0153] 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.

[0154] In some embodiments, the pharmaceutical composition comprises a dosage amount of the ALDH-2 inhibitor of formula (I) in an amount from about 2.5 mg to about 1200 mg, from about 5.0 mg to about 600 mg, from about 15 mg to about 400 mg, or from 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 2.5 mg, about 5.0 mg, about 10 mg, about 15 mg, about 20 mg, 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.

[0155] 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 the present disclosure, including the examples disclosed herein. Useful synthetic methods for 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.

[0156] Administration Modes of ALDH-2 Inhibitors

[0157] In the uses and methods of the present disclosure, ALDH-2 inhibitory compounds such as compounds of formula (I) or formula (II) (e.g., compounds (1a), (1b), (1c), and (1d)), or pharmaceutical compositions (plural) containing pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers of such compounds can be administered by any of the acceptable administration modes of the active ingredient having similar usefulness, either as a single dose or multiple doses. For example, as described in U.S. Patent No. 8,558,001, pharmaceutical compositions containing an ALDH-2 inhibitor can be administered by rectal, buccal, intranasal, and transdermal routes, by intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, inhalation, or, for example, via an impregnated or coated device such as a stent, or via a cylindrical polymer inserted into an artery, using a variety of different methods.

[0158] One exemplary administration route useful in the methods of the present disclosure is oral. Oral administration can be carried out via capsules, enteric-coated tablets, etc. Generally, when preparing a pharmaceutical composition containing an ALDH-2 inhibitor, for example, a compound of structural formula (I) or formula (II), or a drug containing a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, the active ingredient(s) is diluted by an excipient and / or enclosed in 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. Thus, the pharmaceutical composition(s) suitable 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 solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0159] Excipients suitable for use in pharmaceutical compositions containing 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 composition may additionally include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying agents and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweetening agents, and flavoring agents.

[0160] 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.

[0161] Pharmaceutical compositions containing ALDH-2 inhibitors useful in the methods of the present disclosure can be formulated to provide rapid release, sustained release, or delayed release of the relevant active ingredient after administration by using procedures known in the art. 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.

[0162] The pharmaceutical compositions containing the ALDH-2 inhibitory compounds of structural formula (I) or (II) 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 a 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. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be configured for continuous, pulsatile, or demand-driven 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.

[0163] 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 about 10 mg to 1 g, in some embodiments 25 mg to 1200 mg, of the ALDH-2 inhibitory compound of structural formula (I) or (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound. 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 10 to 700 mg, in some embodiments about 50 mg to 300 mg.

[0164] Generally, in the methods of the present disclosure, the amount of the ALDH-2 inhibitory compound such as the compound of formula (I) or (II), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer of such a compound 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, etc.

[0165] 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 a dosage form that provides the advantage of long-term action or protects from the acidic conditions of the stomach. For example, a tablet or pill may include 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, allowing the inner component to enter the duodenum intact or 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, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetates.

[0166] 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. Appropriate 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. Suppression of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0167] Aseptic injectable solutions are prepared by incorporating the active ingredient of the present disclosure in the required amounts in a suitable solvent, together with the various other ingredients described above, and then, if necessary, filter 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 aseptic injectable solutions, known methods for their preparation include vacuum drying and lyophilization techniques, whereby a powder is obtained from a pre-sterile filtered solution by combining the active ingredient and any desired additional ingredients.

[0168] 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, a pharmaceutical composition of an ALDH-2 inhibitory compound of structural formula (I) or (II) (e.g., compounds (1a), (1b), (1c), and (1d)), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof, can be administered via an 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 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 composition useful in the method can be a solution, suspension, or powder composition and can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

Examples

[0169] 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 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.

[0170] In Examples 1 to 10 below, methods for synthesizing exemplary ALDH-2 inhibitory compounds of Structural Formulas (I) and (II) shown in Table 1 (above) are described.

[0171] The reagents used in the syntheses of Examples 1 to 10 were purchased from commercial sources and used as received. Other general methods and equipment used in the syntheses of Examples 1 to 10 were as follows. 1 1H NMR spectra were obtained on a Bruker AVANCE 300 spectrometer at 300 MHz and a Bruker AVANCE 400 spectrometer at 400 MHz 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 on a Waters Acquity UPLC-MS spectrometer using 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).

[0172] Example 1: Synthesis of 2-chloro-6-methyl-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1a)

Chemical formula

[0173] Compound 1a was prepared via the syntheses summarized in Schemes 1 and 2 (below). Scheme 1 [Chemical formula] Scheme 2 [Chemical formula]

[0174] Step 1: Synthesis of 2-chloro-6-methylbenzoyl chloride (I): To a stirred solution of 4-chloro-2-methylbenzoic acid (1) (200 mg, 1.16 mmol) in anhydrous CH2Cl2 (5.0 mL) were added SOCl2 (0.276 mL, 15.70 mmol) and DMF (0.05 mL) 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 4-chloro-2-methylbenzoyl chloride (I) (200 mg) as a colorless liquid. The crude compound was used directly in Step 16.

[0175] Step 2: Synthesis of 6-(3-oxopiperazin-1-yl)nicotinonitrile (4): To a stirred solution of piperazin-2-one (2) (245 mg, 2.45 mmol) in NMP (1.8 mL) were added K2CO3 (678 mg, 4.91 mmol) and 6-fluoronicotinonitrile (3) (300 mg, 2.45 mmol) at room temperature under a N2 atmosphere. The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was poured into ice-cold water (50 mL), and the precipitated solid was filtered and washed with water to give 6-(3-oxopiperazin-1-yl)nicotinonitrile (4) (315 mg, 64% yield) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6): δ 8.52 (dd, J = 0.8 Hz, 2.4 Hz 1H), 8.19 (s, 1H), 7.90 (dd, J = 2.4 Hz, 9.28 Hz 1H), 6.89 (dd, J = 0.4 Hz, 9.2 Hz, 1H), 4.11 (s, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.30 - 3.28 (m, 2H). MS (ESI + APCI; multi-mode): 203.0 [M + H] + .

[0176] Step 3: Synthesis of tert-butyl ((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)carbamate (5): To a stirred solution of 6-(3-oxopiperazin-1-yl)nicotinonitrile (4) (9.00 g, 44.7 mmol) in MeOH:THF (1:3 ratio, 180 mL), NiCl2·6H2O (10.6 g, 44.7 mmol), (Boc)2O (19.4 g, 89.4 mmol) and NaBH4 (5.09 g, 134 mmol) were added 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 × 300 mL). The organic extracts were separated, washed with water, brine (2 × 500 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel chromatography (5% CH3OH:CH2Cl2) to give tert-butyl ((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)carbamate (5) (210 mg, 47% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.29 (t, J = 6.0 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.94 (s, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.26 (t, J = 6.8 Hz, 2H), 1.35 (s, 9H). MS (ESI + APCI; multi-mode): 307.0 [M + H] + .

[0177] Step 4: Synthesis of 4-(5-(aminomethyl)pyridin-2-yl)piperazin-2-one hydrochloride (6): TMSCl (5.93 mL, 49.3 mmol) was added to a stirred solution of tert-butyl ((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)carbamate (5) (5.00 g, 16.3 mmol) in 2,2,2-trifluoroethanol (50.0 mL) 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 give 4-(5-(aminomethyl)pyridin-2-yl)piperazin-2-one hydrochloride (6) (90.0 mg, 74% yield) as an off-white solid. MS (ESI + APCI; multi-mode): 207.0 [M + H] + .

[0178] Step 5: Synthesis of 2-chloro-6-methyl-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1a): To a stirred solution of 4-(5-(aminomethyl)pyridin-2-yl)piperazin-2-one hydrochloride (6) (150 mg, 0.956 mmol) in CH2Cl2 (5.0 mL), Et3N (0.22 mL, 1.66 mmol) and 4-chloro-2-methylbenzoyl chloride (I) (130 mg, 0.58 mmol) were added at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water, basified with saturated aqueous sodium bicarbonate, and extracted with 10% CH3OH in CH2Cl2 (2 × 100 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. The residue was purified by C-18 column chromatography using 50% ACN:H2O to give 2-chloro-6-methyl-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1a) (15.0 mg, yield 15%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.90 (t, J = 5.6 Hz, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.20 (d, J = 4.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 3.96 (s, 2H), 3.70 (t, J = 4.8 Hz, 2H) 3.27 (s, 2H), 2.19 (s, 3H). MS (ESI + APCI; multi-mode): 359.0 [M + H] + . HPLC: 98.5 (AUC %).

[0179] Example 2: Synthesis of 2-chloro-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1b)

Chemical formula

[0180] Compound 1b was prepared via the synthesis summarized in Scheme 3 (below). Scheme 3

Chem.

[0181] Step 6: Synthesis of 2-chlorobenzoyl chloride (II): To a stirred solution of 2-chlorobenzoic acid (7) (200 mg, 1.16 mmol) in anhydrous CH2Cl2 (5.0 mL), SOCl2 (0.276 mL, 15.70 mmol) and DMF (0.05 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 afford crude 2-chlorobenzoyl chloride (II) (200 mg) as a colorless liquid. The crude compound was used directly in Step 17.

[0182] Step 7: Synthesis of 2-chloro-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1b): To a stirred solution of 4-(5-(aminomethyl)pyridin-2-yl)piperazin-2-one hydrochloride (6) (150 mg, 0.956 mmol) (prepared as in Example 1) in CH2Cl2 (5.0 mL), Et3N (0.22 mL, 1.66 mmol) and 2-chlorobenzoyl chloride (II) (130 mg, 0.58 mmol) were added at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water, basified with saturated aqueous sodium bicarbonate, and extracted with 10% CH3OH in CH2Cl2 (2 × 100 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. The residue was purified by silica gel chromatography (10% CH3OH in CH2Cl2) to afford 2-chloro-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1b) (55.0 mg, 41% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 8.89 (t, J = 5.6 Hz, 1H), 8.11 (d J = 2.0, Hz, 1H), 8.06 (s, 1H), 7.58 - 7.38 (m, 5H), 6.82 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.0 Hz, 2H), 3.96 (s, 2H), 3.70 (t, J = 5.2 Hz, 2H), 3.28 (t, J = 2.8 Hz, 2H). MS (ESI + APCI; multi-mode): 345.0 [M + H] + . HPLC: 99.4 (AUC %).

[0183] Example 3: Synthesis of 4-chloro-2-methyl-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)nicotinamide (1c)

Chem.

[0184] Compound 1c was prepared via the synthesis summarized in Scheme 4 (below). Scheme 4

Chem.

[0185] Step 8: Synthesis of methyl 2,4-dichloronicotinate (2): To a stirred solution of 2,4-dichloronicotinic acid (8) (5.00 g, 26.04 mmol) in CH3CN (50.0 mL), DBU (7.76 mL, 52.08 mmol) and CH3I (2.30 mL, 39.06 mmol) were added 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. The residue was diluted with water and extracted with EtOAc (2 × 500 mL). The organic extracts were separated, washed with water, brine (2 × 500 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel chromatography (5% EtOAc in hexane) to give methyl 2,4-dichloronicotinate (9) (4.00 g, 75% yield) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 4.01 (s, 3H).

[0186] Step 9: Synthesis of methyl 4-chloro-2-methylnicotinate (10): To a stirred solution of methyl 2,4-dichloronicotinate (9) (2.00 g, 9.705 mmol) in 1,4-dioxane (20.0 mL), methylboronic acid (1.16 g, 19.40 mmol) and K2CO3 (4.02 g, 29.12 mmol) were added. The mixture was degassed with Ar(g) for 10 min. Pd(PPh3)4 (561 mg, 0.48 mmol) was added to the reaction mixture at once under a N2 atmosphere. The reaction mixture was stirred at 110 °C for 20 h. The reaction mixture was diluted with water and extracted with EtOAc (2 × 100 mL). The organic extracts were separated, washed with water, brine (2 × 50 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel chromatography (5% EtOAc in hexane) to give methyl 4-chloro-2-methylnicotinate (10) (700 mg, 39% yield) as a pale yellow solid. 11H NMR (400 MHz, CDCl3): δ 8.43 (d, J = 5.6 Hz, 1H), 7.21(d, J = 5.2 Hz, 1H), 3.98 (s, 3H), 2.57 (s, 3H). MS (ESI + APCI; multi-mode): 186.0 [M + H] + .

[0187] Step 10: Synthesis of 4-chloro-2-methylnicotinic acid (11): An aqueous NaOH solution (6.25 M, 1.12 mL) was added to a stirred solution of methyl 4-chloro-2-methylnicotinate (10) (700 mg, 3.78 mmol) in THF:MeOH:H2O (4:1:1 ratio, 20.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 days. 2N aqueous HCl was added to the reaction mixture to adjust the pH to 7. The reaction mixture was extracted with EtOAc (2 × 50 mL). The aqueous layer was concentrated under reduced pressure to a minimal amount of solvent and purified by reverse-phase C-18 column chromatography (50% CAN in H2O) to give 4-chloro-2-methylnicotinic acid (11) (250 mg, 36% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 14.10 (brs, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.48 (dd, J = 0.4 Hz, 5.6 Hz, 1H), 2.50 (s, 3H). MS (ESI + APCI; multi-mode): 172.0 [M + H] + .

[0188] Step 11: Synthesis of 4-chloro-2-methyl-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)nicotinamide (1c): To a stirred solution of 4-chloro-2-methylnicotinic acid (11) (70.0 mg, 0.41 mmol) in DMF (2.0 mL), NMM (0.20 mL, 2.06 mmol), HATU (235 mg, 0.62 mmol), and 4-(5-(aminomethyl)pyridin-2-yl)piperazin-2-one hydrochloride (6) (100 mg, 0.413 mmol) (prepared as in Example 1) were added at 0 °C and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was purified by C-18 column chromatography using 50% ACN:H2O to give 4-chloro-2-methyl-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)nicotinamide (1c) (35.0 mg, 18% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.06 (t, J = 6.0 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.57 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.35 (d, J = 6.0 Hz, 2H), 3.97 (s, 2H), 3.70 (t, J = 5.2 Hz, 2H) 3.32 - 3.26 (m, 2H), 2.38 (s, 3H). MS (ESI + APCI; multimode): 360.0 [M + H] + . HPLC: 98.3 (AUC %).

[0189] Example 4: Synthesis of 2,6-dichloro-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1d)

Chemical Structure

[0190] Compound 1d was prepared via the synthesis summarized in Scheme 5 (below). Scheme 5

Chemical formula

[0191] Step 12: Synthesis of 2,6-dichlorobenzoyl chloride (III): To a stirred solution of 2,6-dichlorobenzoic acid (11) (200 mg, 1.16 mmol) in anhydrous CH2Cl2 (5.0 mL) were added SOCl2 (0.276 mL, 15.70 mmol) and DMF (0.05 mL) 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 2,6-dichlorobenzoyl chloride (III) (200 mg) as a colorless liquid. The crude compound was used directly in Step 13.

[0192] Step 13: Synthesis of 2,6-dichloro-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1d): To a stirred solution of 4-(5-(aminomethyl)pyridin-2-yl)piperazin-2-one hydrochloride (6) (150 mg, 0.956 mmol) (prepared as in Example 1) in CH2Cl2 (5.0 mL) were added Et3N (0.22 mL, 1.66 mmol) and 2,6-dichlorobenzoyl chloride (III) (130 mg, 0.58 mmol) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water, basified with saturated aqueous sodium bicarbonate, and extracted with 10% CH3OH in CH2Cl2 (2 × 100 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. The residue was purified by silica gel chromatography (10% CH3OH in CH2Cl2) to give 2,6-dichloro-N-((6-(3-oxopiperazin-1-yl)pyridin-3-yl)methyl)benzamide (1d) (100 mg, yield 21%) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 9.07 (t, J = 5.6 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.57 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.50 - 7.48 (m, 2H), 7.42 (dd, J = 7.2 Hz, 9.2 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H), 3.96 (s, 2H), 3.70 (t, J = 5.2 Hz, 2H) 3.29 - 3.25 (m, 2H). MS (ESI + APCI; multi-mode): 379.0 [M + H] + . HPLC: 98.7 (area %).

[0193] Example 5: ALDH-1, ALDH-2, ALDH-3, MAO-A, MAO-B, and HepaRG spheroid assays of ALDH-2 inhibitory compounds

[0194] 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 a HepaRG 3D spheroid assay that provides a measure of potential hepatotoxicity.

[0195] Materials and methods

[0196] 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. After pre-incubating the test ALDH-2 inhibitory compound with ALDH-2 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-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%.

[0197] 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, a 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%.

[0198] 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), and had a final volume of 10 μL using a 384-well Corning 3820 plate. The test ALDH-2 inhibitory compound was pre-incubated with ALDH-3 for 60 minutes, and then 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%.

[0199] D. MAO-A and MAO-B Inhibition Assays: The MAO assay included a reconstitution buffer containing a luminescent MAO substrate, reaction buffer, luciferin detection, and esterase. The MAO reaction mixture used in the assay contained microsomes containing MAO-A (2 μg) or MAO-B (10 μg), 160 μM substrate for MAO-A or 16 μM substrate for MAO-B, 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), and had 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 enzyme activity was measured using a Perkin-Elmer Envision reader. Inhibition was determined as IC 50It was determined as such. This refers to the concentration of the test ALDH-2 inhibitory compound that inhibited the reaction by 50%.

[0200] E. HepaRG® 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® cells were seeded into ultra-low attachment 96-well black wall clear bottom spheroid microplates. After formation, test ALDH-2 inhibitory compounds at a range of concentrations 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, 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 relevant dye / antibody was loaded onto the spheroids. Next, the plates were scanned using an automated fluorescence cell imager ArrayScan® (Thermo Scientific Cellomics). The minimum effective concentration (“MEC”) was determined as the amount of the test compound that significantly exceeded the vehicle control threshold for the cell health marker.

[0201] Results

[0202] 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 in Table 1 are summarized in Table 3 below.

[0203] [Table 3]

[0204] 6. Formulation of Pharmaceutical Compositions

[0205] This example describes the formulation of a pharmaceutical composition comprising an ALDH-2 inhibitor of structural formula (I) and formula (II) that can be used in the methods of the present disclosure for treating substance dependence or dependence or abuse conditions.

[0206] 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

[0207] 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

[0208] 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

[0209] Pass the active ingredient, starch, and cellulose through a No. 20 US mesh sieve and mix well. Mix with the solution of polyvinylpyrrolidone and then pass this through a 16 US mesh sieve. Dry the granules thus produced at 50 °C to 60 °C and pass through a 16 US mesh sieve. Then add sodium carboxymethyl starch, magnesium stearate, and talc passed through a No. 30 US mesh sieve to the granules and, after mixing, compress this with a tablet machine to obtain tablets each weighing 120 mg.

[0210] 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

[0211] Pass the active ingredient through a No. 60 US mesh sieve and suspend it in the saturated fatty acid glyceride pre-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.

[0212] 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

[0213] 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.

[0214] Subcutaneous: Prepare the subcutaneous preparation as follows: Ingredient Amount Active ingredient 5.0 mg Corn oil 1.0 mL

[0215] For injection: 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.

[0216] 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

[0217] 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.

[0218] 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 were individually indicated to be incorporated by reference for all purposes.

[0219] 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. Compounds with structural formula (I): 【Chemistry 31】 (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 , provided that at most one of X １ , X ２ , and X ３ is N, R １０ H is replaced by C of any choice. １－６ Alkyl, -CH ２ OH, -CH ２ OP(O)(OR ２０ ) ( OR ２１ ) 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 , and R ９ 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, R ２０ and R ２１ Each of these 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 ７ , R ８ , R ９ , R １０ , and R １１ The compound according to claim 1, wherein each of them is H.

3. R ３ , R ４ , and R ５ The compound according to claim 1, wherein each of them is H.

4. X １ However, CR ３ X ２ However, CR ４ And R ３ , R ４ , and R ５ However, independently, H, Cl, F, CH ３ , or CF ３ The compound according to claim 1.

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

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

7. Compounds of structural formula (II): 【Chemistry 32】 (In the formula, R １ The following can be selected: 【Transformation 33】 R ２ , and R ６ Each of these is independently H, Br, Cl, F, CH ３ , or CF ３ And, R １０ H is replaced by C of any choice. １－６ Alkyl, -CH ２ OH, -CH ２ OP(O)(OR ２０ ) ( OR ２１ ) and R １１ C is substituted with H, halogen, or of any choice. １－６ Alkyl or cycloalkyl, R ７ is H or optionally substituted C １－６ alkyl, R ３ , R ４ , R ５ , R ８ , and R ９ are each 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 ), or a pharmaceutically acceptable salt, ester, single stereoisomer, mixture of stereoisomers, or tautomer thereof.

8. R ３ , R ４ , and R ５ However, independently, H, Cl, F, CH ３ , or CF ３ The compound according to claim 7.

9. R ３ , R ４ , and R ５ The compound according to claim 7, wherein H is present.

10. R ２ However, H, Cl, F, or CH ３ The compound according to claim 7.

11. R ６ However, H, Cl, F, or CF ３ The compound according to claim 7.

12. R １ However, the compound according to claim 7, selected from the following: 【Transformation 34】

13. The compound according to claim 1, wherein the compound is selected from compounds (1a), (1b), (1c), and (1d), or pharmaceutically acceptable salts, esters, single stereoisomers, mixtures of stereoisomers, or tautomers thereof. Table 4

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. A composition comprising the compound according to any one of claims 1 to 13 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 13 and a pharmaceutically acceptable carrier.

16. The composition according to claim 15, wherein the substance or the addiction state is selected from the group consisting of alcohol, nicotine, cocaine, opiates, amphetamines, obsessive-compulsive eating disorders, and / or anxiety disorders.

17. A composition comprising the compound according to any one of claims 1 to 13 for the treatment of obsessive-compulsive eating disorder in human patients, or a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

18. A composition comprising the compound according to any one of claims 1 to 13 for the treatment of anxiety disorders in human patients, or a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

19. A composition comprising the compound according to any one of claims 1 to 13 for use in therapy.

20. A composition comprising the compound according to any one of claims 1 to 13, for use as a pharmaceutical.

21. A composition comprising the compound according to any one of claims 1 to 13 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.

22. Use of the compound according to any one of claims 1 to 13 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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