Squalamide derivatives as CB1 allosteric modulators

Abstract

Squalamide-based cannabinoid 1 receptor (CB1R) allosteric modulators are described. Exemplary analogs may provide improved potency and pharmacokinetic properties. Methods of using the analogs for treating CB1R-mediated diseases such as substance abuse and obesity are described. The subject matter of the present disclosure relates to squalamide-based cannabinoid 1 receptor (CB1R) allosteric modulator compounds, as well as pharmaceutical compositions and uses thereof. Use of the compounds includes modulation of CB1R activity and treatment of CB1R-mediated diseases and conditions such as obesity, substance abuse, alcoholism, alcohol dependence, anxiety, depression, metabolic syndrome, stroke, hypotension, infertility, cancer, inflammation, Parkinson's disease, paralytic ileus, and osteoporosis.

Description

Technical Field

[0001] Government subsidy This invention was made with government support under grant number 5R01DA040693 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] The subject matter of this disclosure relates to squaramide-based cannabinoid 1 receptor (CB1R) allosteric modulator compounds, as well as pharmaceutical compositions and uses thereof. The uses of the compounds include the regulation of CB1R activity and the treatment of diseases and conditions mediated by CB1R, such as obesity, substance abuse, alcohol addition, alcohol dependence, anxiety, depression, metabolic syndrome, stroke, hypotension, infertility, cancer, inflammation, Parkinson's disease, paralytic ileus, and osteoporosis.

Background Art

[0003] According to the 2017 National Survey on Drug Use and Health, 18.7 million adults in the United States suffered from a substance use disorder. Currently, there are no FDA-approved drugs for the treatment of cravings for stimulants (e.g., cocaine, methamphetamine) and cannabis (marijuana). There are available drugs for the prevention of relapse of other addictive substances (e.g., opioids, tobacco, alcohol). However, although these drugs may be effective in treating withdrawal symptoms, the long-term abstinence rate remains low. For example, even for some drugs for smoking cessation, the one-year smoking abstinence rate is only about 20% compared to about 10% for placebo. Therefore, there is an unmet need for drugs that relieve substance cravings on a long-term basis.

[0004] Cannabinoid 1 and cannabinoid 2 receptors (CB1R and CB2R, respectively) belong to the class A rhodopsin-like superfamily of G protein-coupled receptors (GPCRs). CB1R is one of the most abundantly expressed receptors in the brain. See Matsuda et al., Nature 1990, 346, 561-564. CB1R plays roles in many physiological processes such as pain, learning and memory, appetite and feeding behavior, anxiety and depression. See Porter et al., Pharmacol. Ther. 2001, 90, 45-60, Harkany et al., Trends Pharmacol. Sci. 2007, 28, 83-92, and Kreitzer and Regehr, Curr. Opin. Neurobiol. 2002, 12, 324-330. The major phytocannabinoid found in marijuana, (-)-trans-Δ 9- Δ9-Tetrahydrocannabinol (THC) has been known for centuries to induce appetite and weight gain, as well as addiction, and the CB1R has been studied to develop therapeutic interventions for obesity, metabolic disorders, and substance abuse. See Van Gaal et al., Lancet 2005, 365, 1389-1397, Pi-Sunyer et al., JAMA 2006, 295, 761-775, Scheen et al., Lancet 2006, 368, 1660-1672, Rosenstock et al., Diabetes Care 2008, 31, 2169-2176, Despres et al., Arterioscler. Thromb. Vasc. Biol. 2009, 29, 416-423, Steinberg and Foulds, Vasc. Health Risk Manag. 2007, 3, 307-311, and Huestis et al., Psychopharmacology (Berl) 2007, 194, 505-515. Other potential uses of CB1R antagonists / inverse agonists include the treatment of cancer, infertility in women, stroke, hypotension, and reduced bowel motility in paralytic ileus. See Pertwee and Thomas, “Therapeutic Applications for Agents that Act at CB1 and CB2 Receptors,” in The Cannabinoid Receptors, Reggio, Ed., Humana Press: 2009, pp. 361-392, and Youssif et al., European Journal of Medicinal Chemistry 2019, 177, 1-11. Unfortunately, rimonabant (also known as SR141716A), the first CB1R inverse agonist / antagonist to receive FDA approval for the treatment of obesity in 2006, was subsequently discontinued due to adverse effects including suicidal ideation. Accordingly, there remains a continuing need for additional compounds that can modulate CB1R activity for treating substance use disorders and other conditions that can be modulated via CB1R. For example, there remains a continuing need for additional CB1R modulator compounds having reduced side effects, improved pharmacokinetic properties (e.g., metabolic stability), and improved efficacy.

PRIOR ART DOCUMENTS

NON-PATENT LITERATURE

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Summary of the Invention

Means for Solving the Problems

[0006] One embodiment of the present disclosure is a compound of formula (I), wherein

Chemical Formula

[0007] In one embodiment, ring A is C6 aryl, i.e., phenyl.

[0008] In one embodiment, each R 1 is independently halo, C1-C4 alkyl, C1-C4 haloalkyl, CN, O-(C1-C6 alkyl), or N(R3 ) 2, and each R 2 is, independently, halo, C1-C4 alkyl, C1-C4 haloalkyl, CN, NO2, O-(C1-C6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 3 )2, C1-C8-alkyl) x -(5- to 13-membered aryl), or (C1-C8-alkyl) x -(5- to 13-membered heteroaryl), where each of the aryl and heteroaryl is optionally substituted with one or more R 5 groups, the heteroaryl contains one, two, or three heteroatoms selected from N, O, and S, and each R 3 is, independently, H or C 1-6 alkyl, or two R 3 groups and the nitrogen atom to which they are attached may contain one or two additional heteroatoms selected from N, O, and S and form a 5- to 7-atom heterocyclic ring, and each R 4 is, independently, H, halo, C 1-6 alkyl, or N(R 5 )2, each R 5 is, independently, H or C 1-6 alkyl, or two R 5 groups and the nitrogen atom to which they are attached may contain one or two additional heteroatoms selected from N, O, and S and form a 5- to 7-atom heterocyclic ring, n is 0, 1, 2, 3, or 4, m is 1, 2, or 3, o is 0, 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

[0009] One embodiment of the present disclosure is a compound of formula (II), wherein

Chemical formula

[0010] In one embodiment, when R 2 is other than pyridyl, two R 5 groups and the nitrogen atom to which they are attached may contain one or two additional heteroatoms selected from N, O, and S and may contain one or more degrees of unsaturation and form a 5- to 7-membered heterocycle.

[0011] In certain embodiments, ring A is pyridinyl, thiophenyl, piperidinyl, or piperazinyl.

[0012] In one aspect, R 1is halogen or CN. In one aspect, R 1 is halogen. In one aspect, R 1 is Cl.

[0013] In one aspect, n is 1 or 2. In one aspect, n is 2.

[0014] In one aspect, o is 0.

[0015] In one aspect, o is at least 1, and each R 2 is C 1-6 alkyl, halogen, O(C 1-6 alkyl), C 1-6 haloalkyl, N(C 1-6 alkyl)2, C(O)C 1-6 alkyl, OH, unsubstituted phenyl, phenyl substituted with halogen, unsubstituted pyridine, pyridine substituted with pyrroline, unsubstituted thiazole, unsubstituted thiophene, unsubstituted phenyl, and phenyl substituted with halogen, and is selected from the group consisting of.

[0016] In one aspect, o is 1 or 2, and each R 2 is C 1-6 alkyl, halogen, O(C 1-6 alkyl), N(C 1-6 alkyl)2, C(O)C 1-6 alkyl, unsubstituted phenyl, and phenyl substituted with halogen, and is selected from the group consisting of.

[0017] In one aspect, R 3 is CH3.

[0018] In one aspect, R 4 is H, halo, or N(R 5 )2, and the two R 5 groups and the nitrogen to which they are attached form pyrrolidine.

[0019] In one aspect, x is 0.

[0020] One embodiment of the present disclosure is 3-(Benzylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (9), 3-[(4-chlorophenyl)amino]-4-[(2-phenylethyl)amino]cyclobut-3-ene-1,2-dione (10), 3-[(4-chlorophenyl)amino]-4-[(3-phenylpropyl)amino]cyclobut-3-ene-1,2-dione (11), 3-[(4-chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (12), 3-[(4-chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (13), 3-[(4-chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (14), 3-[(4-chlorophenyl)amino]-4-{[2-(2-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (15), 3-[(4-chlorophenyl)amino]-4-{[2-(3-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (16), 3-[(4-chlorophenyl)amino]-4-{[2-(4-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (17), 3-[(4-chlorophenyl)amino]-4-({2-[2-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (18), 3-[(4-chlorophenyl)amino]-4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (19), 3-[(4-chlorophenyl)amino]-4-({2-[4-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (20), 3-[(4-Chlorophenyl)amino]-4-{[2-(4-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (21), 3-[(4-Chlorophenyl)amino]-4-{[2-(2-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (22), 3-[(4-Chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (6), 3-[(4-Chlorophenyl)amino]-4-{[2-(2-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (23), 3-[(4-Chlorophenyl)amino]-4-{[2-(3-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (24), 3-[(4-Chlorophenyl)amino]-4-({2-[3-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (25), 3-[(4-Chlorophenyl)amino]-4-({2-[4-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (26), 4-[(2-{[2-(3-Chlorophenyl)ethyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzonitrile (27), 3-(Biphenyl-3-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (28), 3-[(4-Chlorophenyl)amino]-4-{[3-(thiophen-3-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (31), 3-[(4-Chlorophenyl)amino]-4-[(4’-fluorobiphenyl-3-yl)amino]cyclobut-3-ene-1,2-dione (32), 3-(Biphenyl-4-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (33), 3-[(4-Chlorophenyl)amino]-4-{[2-(2-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(pyridin-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(pyridin-4-yl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(4-bromophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(thiophen-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-{[2-(A-acetylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(3,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(3,4-dimethylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(3-hydroxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(2,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(piperidin-1-yl)ethyl]amino}cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-({2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}amino)cyclobut-3-ene-1,2-dione, 3-[(4-Chlorophenyl)amino]-4-{[2-(2,4-difluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione, and A compound selected from 3-[(4-chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione, or a pharmaceutically acceptable salt thereof.

[0021] One embodiment of the present disclosure includes a compound selected from Compounds 6, 12, 13, 14, or a pharmaceutically acceptable salt thereof.

[0022] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0023] A method of doing so in a subject in need of treatment for a cannabinoid 1 receptor (CB1R)-mediated disease or condition, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0024] In one aspect, the subject is a mammal, optionally a human.

[0025] In one aspect, the disease or condition is selected from the group consisting of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette syndrome, stroke, atherosclerosis, hypotension, hypomotility of the intestine in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression, and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0026] In one aspect, the disease is obesity or addiction, and optionally, the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

[0027] One embodiment of the present disclosure includes a method for inhibiting drug abuse, addiction, addictive behavior, or symptoms, behaviors, or conditions associated with addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0028] In one aspect, the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

[0029] In one aspect, administration of the compound of the present disclosure prevents drug intake.

[0030] In one aspect, administration of the compound of the present disclosure prevents or inhibits relapse.

[0031] One embodiment of the present disclosure includes a method for modulating the activity of the cannabinoid 1 receptor (CB1R), the method comprising contacting a sample containing CB1R with a compound of the present disclosure.

[0032] One embodiment of the present disclosure includes a compound of the present disclosure for use in medicine.

[0033] One embodiment of the present disclosure includes a compound of the present disclosure for the manufacture of a drug for the treatment of one or more diseases or disorders of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette syndrome, stroke, atherosclerosis, hypotension, reduced intestinal motility in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression, and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0034] In one aspect, the disease or disorder is obesity or addiction, and optionally, the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

[0035] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the treatment of one or more diseases or disorders of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette syndrome, stroke, atherosclerosis, hypotension, hypomotility of the intestine in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression, and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0036] In one aspect, the disease or disorder is obesity or addiction, and optionally, the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

[0037] One or more aspects and embodiments, although not specifically described, may be incorporated into different embodiments. That is, all aspects and embodiments may be combined in any manner or combination.

[0038] The subject matter of the present disclosure can be better understood by reference to the following drawings. The components of the drawings are not necessarily to scale, and instead, emphasis is placed on illustrating the principles of the subject matter of the present disclosure. The drawings are not intended to limit the scope of the subject matter of the present disclosure, which is specifically set forth in the appended or subsequently amended claims, but are intended to clarify and exemplify the subject matter of the present disclosure. To better understand the subject matter of the present disclosure, reference is now made to the following drawings.

Brief Description of the Drawings

[0039]

Figure 1

Mode for Carrying Out the Invention

[0040] Here, with reference to the accompanying examples in which representative embodiments are shown, the subject matter of the present disclosure will be more fully described below. However, the subject matter of the present disclosure may be embodied in different forms and should not be construed as limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the embodiments to those skilled in the art.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this disclosure belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0042] Throughout this specification and the claims, a given chemical formula or name shall be taken to include all optical and stereoisomers and racemic mixtures thereof in which such isomers and mixtures exist, unless specifically indicated otherwise.

[0043] Definitions Unless otherwise indicated, all numbers expressing amounts of materials, reaction conditions, etc. used in this specification and the claims are to be understood as being modified in all instances by the term "about" unless otherwise specifically noted. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the subject matter of this disclosure. As used herein, the term "about" when referring to a measurable value such as an amount of weight, molar equivalent, time, temperature, etc. means that such a variable is within a variation of, in one example, ±20% or ±10% from a particular amount, in another example ±5%, in another example ±1%, and in yet another example ±0.1% because such variations are appropriate for carrying out the disclosed methods.

[0044] As used herein, the term "alkyl" refers to C1-C20 Refers to linear (i.e., "straight-chain"), branched, saturated, partially saturated, and fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon chains, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and aryl groups. "Branched" refers to an alkyl group in which a lower alkyl group such as methyl, ethyl, or propyl is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having from 1 to about 8 carbon atoms (i.e., C1-C8 alkyl), for example, an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In some embodiments, "lower alkyl" may refer to a C 1-6 or C 1-5 alkyl group.

[0045] The alkyl group may optionally be substituted with one or more substituents, which may be the same or different ("substituted alkyl"). The term "substituent" includes, but is not limited to, alkyl, halo, haloalkyl, nitro, cyano, amino, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. Along the alkyl chain, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may optionally be inserted, and the nitrogen substituents are hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0046] Accordingly, as used herein, the term "substituted alkyl" includes an alkyl group in which one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group including, for example, alkyl, halogen, haloalkyl, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, cyano, amino, alkylamino, dialkylamino, ester, acyl, amide, sulfonyl, sulfate, and mercapto, as defined herein.

[0047] The term "alkenyl" refers to an alkyl group as defined above that contains at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, and arylenyl groups. The alkenyl group may optionally be substituted with one or more alkyl group substituents which may be the same or different and include, but are not limited to, alkyl (saturated or unsaturated), substituted alkyl (e.g., halo-substituted and perhalo-substituted alkyl such as, but not limited to, -CF3), cycloalkyl, halogen, nitro, hydroxyl, carbonyl, carboxyl, acyl, alkoxyl, aryloxyl, aralkoxyl, thioalkyl, thioaryl, thioaralkyl, amino (e.g., aminoalkyl, aminodialkyl, aminoaryl, etc.), sulfonyl, and sulfinyl.

[0048] "Cyclic" and "cycloalkyl" refer to non-aromatic monocyclic or polycyclic ring systems having from about 3 to about 10 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. In some embodiments, the cycloalkyl ring system contains 3 to 6 carbon atoms. The cycloalkyl group can optionally be partially unsaturated. The cycloalkyl group can also be optionally substituted with substituents as defined herein. Representative monocyclic cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Further, the cycloalkyl group can optionally be attached via a linking group such as an alkylene group as defined hereinbelow, for example, methylene, ethylene, propylene, and the like. In such cases, the cycloalkyl group can be referred to, for example, as cyclopropylmethyl, cyclobutylmethyl, and the like. Additionally, polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphan, and noradamantyl.

[0049] Accordingly, as used herein, the term "substituted cycloalkyl" includes a cycloalkyl group in which one or more atoms or functional groups of the cycloalkyl group are replaced with another atom or functional group including, for example, alkyl, halogen, haloalkyl, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, cyano, amino, alkylamino, dialkylamino, ester, acyl, amide, sulfonyl, sulfate, and mercapto, as defined herein.

[0050] As used herein, the term "aryl" refers to an aromatic substituent that can be a single aromatic ring, or a plurality of aromatic rings that are fused together, covalently bonded, or bonded to a common group, such as, but not limited to, a methylene or ethylene moiety, etc., but not limited thereto. The common linking group can also be a carbonyl such as benzophenone, or an oxygen such as diphenyl ether, or a nitrogen such as diphenylamine. The term "aryl" specifically includes heteroaromatic compounds (i.e., "heteroaryl"). The aromatic ring(s) can include, inter alia, phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone. In certain embodiments, the term "aryl" means a cyclic aromatic containing from about 5 to about 10 carbon atoms, such as 5, 6, 7, 8, 9, or 10 carbon atoms, including 5- and 6-membered hydrocarbon and heteroaromatic rings.

[0051] An aryl group can optionally be substituted with one or more substituents, which can be the same or different ("substituted aryl"), including alkyl, aryl, halogen, haloalkyl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR’R’’, wherein R’ and R’’ can each independently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.

[0052] Accordingly, as used herein, the term "substituted aryl" includes an aryl group in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group including, for example, alkyl, halogen, haloalkyl, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto, as defined herein.

[0053] Specific examples of the aryl group include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, thiazole, pyrimidine, quinoline, isoquinoline, indole, carbazole, naphthyl and the like.

[0054] As used herein alone or as part of another group, "heterocyclic", "heterocycle", or "heterocyclo" refers to an aliphatic (e.g., fully or partially saturated heterocycle) monocyclic or bicyclic ring system containing one or more heteroatoms (e.g., one, two, or three heteroatoms selected from oxygen, sulfur, and substituted or unsubstituted nitrogen) inserted along a cyclic alkyl or aryl carbon chain. The monocyclic ring system is exemplified by any 5-membered or 6-membered ring containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur. The 5-membered ring has 0 to 2 double bonds, and the 6-membered ring has 0 to 3 double bonds. Representative examples of the monocyclic ring system include, but are not limited to, ethylene oxide, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene (also known as thiolane), tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, etc. The bicyclic ring system is exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.Typical examples of bicyclic ring systems include, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxin, 1,3-benzodioxole, carbazole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolidine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, etc., but are not limited thereto. These rings include their quaternized derivatives and may optionally be substituted with one or more alkyl and / or aryl group substituents.

[0055] As used herein, "substituted heterocyclic" refers to a heterocyclic group in which one or more hydrogen atoms are replaced by a substituent.

[0056] The term "N-heterocycle" refers to a heterocycle in which at least one of the heteroatoms is a nitrogen atom. Examples of N-heterocycles include, but are not limited to, azetidine, pyrrolidine, pyrrole, pyrroline, pyrazole, pyrazoline, pyrazolidine, piperidine, pyridine, piperazine, pyrazine, pyrimidine, pyridazine, morpholine, imidazole, benzimidazole, imidazoline, imidazolidine, indole, carbazole, quinoline, isoquinoline, oxazole, thiazole, isothiazole, and thiazine.

[0057] "Substituted N-heterocycle" refers to an N-heterocycle in which one or more hydrogens are replaced by a substituent.

[0058] The term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system (a fused ring system, a bridged ring system, or a spirocyclic ring system) containing one or more heteroatoms (e.g., one, two, or three heteroatoms selected from oxygen, sulfur, and substituted or unsubstituted nitrogen, with heteroatom substitutions including N-oxides, sulfur oxides, and dioxides) inserted along the cyclic aryl carbon chain. In some embodiments, the monocyclic heteroaryl group is a 5- to 7-membered aromatic ring. Representative heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiaciazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyrindine, and pyrazolopyrimidine.

[0059] The term "substituted heteroaryl" refers to a heteroaryl group as defined herein in which one or more hydrogen atoms have been replaced by a substituent.

[0060] "Aralkyl" refers to an aryl-alkyl- or -alkyl-aryl group, where aryl and alkyl are as described above and may include substituted aryl and substituted alkyl. Thus, "substituted aralkyl" may refer to an aralkyl group containing one or more substituents. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0061] "Alkylene" can refer to a linear or branched divalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be linear or branched. The alkylene group may also optionally be unsaturated (i.e., contain an alkene or alkyne group) and / or substituted with one or more "alkyl group substituents". Along the alkylene group, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") can be optionally inserted, and the nitrogen substituents are the aforementioned alkyl. Exemplary alkylene groups include methylene (-CH2-), ethylene (-CH2-CH2-), propylene (-(CH2)3-), cyclohexylene (-C6H 10 -), -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2) q -N(R)-(CH2) r -, where each of q and r is independently an integer from 0 to about 20, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl, methylenedioxyl (-O-CH2-O-), and ethylenedioxyl (-O-(CH2)2-O-). The alkylene group can have from about 2 to about 3 carbon atoms and can further have from 6 to 20 carbons.

[0062] "Arylene" refers to a divalent aryl group which can be substituted or unsubstituted.

[0063] The term "aralkylene" refers to a divalent group containing a combination of alkylene and arylene groups (e.g., -arylene-alkylene-, alkylene-arylene-alkylene-, arylene-alkylene-arylene, etc.).

[0064] Similarly, the terms "cycloalkylene", "heterocycloalkylene", and "heteroarylene" refer to divalent cycloalkyl, heterocyclic, and heteroaryl groups, respectively, which may be optionally substituted with one or more substituents.

[0065] As used herein, the term "acyl" refers to an organic carboxylic acid group in which the -OH of the carboxylic acid group is replaced by another substituent. Thus, an acyl group can be represented by RC(=O)-, where R is an alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl group as defined herein. As such, the term "acyl" specifically includes arylacyl groups such as the phenacyl group. Specific examples of acyl groups include acetyl (i.e., -C(=O)CH3) and benzoyl.

[0066] "Alkoxyl" refers to an alkyl-O- group, where alkyl is as described above and includes substituted alkyl. As used herein, the term "alkoxyl" can refer to, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, t-butoxyl, and pentoxyl. The terms "oxyalkyl" and "alkoxy" can be used interchangeably with "alkoxyl".

[0067] "Aryloxyl" and "aryloxy" refer to an aryl-O- group, where the aryl group is as described above and includes substituted aryl. As used herein, the term "aryloxyl" can refer to phenyloxyl or hexyloxyl, as well as alkyl-, substituted alkyl-, or alkoxyl-substituted phenyloxyl or hexyloxyl.

[0068] "Aralkyloxyl" or "aralkoxy" refers to an aralkyl-O- group, where the aralkyl group is as described above. An exemplary aralkyloxyl group is benzyloxyl.

[0069] The term "carbonyl" refers to the -C(=O)- group. The term "carbonyl carbon" refers to the carbon atom of the carbonyl group. Other groups include, but are not limited to, acyl groups, anhydrides, aldehydes, esters, lactones, amides, ketones, carbonates, and carboxylic acids, which include carbonyl groups.

[0070] The terms "carboxyl" and "carboxylic acid" refer to the -C(=O)OH or -C(=O)O - group.

[0071] The term "acid chloride" may refer to the -C(=O)Cl group.

[0072] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo groups.

[0073] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted by one or more halo groups. The term "perhaloalkyl" refers to an alkyl group as defined herein in which all C-H bonds have been replaced by carbon-halogen bonds. The term "perfluoroalkyl" refers to an alkyl group in which all C-H bonds have been replaced by C-F bonds. An exemplary perfluoroalkyl group is trifluoromethyl (-CF3).

[0074] The term "sulfonyl" refers to the -S(=O)2R group, where R is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl. The term "alkylsulfonyl" refers to the -S(=O)2R group, where R is alkyl or substituted alkyl. In some embodiments, the sulfonyl group is -S(=O)2CH3.

[0075] The term "ester" refers to an R'-O-C(=O)- group, where the carbonyl carbon is bonded to another carbon atom, and in the formula, R' is alkyl, cycloalkyl, aralkyl, or aryl, and the alkyl, cycloalkyl, aralkyl, or aryl is optionally substituted. The term "esterification" can refer to forming an ester by contacting a compound containing a carboxylic acid or its derivative (e.g., acid chloride) with a compound containing a hydroxyl group (e.g., alcohol or phenol).

[0076] The term "amide" refers to a compound containing the structure R'-NR''-C(=O)-R, where in the formula, R is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl, and R' and R'' are independently hydrogen, alkyl, aralkyl, or aryl, and the alkyl, aralkyl, or aryl is optionally substituted. In some embodiments, R' is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl.

[0077] As used herein, the term "urea" refers to a compound containing the structure R-NR'-C(=O)-NR'-R, where in the formula, each R is independently alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl, and each R' is independently H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl.

[0078] The term "amine" refers to a molecule having the formula N(R)3 or its protonated form, where each R is independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, or two R groups together form an alkylene or arylene group. The term "primary amine" refers to an amine in which at least two R groups are H. The term "secondary amine" refers to an amine in which only one R group is H. The term "alkylamine" may refer to an amine in which two R groups are H and the other R group is alkyl or substituted alkyl. "Dialkylamine" may refer to an amine in which two R groups are alkyl. "Arylamine" may refer to an amine in which one R group is aryl. An amine can also be protonated, i.e., it can have the formula [NH(R)3] + and can have.

[0079] The term "amino" refers to the group -N(R)2, where each R is independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl. The terms "aminoalkyl" and "alkylamino" may refer to the group -N(R)2, where each R is H, alkyl, or substituted alkyl and at least one R is alkyl or substituted alkyl. The term "dialkylamino" refers to an aminoalkyl group in which both R groups are alkyl or substituted alkyl, which may be the same or different.

[0080] The terms "acylamino" and "aminoacyl" refer to the -N(R)-C(=O)R' group, where R is selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R' is selected from alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl.

[0081] The term "cyano" refers to the -C≡N group.

[0082] The terms "hydroxyl" and "hydroxy" refer to the -OH group.

[0083] The terms "mercapto" and "thiol" refer to the -SH group.

[0084] The term "oxo" refers to a compound described previously herein in which a carbon atom is replaced by an oxygen atom.

[0085] The term "nitro" refers to the -NO2 group.

[0086] The term "thioalkyl" may refer to the group -SR, wherein R is selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl. Similarly, the terms "thioaralkyl" and "thioaryl" refer to the -SR group, wherein R is aralkyl and aryl, respectively.

[0087] As used herein, terms such as "treatment" and "treating" refer to any treatment of a disease and / or condition in an animal or mammal (particularly a human), including inhibiting a disease, disorder, and / or condition, i.e., preventing its onset, and alleviating a disease, disorder, and / or condition, i.e., causing regression of the disease, disorder, and / or condition.

[0088] As used herein, the term "protecting group" includes any suitable protecting group, and "protected form" refers to a substituent in which an atom such as hydrogen has been removed and replaced with the corresponding protecting group. Protecting groups are known. Generally, see T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples include, but are not limited to: hydroxy protecting groups (for generating protected forms of hydroxy); carboxy protecting groups (for generating protected forms of carboxylic acids); amino protecting groups (for generating protected forms of amino); sulfhydryl protecting groups (for generating protected forms of sulfhydryl), etc.Specific examples include, but are not limited to: benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryl-oxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, acetyl (Ac), benzoyl (Bn), and trimethylsilyl (TMS), etc.; formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz), etc.; and hemi-thioacetals, thioesters, or thiocarbonates such as 1-ethoxyethyl and methoxymethyl, etc.

[0089] As used herein, the term "allosteric modulator" refers to a compound (or "ligand") that binds to a site on a macromolecule (e.g., a receptor) that is distinct from the orthosteric site (i.e., the primary binding site of the macromolecule). Allosteric modulators can indirectly affect the effects of orthosteric or primary ligands that bind at the orthosteric site. For example, an allosteric modulator of the CB1 receptor can bind to the receptor at a site distinct from the orthosteric site(s) and can result in a change in receptor conformation. As a result, the interaction characteristics of the orthosteric ligand(s) and the receptor with respect to the cellular host environment can be modified in either a positive or negative direction, and are referred to as positive allosteric modulators ("PAMs") and negative allosteric modulators ("NAMs"), respectively. Allosteric modulators can exhibit the following pharmacological properties: (i) affinity modulation (the resulting conformation can change either the association or dissociation rate of the orthosteric ligand), (ii) efficacy modulation (the allosteric effect can modify the intracellular response and result in a change in the signaling ability of the orthosteric ligand), and / or (iii) agonism / antagonism (the allosteric modulator can perturb receptor signaling in either a positive or negative direction, regardless of the presence of the orthosteric modulator).

[0090] Preclinical and clinical studies suggest that blockade of the CB1R is a promising strategy for the treatment of many common abused drugs as well as many other conditions including, but not limited to, obesity, anxiety, cancer, inflammation, Parkinson's disease, osteoporosis, female infertility, metabolic disorders, pain, stroke, hypotension, and gastrointestinal hypofunction. Unfortunately, to date, psychiatric side effects such as depression, anxiety, or even suicidal ideation have limited the use of CB1R antagonists / inverse agonists in the clinic.

[0091] Despite this setback, CB1R has remained a target for drug development, and various strategies have been explored to overcome the psychiatrically adverse effects of CB1R signaling while maintaining beneficial therapeutic effects. Similar to many GPCRs, CB1R exhibits a high level of constitutive activity in the absence of exogenous ligands in both neurons (see Pan et al., Mol. Pharmacol. 1998, 54, 1064 - 1072, and Hillard et al, FEBS Lett. 1999, 459, 277 - 281) and non-neuronal cells. See Bouaboula et al., J. Biol. Chem. 1997, 272, 22330 - 22339. Since constitutive activity is important for maintaining cellular homeostasis, the adverse effects of rimonabant, a CB1R antagonist / inverse agonist, are thought to stem from its CB1R inverse agonism that reduces the basal tone of CB1R. Therefore, neutral antagonists that attenuate CB1R signaling under hyperactive conditions but do not change the CB1R basal level are hypothesized to have fewer side effects. See Greasley and Clapham, Eur. J. Pharmacol. 2006, 553, 1 - 9. Peripherally restricted antagonists that do not cross the blood-brain barrier have shown promising therapeutic effects in the treatment of obesity and diabetes without the burden of central nervous system (CNS) side effects. See Chorvat, Bioorg. Med. Chem. Lett. 2013, 23, 4751 - 4760.

[0092] In addition, the discovery of allosteric binding sites on CB1R has provided a promising alternative approach to modulating CB1R signaling for therapeutic benefit. Allosteric modulators target CB1R at allosteric binding sites and offer several advantages over orthosteric ligands, such as better receptor subtype selectivity, reduced risk of overdose due to a "ceiling" effect, and more transient pharmacological effects (as a result of dependence on the presence of endogenous cannabinoids). See Nguyen et al. Med. Res. Rev. 2017, 37, 441 - 474.

[0093] The structures of Org27569 (known compound 1) and PSNCBAM-1 (known compound 2), which are negative allosteric modulators of CB1R studied previously, are shown below. See German et al., J. Med. Chem. 2014, 57, 7758 - 7769 and Nguyen et al., Bioorg. Med. Chem. 2015, 23, 2195 - 2203. Known compound 2 shows positive binding cooperativity with the cannabinoid receptor agonist CP55,940, which mimics the effects of THC, and in some functional assays, reduces the efficacy of the agonist and reduces food intake and body weight in rats. See Horswill et al., Br. J. Pharmacol. 2007, 152, 805 - 814.

[0094] The effort on structure - activity relationship (SAR) for PSNCBAM - 1 / known compound 2 indicates that the pyrrolidinyl ring is not necessary for CB1R modulating activity, and the pyridinyl ring can be replaced by a substituted phenyl ring such as RTICBM - 229 (known compound 5) or a 5 - membered heterocyclic ring, 35 S]being more potent than known compound 2 in the [S]GTPγS binding assay, 3 H]and also showing a higher maximum binding level in the [H]CP55,940 binding assay. See German et al., J. Med. Chem. 2014, 57, 7758 - 7769, Nguyen et al., J. Med. Chem. 2017, 60, 7410 - 7424, and Nguyen et al., ACS Chem. Neurosci. 2019, 10, 518 - 527.

Chemical Structure

Chemical Structure

[0095] In addition, through efforts to optimize the known compound 2 based on diarylurea, compound RTICBM-74 (known compound 4) was obtained. Known compound 4 attenuates the prime-induced restatement of cocaine seeking. RTICBM-28 (known compound 3) has the chloro group of the outer phenyl ring of known compound 2 replaced by cyano, reducing the potency of THC in drug discrimination and demonstrating the therapeutic potential of these CB1R allosteric modulators for the treatment of cocaine dependence (see Nguyen et al. J. Med. Chem. 2017, 60, 7410-7424) and relapse of THC dependence. See Gamage et al., Neuropharmacology 2017, 125, 365-375. Overall, the SAR of the outer phenyl ring showed that the 4-position is favorable for an electron-withdrawing functional group. See German et al. J. Med. Chem. 2014, 57, 7758-7769.

[0096] The subject matter of the present disclosure is based in part on further efforts to expand the understanding of the diarylurea-based scaffold of known compound 2 through structure optimization at the intermediate phenyl ring shown by previously studied compounds, and to expand the understanding of the aryl-alkylurea-based scaffold (RTICBM-189) of known compound 6. RTICBM-189 (6) has the central phenyl group of known compound 2 replaced by an ethylene group and attenuates the drug-induced restatement of cocaine seeking in rats at 10 mg / kg. See Nugyen et al., J. Med. Chem. 2022, 65, 257-270. The SAR of the central phenyl ring showed that an aromatic ring is not necessary and an alkyl linker is tolerated.

[0097] In the novel series of CB1 allosteric modulators of the present invention, the urea functional group is replaced by a squaramide moiety, a group that has not been well studied. This squaramide is connected to either an aliphatic (e.g., ethylene) or an aromatic group (e.g., phenyl) (right side of the figure). [Chemical formula]

[0098] By replacing the urea functional group with squaramide, a series with different chemical structures was obtained. These novel compounds have equivalent in vitro activity in calcium mobilization and 35 S]GTPγS binding assays (Tables 1 and 2). Compound 7 has better metabolic stability than PSNCBAM-1 (t 1 / 2 : 40 minutes vs. 13 minutes in rat liver microsomes), and demonstrated better in vivo efficacy at a low dose of 5.6 mg / kg (i.p.) without affecting locomotion (Figure 1B) in attenuating cocaine reinstatement behavior in rats (Figure 1A). In summary, this novel series of CB1 receptor allosteric modulators has promising properties in vitro and in vivo.

Chemical formula

[0099] Therefore, an alternative approach targeting the CB1 pathway with allosteric modulators is emerging as a promising strategy to modulate this therapeutically valuable CB1 receptor while avoiding the side effects of orthosteric ligands.

[0100] This disclosure describes the development of squaramide-based CB1 allosteric modulators. These are structurally different from the previously disclosed urea-based CB1 allosteric modulators. In particular, Compound 1 (Figure 1) showed better metabolic stability than PSNCBAM-1 / known Compound 2 in rat liver microsomes and was effective in attenuating cocaine reinstatement behavior at a low dose of 5.6 mg / kg (i.p.).

[0101] In some embodiments, the subject matter of this disclosure provides compounds having the structure of formula (I) or formula (II).

[0102] The compounds disclosed in this specification may include pharmaceutically acceptable salts. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable basic addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts, and combinations thereof.

[0103] Examples of acid addition salts include salts of inorganic acids and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate, hydroxynaphthoate, glycerophosphate, ketoglutaric acid, and the like.

[0104] Examples of basic addition salts include ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, phenetylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, and dicyclohexylamine, etc., but are not limited thereto.

[0105] Examples of metal salts include lithium, sodium, potassium, magnesium salts, etc. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc.

[0106] Furthermore, the compounds disclosed herein may have one or more polymorphic or amorphous crystalline forms and are intended to be included within the scope of the subject matter disclosed herein. In addition, some of the compounds of the subject matter of the present disclosure may form solvates with water (i.e., hydrates) or common organic solvents (e.g., tetrahydrofuran (THF), ethanol (EtOH), methanol (MeOH), etc.). Accordingly, solvates of the compounds of the present disclosure are also intended to be encompassed within the scope of the subject matter disclosed herein.

[0107] The compounds disclosed herein can be formulated according to routine procedures adapted to the desired route of administration. Accordingly, in some embodiments, the subject matter of the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed above (e.g., a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier. The therapeutically effective amount can be determined by testing the compound in in vitro or in vivo models and then extrapolating therefrom for the dosage in a subject, such as a human. The therapeutically effective amount should be sufficient to exert a therapeutically useful effect without undesirable side effects in the subject being treated with the composition.

[0108] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, phosphate buffer solutions of about 0.01 to about 0.1 M, preferably 0.05 M, or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents suitable for use in the subject matter of the present disclosure include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Examples of aqueous carriers suitable for use in the subject matter of the present disclosure include, but are not limited to, water, ethanol, alcohol / aqueous solutions, glycerol, emulsions, or suspensions containing saline and buffer media. Oral carriers can be elixirs, syrups, capsules, tablets, and the like.

[0109] Liquid carriers suitable for use in the subject matter of the present disclosure can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizing agents, emulsifying agents, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, or osmolality regulators.

[0110] Examples of liquid carriers suitable for use in the subject matter of the present disclosure include, but are not limited to, water (partially containing additives as described above, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid forms containing compounds for parenteral administration. The liquid carrier for the pressurized compounds disclosed herein can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0111] Suitable solid carriers for use in the subject matter of the present disclosure include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol, etc. The solid carrier can further contain one or more substances that act as flavoring agents, lubricants, solubilizing agents, suspending agents, fillers, flow promoters, compression aids, binders, or tablet disintegrants, which can also be encapsulating materials. In powders, the carrier can be a finely divided solid mixed with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the required compression properties in a suitable ratio and compressed into the desired shape and size. Powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

[0112] Suitable parenteral carriers for use in the subject matter of the present disclosure include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluids and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), etc. For example, preservatives and other additives such as antibacterial agents, antioxidants, chelating agents, inert gases, etc. may also be present.

[0113] Carriers suitable for use in the subject matter of the present disclosure can be mixed, if desired, with disintegrants, diluents, granulating agents, lubricants, binders, etc. using conventional techniques known in the art. The carrier can also be sterilized using methods that do not react detrimentally with the compound, as is generally known in the art. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. The compounds disclosed herein can also be formulated as preparations for implantation or injection. Thus, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a poorly soluble derivative (e.g., as a poorly soluble salt). Alternatively, the active ingredient can be in powder form for constitution, prior to use, with a suitable vehicle, such as sterile pyrogen-free water. Formulations suitable for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0114] For example, formulations for parenteral administration may contain, as common excipients, sterile water or physiological saline, polyalkylene glycols such as polyethylene glycol, plant-derived oils, hydrogenated naphthalene, etc. In particular, biocompatible biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be excipients useful for controlling the release of the active compound. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration may contain, as excipients, for example, lactose, or an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycolate, and deoxycholate, or an oily solution for administration in the form of a nasal drop or as a gel applied intranasally. Formulations for parenteral administration may also contain glycolate for oral administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

[0115] Furthermore, formulations for intravenous administration may contain a solution in a sterile isotonic aqueous buffer. Optionally, the formulation may also contain solubilizing agents and local anesthetics to relieve pain at the injection site. Generally, the components are supplied either separately or mixed together in unit dosage form as a dry lyophilized powder or a water-free concentrate in a sealed container such as an ampoule or sachet indicating the amount of the active agent. When the compound is administered by injection, it can be dispensed in a formulation in an injection bottle containing sterile pharmaceutical grade water, physiological saline, or dextrose / water. When the compound is administered by injection, an ampoule of sterile water for injection or physiological saline may be provided so that the components can be mixed prior to administration.

[0116] Suitable formulations may further include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, bactericidal antibiotics, and solutes that make the formulation isotonic with the body fluid of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.

[0117] This compound can be further formulated for topical administration. Suitable topical formulations include one or more compounds in the form of a liquid, lotion, cream, or gel. Topical administration can be achieved by direct application to the treatment area. For example, such application can be achieved by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by spray application of a liquid formulation to the treatment area.

[0118] In some formulations, the bioimplant material can be coated with this compound to improve the interaction between cells and the implant.

[0119] The formulation of this compound can contain a small amount of wetting agent or emulsifier, or a pH buffer. The formulation containing this compound can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained-release formulation, or powder.

[0120] This compound can be formulated as a suppository together with conventional binders and carriers such as triglycerides.

[0121] Oral formulations can contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate, etc.

[0122] In some embodiments, the pharmaceutical composition containing the compound of the subject matter of the present disclosure can contain an agent that controls the release of the compound, thereby providing a sustained-release or extended-release compound.

[0123] As described above, the CB1 and CB2 cannabinoid receptors belong to the G protein-coupled receptor (GCPR) family, a receptor superfamily having a unique pattern of seven transmembrane domains, and inhibit N-type calcium channels and / or adenylate cyclase to inhibit Q-type calcium channels. The CB1 receptor is present in the CNS and is mainly expressed in brain regions related to memory and movement, such as the hippocampus (memory storage), cerebellum (coordination of motor function, posture, and balance), basal ganglia (motor control), hypothalamus (body temperature regulation, neuroendocrine release, appetite), spinal cord (pain sensation), cerebral cortex (vomiting), and also in peripheral regions, such as lymphoid organs (cell-mediated and innate immunity), vascular smooth muscle cells (blood pressure), gastrointestinal tract (innate anti-inflammatory response in the gastrointestinal tract (e.g., in the esophagus, duodenum, jejunum, ileum, and colon), control of esophageal and gastrointestinal motility), lung smooth muscle cells (bronchodilation), and ciliary body of the eye (intraocular pressure). The CB2 receptor appears to be mainly peripherally expressed in lymphoid tissue (cell-mediated and innate immunity), peripheral nerve endings (peripheral nervous system), splenic immune cells (regulation of the immune system), and retina (intraocular pressure). CB2 mRNA is also found in the CNS in cerebellar granule cells (coordination of motor function).

[0124] Therefore, cannabinoid receptor allosteric modulators containing the compounds of the present disclosure are useful for the treatment, improvement, or prevention of cannabinoid receptor-mediated syndromes, disorders, or diseases, including but not limited to control of appetite, regulation of metabolism, diabetes, glaucoma-related intraocular pressure, pain, social and mood disorders, seizure-related disorders, substance use disorders, learning, cognitive, and / or memory disorders, intestinal disorders, respiratory disorders, motor activity disorders, movement disorders, immune disorders or inflammatory disorders, control of organ contraction and muscle spasm, enhancement of learning, cognition and / or memory, regulation of cell proliferation (e.g., treatment of cancer), provision of neuroprotection, etc.

[0125] Appetite-related syndromes, disorders, or diseases include obesity, overweight, anorexia, bulimia, cachexia, appetite regulation disorders, etc. Obesity-related syndromes, disorders, or diseases include obesity as a result of genetics, diet, food intake, metabolic syndrome, disorder, or disease, hypothalamic disorder or disease, age, decreased activity, abnormal distribution of fat mass, abnormal distribution of fat compartments, etc. Metabolic-related syndromes, disorders, or diseases include metabolic syndrome, dyslipidemia, elevated blood pressure, diabetes, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, inflammation, atherosclerosis, etc. Diabetes-related syndromes, disorders, or diseases include glucose regulation disorders, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, etc.

[0126] Type II diabetes (non-insulin-dependent diabetes mellitus (NIDDM)) is a metabolic disorder (i.e., a metabolic syndrome, disorder, or disease), and glucose regulation disorders and insulin resistance lead to chronic long-term medical complications that affect the eyes, kidneys, nerves, and blood vessels in both adolescents and adults, which can lead to blindness, end-stage renal disease, myocardial infarction, or limb amputation. Glucose regulation disorders include the inability to produce sufficient insulin (abnormal insulin secretion) and the inability to effectively use insulin (resistance to insulin action in target organs and tissues). Individuals with type II diabetes have relative insulin deficiency. That is, in such individuals, plasma insulin levels are lower than the levels predicted for the existing plasma glucose levels, but are normal to high in absolute value. Type II diabetes is characterized by the following clinical signs or symptoms: persistent elevation of plasma glucose concentration or hyperglycemia, polyuria, polydipsia, and / or polyphagia, chronic microvascular complications (e.g., retinopathy, nephropathy, and neuropathy), and macrovascular complications (e.g., hyperlipidemia and hypertension). These microvascular and macrovascular complications can lead to blindness, end-stage renal disease, limb amputation, and myocardial infarction. The insulin resistance syndrome (IRS) (also known as syndrome X, metabolic syndrome, or metabolic syndrome X) is a disorder that exhibits risk factors for the development of type II diabetes and cardiovascular disease, including glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL cholesterol, etc.), hypertension, and obesity.

[0127] Examples of social or mood-related syndromes, disorders, or diseases include depression, anxiety, psychosis, social-emotional disorders, or cognitive disorders. Examples of drug abuse-related syndromes, disorders, or diseases include drug abuse, drug withdrawal, alcohol abuse, alcohol withdrawal, nicotine withdrawal, cocaine abuse, cocaine withdrawal, heroin abuse, heroin withdrawal, etc. Examples of learning, cognitive, or memory-related syndromes, disorders, or diseases include memory loss or impairment as a result of age, disease, side effects of drugs (adverse events), etc.

[0128] Examples of muscle spasm syndromes, disorders, or diseases include multiple sclerosis, cerebral palsy, etc. Examples of motor activity and movement syndromes, disorders, or diseases include stroke, Parkinson's disease, multiple sclerosis, epilepsy, etc. Examples of intestine-related syndromes, disorders, or diseases include disorders related to intestinal motility disorders (with or without pain, diarrhea, or constipation), irritable bowel syndrome (and other forms of intestinal motility disorders, etc.), inflammatory bowel diseases (ulcerative colitis, Crohn's disease, etc.), and celiac disease. Examples of respiration-related syndromes, disorders, or diseases include chronic obstructive pulmonary disease, emphysema, asthma, bronchitis, etc. Examples of immune or inflammation-related syndromes, disorders, or diseases include allergies, rheumatoid arthritis, dermatitis, autoimmune diseases, immunodeficiency, chronic neuropathic pain, etc.

[0129] Examples of cell proliferation-related syndromes, disorders, or diseases include cancers, such as endometrial cancer, hepatocellular cancer, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, and renal cell cancer, etc., but are not limited thereto. Examples of pain-related syndromes, disorders, or diseases include pain mediated by central and peripheral pathways, bone and joint pain, migraine-related pain, cancer pain, menstrual pain, labor pain, etc. Examples of neurodegeneration-related syndromes, disorders, or diseases include Parkinson's disease, multiple sclerosis, epilepsy, ischemia, or secondary biochemical damage associated with traumatic head or brain injury, encephalitis, eye injury, or stroke, etc.

[0130] Based on the antagonistic activity, the compounds of the present disclosure are useful for the prevention and / or treatment of CB1 receptor-mediated diseases such as psychoses including schizophrenia, anxiety disorders, stress, depression, epilepsy, neurodegenerative diseases, spinocerebellar disorders, cognitive disorders, traumatic brain injury, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremors, obsessive-compulsive disorder (OCD), amnesia, senile dementia, thymus disorders, Tourette syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced dyskinesia, dystonia, septic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, eating disorders such as hyperphagia anorexia, anorexia, obesity, non-insulin-dependent diabetes mellitus (NIDDM), memory disorders, urinary disorders, cardiovascular disorders, infertility disorders, infections, demyelination-related diseases, neuroinflammation, viral encephalitis, cerebrovascular incidents, gastrointestinal disorders including cirrhosis or intestinal passage disorders, etc. Additionally, the compounds disclosed herein can be used as agents for the treatment of substance dependence. For example, in some embodiments, the compounds of the present disclosure can be used to treat chronic treatment, alcohol dependence, or drug abuse (e.g., opioids, barbiturates, marijuana, cocaine, heroin, amphetamines, fenciclovir, hallucinogens, benzodiazepine compounds, etc.). Furthermore, the compounds of the present disclosure can be useful as agents for enhancing analgesic activity such as analgesics or narcotics, or as agents for smoking cessation (quitting smoking or withdrawal from nicotine dependence).

[0131] Accordingly, in some embodiments, the subject matter of the present disclosure provides a method of treating a subject in need of treatment for a CB1R-mediated disease or condition, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0132] With respect to the methods of the subject matter of the present disclosure, a preferred subject is a vertebrate subject. Preferred vertebrates are warm-blooded animals, and preferred warm-blooded animals are mammals. The subject treated by the methods of the present disclosure is desirably a human, but it should be understood that the principles of the subject matter of the present disclosure demonstrate effectiveness for all vertebrate species included in the term "subject". In this context, a vertebrate is understood to be any vertebrate species for which treatment of a CB1R-mediated condition is desirable. As used herein, the term "subject" includes both human subjects and animal subjects. Accordingly, veterinary therapeutic uses are provided in accordance with the subject matter of the present disclosure.

[0133] Thus, the subject matter of the present disclosure provides treatment for mammals such as humans, as well as for critically endangered mammals such as the Siberian tiger, economically important mammals such as animals raised on farms for human consumption, and / or socially important animals for humans such as animals kept as pets or in zoos. Examples of such animals include carnivores such as cats and dogs, swine including pigs, hogs, and wild boars, ruminants and / or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels, and horses. Also provided is treatment of birds, including birds in zoos that are critically endangered and / or captive, and more specifically, treatment of poultry, i.e., domestic fowl such as turkeys, chickens, ducks, geese, and guinea fowl, which are also economically important for humans. Accordingly, treatment of livestock is provided, including but not limited to domestic swine, ruminants, ungulates, horses (including racehorses), poultry, etc. In some embodiments, the subject is a human.

[0134] In some embodiments, the CB1R-mediated disease or condition is drug addiction (e.g., alcohol, tobacco, or other substance addiction), obesity, cancer (e.g., endometrial cancer, hepatocellular cancer, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, renal cell cancer, or desmoplastic small round cell tumor), pain (e.g., chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain), female infertility, memory loss, cognitive dysfunction, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette syndrome, stroke, atherosclerosis, hypotension, hypomotility of the intestine in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders, and is selected from the group consisting of, but not limited to, these.

[0135] Treatment of anxiety can include, for example, but is not limited to, treatment of anxiety disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, social phobia, agoraphobia, or other more specific phobias. Eating disorders include, but are not limited to, anorexia, polyphagia, and binge eating. Mood disorders include, but are not limited to, bipolar disorder, major depressive disorder, and postpartum depression. Cognitive dysfunction includes, for example, disorders such as dementia, attention deficit hyperactivity disorder (ADHD), autism and autism spectrum disorder (ASD), Down syndrome, traumatic brain injury (TBI), and dyslexia. Alcoholism and drug abuse-related disorders can include abuse and / or addiction to alcohol, nicotine, or other drugs (e.g., opium, cannabinoids, inhalants, and stimulants such as cocaine, amphetamine, and methamphetamine).

[0136] More specifically, diseases or conditions in which inhibition of biological activity in CB1R or signal transduction via CB1R is desirable include, but are not limited to, obesity, alcohol dependence, and other drug abuse and / or dependence-related disorders. Thus, in some embodiments, the subject matter of the present disclosure provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is a human.

[0137] As a further example, as exemplified herein, the CB1R allosteric modulators of the present disclosure can be applied to the treatment of drug use, abuse, and / or dependence (including drug, alcohol, and nicotine dependence), addictive behaviors, and symptoms and conditions associated with drug abuse and dependence. In some embodiments, the dependence is on at least one of nicotine, ethanol, cocaine, opioid, amphetamine, marijuana, or synthetic cannabinoid agonist.

[0138] Dependence on drugs such as alcohol, heroin, cannabinoids, nicotine, marijuana, and stimulants is typically associated with many harmful or negative behaviors exhibited by the dependent person, which behaviors can exacerbate, prolong, or induce relapse to drug use or abuse, strengthen or worsen the dependence, or induce relapse to dependence and addictive behavior patterns. Other examples of negative behaviors associated with drug use or intoxication include anxiety, discomfort, stress reactivity, and cue reactivity. One particular problem with alcohol dependence, like common drug dependence, is the chronic relapsing nature of this disorder. This behavior pattern can be effectively modeled in rodents, and many studies have demonstrated the ability to reinstate drug-seeking behavior after extinction, even without subsequent drug reward, by drug priming, psychological stress, or re-presentation of cues previously associated with drug availability.

[0139] In some embodiments, the subject matter of the present disclosure provides a method for preventing or inhibiting drug abuse and / or addiction, addictive behavior, or symptoms, behaviors, or conditions associated with drug abuse and / or addiction, and administering to a subject in need thereof an effective amount of a CB1R allosteric modulator compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable composition comprising such a compound. In some embodiments, the subject is a human.

[0140] In some embodiments, behaviors associated with drug abuse and / or intoxication include drug use (i.e., self - administration) and / or drug - seeking behavior. In some embodiments, drug abuse and / or addiction includes alcohol abuse and / or addiction (i.e., alcoholism). In some embodiments, drug abuse and / or addiction includes nicotine abuse and / or addiction. In some embodiments, drug abuse and / or addiction includes opioid abuse and / or addiction. In some embodiments, behaviors associated with drug abuse or addiction are relapsing.

[0141] The effective amount of the compounds disclosed herein includes an amount sufficient to produce a significant effect, such as, but not limited to, a decrease or cessation of self - administration of alcohol or another drug of abuse, weight loss, absence of weight gain. The actual dosage level of the active ingredient in the therapeutic compounds of the present disclosure can vary to administer an amount of the active compound that is effective to achieve the desired therapeutic response for a particular subject and / or use. Preferably, the minimum dosage is administered and the dosage is incrementally increased to the minimum effective amount in the absence of dose - limiting toxicity. Determination and adjustment of therapeutically effective dosages, and evaluation of when and how to make such adjustments are known to those of ordinary skill in the art.

[0142] The therapeutically effective amount of the compound can depend on several factors. For example, the species, age, and weight of the subject, the exact condition and its severity that requires treatment, the nature of the formulation, and the route of administration are all factors that can be considered. In some embodiments, the therapeutically effective amount is in the range of about 0.1 to about 100 mg / kg of the subject's body weight per day. In some embodiments, the therapeutically effective amount is in the range of about 0.1 to about 20 mg / kg of body weight per day. Thus, for a 70 kg adult mammal, an example of the actual amount per day is about 10 to about 2000 mg. This amount can be administered as a single dose per day or as multiple (e.g., 2, 3, 4, or 5) divided doses per day such that the total daily dose is the same. The effective amount of the salt or its solvate can be determined as a proportion of the effective amount of the compound itself.

[0143] The compounds of the subject matter of the present disclosure can also be useful as adjuvant, add-on, or complementary therapies for the treatment of the above-mentioned diseases / disorders. Such adjuvant, add-on, or complementary therapies mean administering the compounds of the subject matter of the present disclosure simultaneously or sequentially to a subject who has already received administration, is receiving administration, or will receive administration of one or more additional therapeutic agents (e.g., one or more known antidepressants, antipsychotics, or anxiolytics) for the treatment of the indicated condition.

[0144] In some embodiments, the subject matter of the present disclosure provides the compounds of the present disclosure for use as an active therapeutic substance. In some embodiments, the compound is for use in the treatment of CB1R-mediated diseases. In some embodiments, the subject matter of the present disclosure provides the use of the compounds of the present disclosure for the preparation of a medicament for the treatment of CB1R-mediated diseases.

[0145] In some embodiments, the subject matter of the present disclosure provides a method of modulating the activity of CB1R, the method comprising contacting a sample comprising CB1R with a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the sample is an ex vivo sample. In some embodiments, the sample comprises a biological fluid, such as plasma, cerebrospinal fluid, saliva. In some embodiments, the sample comprises an organ, tissue, cell, or cell extract. In some embodiments, the sample is a sample from a subject. In some embodiments, the method may further comprise contacting the sample with a second compound, such as a compound having or suspected of having CB1R agonist or antagonist activity.

[0146] The antagonists of the present disclosure can be prepared using standard synthetic methods known in the art. For example, the compounds can be made by the methods described herein below or modifications thereof that will be apparent to those skilled in the art based on the present disclosure. Protecting groups known in the art can be utilized during the synthesis of the compounds as needed.

[0147] Synthetic Schemes and Examples

Chemical formula

[0148] General Procedure (GP): A solution of 2 (1 equivalent) in ethanol (0.15 M), the corresponding amine (1.2 equivalents), and triethylamine (1.1 equivalents) was refluxed for 24 h. After cooling to room temperature, the precipitate was filtered and dried to obtain the desired product.

[0149] 3-[(4-Chlorophenyl)amino]-4-ethoxycyclobut-3-ene-1,2-dione (8): A solution of 4-chloroaniline (0.38 g, 3 mmol) in ethanol was added dropwise to a refluxing solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (0.53 mL, 3.6 mmol) in ethanol. The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered, and the white solid precipitate was washed with ice-cold ethanol and recovered as the desired product (0.39 g, 51%). 1 H NMR (300 MHz, CHCl3) δ 7.32 - 7.37 (m, 2H), 7.27 - 7.30 (m, 2H), 4.89 (q, J = 7.16 Hz, 2H), 1.52 (t, J = 7.16 Hz, 3H). MS (ESI) [M+H] + m / z = 252.2.

[0150] In a similar manner to 8, 3-[(4-cyanophenyl)amino]-4-ethoxycyclobut-3-ene-1,2-dione (9) was prepared as a white solid (1.5 g, 75%) from 3,4-diethoxy-3-cyclobutene-1,2-dione (1.5 mL, 10.2 mmol) and 4-cyanoaniline (1 g, 8.5 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.82 (d, J = 8.67 Hz, 2H), 7.56 (d, J = 8.85 Hz, 2H), 4.79 (q, J = 6.97 Hz, 2H), 1.43 (t, J = 7.06 Hz, 3H). MS (ESI) [M+H] + m / z = 243.2.

[0151] According to GP, 3-(benzylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (10) was prepared as a white solid (0.09 g, 90% yield) from 8 (0.08 g, 0.3 mmol) and benzylamine (0.04 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.73 (br.s., 1H), 8.02 (br.s., 1H), 7.28 - 7.49 (m, 9H), 4.81 (s, 2H). MS (ESI) [M+H] + m / z = 313.2.

[0152] According to GP, 3-[(4-chlorophenyl)amino]-4-[(2-phenylethyl)amino]cyclobut-3-ene-1,2-dione (11) was prepared as a white solid (0.09 g, yield 92%) from 8 (0.08 g, 0.3 mmol) and phenethylamine (0.045 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.73 (br.s., 1H), 7.65 (br.s., 1H), 7.19 - 7.47 (m, 9H), 3.86 (d, J = 5.46 Hz, 2H), 2.90 (t, J = 5.84 Hz, 2H). MS(ESI) [M+H] + m / z = 327.2

[0153] According to GP, 3-[(4-chlorophenyl)amino]-4-[(3-phenylpropyl)amino]cyclobut-3-ene-1,2-dione (12) was prepared as a white solid (0.10 g, yield 93%) from 8 (0.08 g, 0.3 mmol) and 3-phenylpropylamine (0.051 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.70 (br.s., 1H), 7.69 (br.s., 1H), 7.41 (q, J = 8.92 Hz, 4H), 7.14 - 7.33 (m, 5H), 3.63 (q, J = 5.97 Hz, 2H), 2.61 - 2.70 (m, 2H), 1.82 - 1.96 (m, 2H). MS(ESI) [M+H] + m / z = 341.2.

[0154] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (13) was prepared as a white solid (0.09 g, yield 86%) from 8 (0.08 g, 0.3 mmol) and 4-chlorophenethylamine (0.05 mL, 0.36 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.71 (br.s., 1H), 7.62 (br.s., 1H), 7.24 - 7.50 (m, 9H), 3.84 (d, J = 4.52 Hz, 2H), 2.89 (t, J = 5.18 Hz, 2H). MS (ESI) [M+H] + m / z = 361.2.

[0155] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (14) was prepared as a white solid (0.09 g, yield 83%) from 8 (0.08 g, 0.3 mmol) and 3-methylphenethylamine (0.051 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.74 (br.s., 1H), 7.64 (br.s., 1H), 7.30 - 7.50 (m, 4H), 7.15 - 7.25 (m, 1H), 7.07 (d, J = 8.85 Hz, 3H), 3.84 (d, J = 5.09 Hz, 2H), 2.85 (t, J = 6.50 Hz, 2H), 2.28 (s, 3H). MS (ESI) [M+H] + m / z = 341.2.

[0156] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (15) was prepared as a white solid (0.09 g, yield 83%) from 8 (0.08 g, 0.3 mmol) and 4-methylphenethylamine (0.051 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.73 (br.s., 1H), 7.62 (br.s., 1H), 7.30 - 7.49 (m, 4H), 7.05 - 7.23 (m, 4H), 3.83 (d, J = 6.03 Hz, 2H), 2.85 (t, J = 6.59 Hz, 2H), 2.27 (s, 3H). MS (ESI) [M+H] + m / z = 341.2.

[0157] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(2-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (16) was prepared as a white solid (0.08 g, yield 75%) from 8 (0.08 g, 0.3 mmol) and 4-methylphenethylamine (0.054 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (br.s., 1H), 7.62 (br.s., 1H), 7.33 - 7.47 (m, 4H), 7.14 - 7.26 (m, 2H), 6.97 (d, J = 8.10 Hz, 1H), 6.85 - 6.92 (m, 1H), 3.81 (d, J = 5.27 Hz, 2H), 3.77 (s, 3H), 2.86 (t, J = 6.78 Hz, 2H). MS(ESI) [M + H] + m / z = 357.2.

[0158] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (17) was prepared as a white solid (0.08 g, yield 75%) from 8 (0.08 g, 0.3 mmol) and 3-methoxyphenethylamine (0.054 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.60 (br.s., 1H), 7.64 (br.s., 1H), 7.33 - 7.46 (m, 4H), 7.23 (t, J = 7.91 Hz, 1H), 6.76 - 6.88 (m, 3H), 3.86 (t, J = 6.12 Hz, 2H), 3.73 (s, 3H), 2.87 (t, J = 6.88 Hz, 2H). MS(ESI) [M + H] + m / z = 357.2.

[0159] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (18) was prepared as a white solid (0.08 g, yield 84%) from 8 (0.08 g, 0.3 mmol) and 3-methoxyphenethylamine (0.053 mL, 0.36 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.70 (br.s., 1H), 7.64 (br.s., 1H), 7.34 - 7.46 (m, 4H), 7.18 (d, J = 8.10 Hz, 2H), 6.88 (d, J = 7.72 Hz, 2H), 3.77 - 3.87 (m, 2H), 3.72 (s, 3H), 2.83 (t, J = 6.50 Hz, 2H). MS (ESI) [M+H] + m / z = 357.2.

[0160] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[2-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (19) was prepared as a white solid (0.09 g, yield 76%) from 8 (0.08 g, 0.3 mmol) and 2-(trifluoromethyl)phenethylamine (0.053 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.71 (br.s., 1H), 7.67 - 7.78 (m, 2H), 7.65 (d, J = 7.35 Hz, 1H), 7.52 - 7.59 (m, 1H), 7.45 - 7.50 (m, 1H), 7.34 - 7.42 (m, 4H), 3.88 (d, J = 6.03 Hz, 2H), 3.08 (t, J = 6.88 Hz, 2H). MS (ESI) [M+H] + m / z = 395.2.

[0161] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (20) was prepared as a white solid (0.095 g, yield 81%) from 8 (0.08 g, 0.3 mmol) and 3-(trifluoromethyl)phenethylamine (0.057 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.72 (br.s., 1H), 7.64 (s, 2H), 7.58 (br.s., 3H), 7.33 - 7.42 (m, 4H), 3.88 (d, J = 5.46 Hz, 2H), 3.01 (t, J = 6.88 Hz, 2H). MS (ESI) [M+H] + m / z = 395.2.

[0162] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[4-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (21) was prepared as a white solid (0.09 g, yield 76%) from 8 (0.08 g, 0.3 mmol) and 4-(trifluoromethyl)phenethylamine (0.057 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.73 (br.s., 1H), 7.69 (d, J = 8.10 Hz, 2H), 7.64 (br.s., 1H), 7.51 (d, J = 7.91 Hz, 2H), 7.33 - 7.44 (m, 4H), 3.89 (d, J = 5.65 Hz, 2H), 3.00 (t, J = 6.78 Hz, 2H). MS(ESI)[M+H] + m / z = 395.2.

[0163] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (22) was prepared as a white solid (0.09 g, yield 87%) from 8 (0.08 g, 0.3 mmol) and 4-fluorophenethylamine (0.057 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (br.s., 1H), 7.63 (br.s., 1H), 7.35 - 7.45 (m, 4H), 7.30 (dd, J = 5.75, 8.38 Hz, 2H), 7.10 - 7.19 (m, 2H), 3.83 (t, J = 6.12 Hz, 2H), 2.89 (t, J = 6.97 Hz, 2H). MS(ESI)[M+H] + m / z = 345.2.

[0164] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(2-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (23) was prepared as a white solid (0.10 g, yield 93%) from 8 (0.08 g, 0.3 mmol) and 2-chlorophenethylamine (0.05 mL, 0.36 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.49 (br.s., 1H), 7.69 (br.s., 1H), 7.23 - 7.54 (m, 8H), 3.74 - 4.04 (m, 2H), 2.90 - 3.13 (m, 2H). MS (ESI) [M+H] + m / z = 361.2.

[0165] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (7) was prepared as a white solid (0.10 g, yield 93%) from 8 (0.08 g, 0.3 mmol) and 3-chlorophenethylamine (0.05 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.72 (br.s., 1H), 7.63 (br.s., 1H), 7.27 - 7.45 (m, 7H), 7.23 (d, J = 7.16 Hz, 1H), 3.86 (d, J = 4.52 Hz, 2H), 2.91 (t, J = 6.78 Hz, 2H). MS (ESI) [M+H] + m / z = 361.2.

[0166] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(2-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (24) was prepared as a white solid (0.09 g, yield 90%) from 8 (0.08 g, 0.3 mmol) and 2-fluorophenethylamine (0.047 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.70 (br.s., 1H), 7.66 (br.s., 1H), 7.24 - 7.45 (m, 6H), 7.11 - 7.21 (m, 2H), 3.85 (d, J = 5.84 Hz, 2H), 2.94 (t, J = 6.59 Hz, 2H). MS (ESI) [M+H] + m / z = 345.2.

[0167] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (25) was prepared as a white solid (0.09 g, yield 90%) from 8 (0.08 g, 0.3 mmol) and 3-fluorophenethylamine (0.047 mL, 0.36 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.69 (br.s., 1H), 7.64 (br.s., 1H), 7.34 - 7.43 (m, 5H), 7.07 - 7.17 (m, 2H), 7.01 - 7.07 (m, 1H), 3.80 - 3.92 (m, 2H), 2.92 (t, J = 6.88 Hz, 2H). MS (ESI) [M+H] + m / z = 345.2.

[0168] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[3-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (26) was prepared as a white solid (0.075 g, yield 58%) from 8 (0.09 g, 0.35 mmol) and 3-(dimethylamino)phenethylamine (0.085 g, 0.42 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 9.79 (br.s., 1H), 7.64 (br.s., 1H), 7.36 - 7.45 (m, 4H), 7.07 - 7.16 (m, 1H), 6.48 - 6.71 (m, 3H), 3.85 (d, J = 6.22 Hz, 2H), 2.86 (s, 6H), 2.78 - 2.85 (m, 2H). MS (ESI) [M+H] + m / z = 370.4.

[0169] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[4-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (27) was prepared as a white solid (0.057 g, yield 40%) from 8 (0.097 g, 0.38 mmol) and 4-(dimethylamino)phenethylamine (0.093 g, 0.46 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.75 (br.s., 1H), 7.61 (br.s., 1H), 7.33 - 7.46 (m, 4H), 7.07 (d, J = 8.48 Hz, 2H), 6.69 (d, J = 8.29 Hz, 2H), 3.79 (d, J = 5.84 Hz, 2H), 2.85 (s, 5H), 2.77 (t, J = 6.78 Hz, 2H). MS (ESI) [M+H] + m / z = 370.4.

[0170] According to GP, 4-[(2-{[2-(3-chlorophenyl)ethyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzonitrile (28) was prepared as a white solid (0.084 g, yield 80%) from 9 (0.072 g, 0.3 mmol) and 3-chloroaniline (0.05 mL, 0.36 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 10.01 (br.s., 1H), 7.77 (d, J = 8.67 Hz, 3H), 7.55 (d, J = 8.48 Hz, 2H), 7.27 - 7.40 (m, 3H), 7.24 (d, J = 6.97 Hz, 1H), 3.81 - 3.93 (m, J = 6.03 Hz, 2H), 2.92 (t, J = 6.88 Hz, 2H). MS (ESI) [M+H] + m / z = 352.2.

[0171] According to GP, 3-(biphenyl-3-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (29) was prepared as a white solid (0.06 g, yield 75%) from 8 (0.053 g, 0.21 mmol) and 3-aminobiphenyl (0.043 g, 0.25 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.70 (d, J = 7.54 Hz, 2H), 7.33 - 7.54 (m, 12H). MS (ESI) [M+H] + m / z = 375.2.

[0172] According to GP, 3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-phenyl}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (30) was prepared as a white solid (0.105 g, yield 81%) from 8 (0.073 g, 0.29 mmol) and 3-[6-(pyrrolidin-1-yl)pyridin-2-yl]aniline (0.084 g, 0.35 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.75 (d, J = 6.78 Hz, 1H), 7.40 - 7.61 (m, 7H), 7.13 (d, J = 7.35 Hz, 1H), 6.43 (d, J = 8.48 Hz, 1H), 1.96 (t, J = 6.40 Hz, 4H). MS (ESI) [M+H] + m / z = 455.2.

[0173] According to GP, 3-[(4-chlorophenyl)amino]-4-{[3-(1,3-thiazol-4-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (31) was prepared as a white solid (0.105 g, yield 72%) from 8 (0.049 g, 0.19 mmol) and 3-(1,3-thiazol-4-yl)aniline (0.034 g, 0.19 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.92 - 10.09 (m, 2H), 9.22 (d, J = 1.70 Hz, 1H), 8.03 - 8.17 (m, 2H), 7.71 (d, J = 7.35 Hz, 1H), 7.38 - 7.56 (m, 7H). MS (ESI) [M+H] + m / z = 382.2.

[0174] According to GP, 3-[(4-chlorophenyl)amino]-4-{[3-(thiophen-3-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (32) was prepared as a white solid (0.06 g, yield 80%) from 8 (0.05 g, 0.2 mmol) and 3-(thiophen-3-yl)aniline (0.034 g, 0.2 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.99 (d, J = 4.90 Hz, 2H), 7.86 - 7.93 (m, 2H), 7.68 (dd, J = 3.01, 4.90 Hz, 1H), 7.56 (d, J = 4.90 Hz, 1H), 7.49 - 7.54 (m, 2H), 7.40 - 7.48 (m, 4H), 7.31 (d, J = 7.35 Hz, 1H). MS (ESI) [M + H] + m / z = 381.2.

[0175] According to GP, 3-[(4-chlorophenyl)amino]-4-[(4'-fluorobiphenyl-3-yl)amino]cyclobut-3-ene-1,2-dione (33) was prepared as a white solid (0.07 g, yield 73%) from 8 (0.07 g, 0.28 mmol) and 4'-fluorobiphenyl-3-amine (0.05 g, 0.28 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.99 (s, 2H), 7.83 (s, 1H), 7.69 - 7.78 (m, 2H), 7.42 - 7.53 (m, 5H), 7.28 - 7.41 (m, 4H). MS (ESI) [M - H] - m / z = 391.2.

[0176] According to GP, 3-(biphenyl-4-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (34) was prepared as a white solid (0.024 g, yield 40%) from 8 (0.04 g, 0.16 mmol) and biphenyl-4-amine (0.03 g, 0.16 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 10.03 (br.s., 2H), 7.65 - 7.73 (m, 4H), 7.58 (d, J = 8.67 Hz, 2H), 7.42 - 7.54 (m, 6H), 7.31 - 7.38 (m, 1H). MS (ESI) [M - H] - m / z = 373.2.

[0177] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(2-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (35) was prepared as a white solid (0.030 g, yield 44%) from 8 (0.05 g, 0.20 mmol) and 2-methylphenethylamine hydrochloride (0.029 g, 0.20 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (br.s., 1H), 7.65 (br.s., 1H), 7.30 - 7.41 (m, 4H), 7.04 - 7.18 (m, 4H), 3.73 - 3.81 (m, 1H), 2.85 (t, J = 7.18 Hz, 2H), 2.27 (s, 3H). MS(ESI) [M + H] + m / z = 341.0.

[0178] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(pyridin-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (36) was prepared as a white solid (0.060 g, yield 92%) from 8 (0.05 g, 0.20 mmol) and 2-(2-pyridyl)ethylamine (0.029 g, 0.20 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (br.s., 1H), 8.49 (d, J = 4.13 Hz, 1H), 7.67 - 7.74 (m, 1H), 7.65 (br.s., 1H), 7.26 - 7.40 (m, 5H), 7.19 - 7.24 (m, 1H), 3.93 - 4.02 (m, 1H), 3.04 (t, J = 6.72 Hz, 2H). MS(ESI) [M + H] + m / z = 328.0.

[0179] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(pyridin-4-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (37) was prepared as a white solid (0.060 g, yield 92%) from 8 (0.05 g, 0.20 mmol) and 2-(4-pyridyl)ethylamine (0.029 g, 0.20 mmol). 11H NMR (400 MHz, DMSO-d6) δ 9.69 (br.s., 1H), 8.46 (d, J = 5.20 Hz, 2H), 7.59 (br.s., 1H), 7.29 - 7.44 (m, 4H), 7.27 (d, J = 5.35 Hz, 2H), 3.86 (m, 2H), 2.89 (t, J = 6.80 Hz, 2H). MS (ESI) [M+H] + m / z = 328.0.

[0180] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-bromophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (38) was prepared as a white solid (0.062 g, yield 77%) from 8 (0.05 g, 0.20 mmol) and 4-bromophenethylamine hydrochloride (0.048 g, 0.20 mmol). 1 1H NMR (400 MHz, DMSO-d6) δ 9.69 (br.s., 1H), 7.57 (br.s., 1H), 7.48 (d, J = 7.95 Hz, 2H), 7.30 - 7.40 (m, 3H), 7.20 (d, J = 8.10 Hz, 2H), 3.80 (d, J = 6.42 Hz, 2H), 2.83 (t, J = 6.80 Hz, 2H). MS (ESI) [M+H] + m / z = 405.0.

[0181] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(thiophen-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (39) was prepared as a white solid (0.058 g, yield 88%) from 8 (0.05 g, 0.20 mmol) and 2-(2-aminoethyl)thiophene (0.030 g, 0.20 mmol). 1 1H NMR (400 MHz, DMSO-d6) δ 9.75 (br.s., 1H), 7.66 (br.s., 1H), 7.31 - 7.41 (m, 5H), 6.93 - 6.97 (m, 1H), 6.89 - 6.92 (m, 1H), 3.83 (m, 2H), 3.08 (t, J = 6.65 Hz, 2H). MS (ESI) [M+H] + m / z = 333.0.

[0182] According to GP, 3-{[2-(A-acetylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (40) was prepared as a white solid (0.060 g, yield 82%) from 8 (0.05 g, 0.20 mmol) and 1-[4-(2-aminoethyl)phenyl]ethanone hydrochloride (0.048 g, 0.20 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (br.s., 1H), 7.88 (d, J = 7.64 Hz, 2H), 7.63 (br.s., 1H), 7.30 - 7.42 (m, 6H), 3.85 (d, J = 5.96 Hz, 2H), 2.95 (t, J = 6.72 Hz, 2H), 2.52 (s, 3H). MS (ESI) [M + H] + m / z = 369.0.

[0183] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (41) was prepared as a white solid (0.060 g, yield 76%) from 8 (0.05 g, 0.20 mmol) and 3,4-dichlorophenethylamine (0.045 g, 0.20 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (br.s., 1H), 7.54 (br.s., 3H), 7.30 - 7.40 (m, 4H), 7.23 (d, J = 7.95 Hz, 1H), 3.81 (m, 2H), 2.87 (t, J = 6.57 Hz, 2H). MS (ESI) [M - H] - m / z = 395.0.

[0184] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3,4-dimethylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (42) was prepared as a white solid (0.064 g, yield 91%) from 8 (0.05 g, 0.20 mmol) and 3,4-dimethylphenethylamine (0.036 g, 0.20 mmol). 11H NMR (400 MHz, DMSO-d6) δ 9.68 (br.s., 1H), 7.57 (br.s., 1H), 7.29 - 7.41 (m, 4H), 6.98 - 7.08 (m, 2H), 6.93 (d, J = 7.03 Hz, 1H), 3.78 (br.s., 2H), 2.77 (t, J = 6.88 Hz, 2H), 2.14 (d, J = 3.67 Hz, 6H). MS (ESI) [M+H] + m / z = 355.0.

[0185] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(3-hydroxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (43) was prepared as a white solid (0.065 g, yield 95%) from 8 (0.05 g, 0.20 mmol) and 3-hydroxyphenethylamine hydrochloride (0.041 g, 0.20 mmol). 1 1H NMR (400 MHz, DMSO-d6) δ 9.72 (br.s., 1H), 9.30 (s, 1H), 7.59 (br.s., 1H), 7.30 - 7.40 (m, 4H), 7.07 (t, J = 7.64 Hz, 1H), 6.61 - 6.67 (m, 2H), 6.58 (d, J = 8.10 Hz, 1H), 3.78 (d, J = 6.11 Hz, 2H), 2.76 (t, J = 6.88 Hz, 2H). MS (ESI) [M-H] - m / z = 342.0.

[0186] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(2,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (44) was prepared as a white solid (0.065 g, yield 83%) from 8 (0.05 g, 0.20 mmol) and 2,4-dichlorophenethylamine (0.045 g, 0.20 mmol). 1 1H NMR (400 MHz, DMSO-d6) δ 9.67 (br.s., 1H), 7.55 - 7.65 (m, 2H), 7.30 - 7.40 (m, 6H), 3.81 (d, J = 6.11 Hz, 2H), 2.98 (t, J = 6.57 Hz, 2H). MS (ESI) [M-H] - m / z = 395.0

[0187] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(piperidin-1-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (45) was prepared as a white solid (0.040 g, yield 60%) from 8 (0.05 g, 0.20 mmol) and 1-(2-aminoethyl)piperidine (0.031 g, 0.20 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (br.s., 1H), 7.56 (br.s., 1H), 7.38 - 7.44 (m, 2H), 7.31 - 7.37 (m, 2H), 3.67 (br.s., 2H), 2.42 (t, J = 5.96 Hz, 2H), 2.34 (br.s., 4H), 1.41 - 1.50 (m, 4H), 1.35 (d, J = 4.74 Hz, 2H). MS (ESI) [M + H] + m / z = 334.0.

[0188] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}amino)cyclobut-3-ene-1,2-dione (46) was prepared as a white solid (0.077 g, yield 96%) from 8 (0.05 g, 0.20 mmol) and 1-(4-chlorophenyl)piperazine (0.047 g, 0.20 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.31 - 7.36 (m, 2H), 7.17 - 7.26 (m, 4H), 6.98 (d, J = 9.02 Hz, 2H), 3.85 (br.s., 4H), 3.23 - 3.29 (m, 4H). MS (ESI) [M - H] - m / z = 401.0.

[0189] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(2,4-difluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (47) was prepared as a white solid (0.030 g, yield 42%) from 8 (0.05 g, 0.20 mmol) and 2,4-difluorophenethylamine (0.045 g, 0.20 mmol). 11H NMR (400 MHz, DMSO-d6) δ 9.69 (br.s., 1H), 7.59 (br.s., 1H), 7.24 - 7.44 (m, 7H), 7.07 (br.s., 1H), 3.74 - 3.87 (m, 2H), 2.81 - 2.90 (m, 2H). MS (ESI) [M+H] + m / z = 363.0.

[0190] According to GP, 3-[(4-chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (48) was prepared as a white solid (0.034 g, yield 43%) from 8 (0.05 g, 0.20 mmol) and 4-(N,N-diethylamino)phenethylamine (0.045 g, 0.20 mmol). 1 1H NMR (400 MHz, DMSO-d6) δ 9.73 (br.s., 1H), 7.58 (br.s., 1H), 7.30 - 7.38 (m, 4H), 7.00 (d, J = 7.64 Hz, 2H), 6.57 (d, J = 7.95 Hz, 2H), 3.74 (d, J = 6.72 Hz, 2H), 3.19 - 3.26 (m, 4H), 2.70 (t, J = 6.80 Hz, 2H), 1.01 (t, J = 6.88 Hz, 6H). MS (ESI) [M+H] + m / z = 398.2.

[0191] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-piperidin-1-ylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (49) was prepared as a white solid (0.05 g, yield 19%) from 8 (0.154 g, 0.61 mmol) and 2-(4-piperidin-1-ylphenyl)ethylamine (0.15 g, 0.73 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.74 (br.s., 1H), 7.61 (br.s., 1H), 7.32 - 7.41 (m, 4H), 7.08 (d, J = 8.48 Hz, 2H), 6.87 (d, J = 8.29 Hz, 2H), 3.79 (d, J = 6.03 Hz, 2H), 3.07 (br.s., 4H), 2.78 (t, J = 6.69 Hz, 2H), 1.60 (br.s., 4H), 1.51 (d, J = 4.52 Hz, 2H). MS (ESI) [M+H] + m / z = 409.0.

[0192] According to GP, 3-[(4-chlorophenyl)amino]-4-{[2-(4-pyrrolidin-1-ylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (50) was prepared as a white solid (0.25 g, yield 79%) from 8 (0.20 g, 0.8 mmol) and 2-(4-pyrrolidin-1-ylphenyl)ethyl]amine (0.23 g, 0.10 mmol). 1 1H NMR (300 MHz, DMSO-d6) δ 9.68 - 9.80 (m, 1H), 7.54 - 7.65 (m, 1H), 7.31 - 7.45 (m, 4H), 7.05 (d, J = 7.54 Hz, 2H), 6.49 (d, J = 7.35 Hz, 2H), 3.77 (br.s., 2H), 3.18 (br.s., 4H), 2.74 (d, J = 6.40 Hz, 2H), 1.93 (br.s., 4H). MS (ESI) [M+H] + m / z = 396.0.

[0193] According to GP, 3-{[2-(4-azetidin-1-ylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (51) was prepared as a white solid (0.30 g, yield 96%) from 8 (0.21 g, 0.82 mmol) and 2-(4-azetidin-1-ylphenyl)ethyl]amine (0.17 g, 0.98 mmol). 11H NMR (300 MHz, DMSO-d6) δ 9.78 (br.s., 1H), 7.65 (br.s., 1H), 7.34 - 7.46 (m, 4H), 7.05 (d, J = 8.48 Hz, 2H), 6.36 (d, J = 7.72 Hz, 2H), 3.68 - 3.84 (m, 6H), 2.76 (t, J = 7.16 Hz, 2H), 2.21 - 2.33 (m, 2H). 1 1H NMR (300 MHz, DMSO-d6) δ 9.78 (br.s., 1H), 7.65 (br.s., 1H), 7.34 - 7.45 (m, 5H), 7.05 (d, J = 8.48 Hz, 2H), 6.36 (d, J = 7.72 Hz, 2H), 3.70 - 3.82 (m, 6H), 2.76 (t, J = 7.16 Hz, 2H), 2.21 - 2.33 (m, 2H). MS(ESI) [M + H] + m / z = 382.0.

[0194] Examples of in vitro assays Calcium mobilization assay: CHO-RD-HGA16 cells (Molecular Devices, San Jose, California, United States of America) stably expressing the human CB1 receptor were seeded at 25,000 cells / well in 100 μL of Ham's F12 (supplemented with 10% fetal bovine serum, 100 units of penicillin / streptomycin, and 100 μg / mL of normocin) in a 96-well black-wall assay plate and incubated overnight at 37 °C, 5% CO2. Calcium 5 dye (Molecular Devices, San Jose, California, United States of America) was reconstituted according to the manufacturer's instructions. The reconstituted dye was diluted 1:40 with pre-warmed (37 °C) assay buffer (1× HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4 at 37 °C). The growth medium was removed and the cells were gently washed with 100 μL of pre-warmed (37 °C) assay buffer. The cells were incubated with 200 μL of the diluted calcium 5 dye solution at 37 °C, 5% CO2 for 45 minutes. For the antagonist assay to determine the IC 50 value, the EC of CP55,940 80The concentration was prepared at 10-fold the desired final concentration in 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer, aliquoted into 96-well polypropylene plates, and warmed to 37°C. Serial dilutions of the test compound were prepared at 10-fold the desired final concentration in 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer. After the dye-loading incubation period, the cells were pretreated with 25 μL of the serial dilutions of the test compound and incubated at 37°C for 15 minutes. After the pretreatment incubation period, the plates were read on a FLIPR Tetra (Molecular Devices, San Jose, California, United States of America). The Tetra added 25 μL of CP55,940 at the EC 80 concentration and monitored the change in calcium-mediated fluorescence every second over a 90-second period (excitation / emission: 485 / 525 nm). Relative fluorescence units (RFU) were plotted against the logarithm of the compound concentration. For agonist screening, the cells were pretreated with 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer and the procedure was followed as above, except that a single concentration dilution of the test compound prepared at 10-fold the desired final concentration in 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer was added by the Tetra. The RFU of the test compound was compared to the CP55,940E max RFU to generate %E max values. For the CB2 agonist and antagonist assays, the same procedure was followed, except that stable human CB2-CHO-RD-HGA16 cells were used.

[0195] 35 ​S]GTPγS Binding Assay: For receptor signaling, membranes (10 μg of protein) from either ICR mouse cerebellum mice (6 - 8 weeks old; Enviga International, Indianapolis, Indiana, United States of America) or HEK cells stably expressing the CB1 receptor were pre-incubated for 10 minutes in assay buffer containing 3 units / ml of adenosine deaminase and then incubated with 30 μM of GDP and 0.1 nM of 35 S]GTPγS (Perkin Elmer Life Sciences, Boston, Massachusetts, United States of America) at 30 °C for 60 minutes. Nonspecific binding was determined by adding 30 μM of unlabeled GTPγS. Concentration - response curves for allosteric modulators were performed in the presence of CP55,940 (100 nM or 1 μM) to calculate the 50 IC values.

[0196] cAMP assay: As described above, the cAMP assay was performed. See Cawston et al. J. Med. Chem. 2015, 58, 5979-5988. Briefly, the production of forskolin (FSK)-stimulated cyclic adenosine monophosphate (cAMP) was measured in real time using a transfected bioluminescence resonance energy transfer (BRET) cAMP sensor. The plasmid encodes a cAMP-binding domain (Epac1) adjacent to the yellow fluorescent protein (YFP) and Renilla luciferase (RLuc) assays, the latter of which can oxidize coelenterazine H and generate photons as a byproduct. When cAMP binds to the Epac1 domain, RLuc and YFP separate, so that only RLuc emits photons at a wavelength of 460 nm. When cAMP is not bound, RLuc can excite YFP and emit light at a wavelength of 535 nm. The plate reader measures both wavelengths and calculates their ratio 460 / 535 to quantify cAMP levels, where an increase in the ratio indicates an increase in cAMP. Human embryonic kidney 293 (HEK293) cells stably transfected with human cannabinoid type 1 (CB1) were maintained at 37 °C, 5% CO2 and seeded in 100 mM dishes for transfection. The next day, the cells were given fresh growth medium and transfected with 5 μg of pcDNA3L-His-CAMYEL using linear polyethyleneimine (25 kDa, Polysciences, Warrington, Pennsylvania, United States of America) at a DNA:PEI (ATCC, Manassas, Virginia, United States of America) ratio of 1:6. The next day, the cells were lifted using 1 mM EDTA in PBS and centrifuged at 200×g for 5 minutes.The supernatant was removed, the cells were resuspended in growth medium, seeded into white 96-well plates coated with poly-D-lysine (Sigma Aldrich, St. Louis, Missouri, United States of America), and filled with 60,000 cells per well, with two columns of 8 wells per plate (i.e., 8 samples in duplicate per plate) (Perkin Elmer, Waltham, Massachusetts, United States of America). The next day, the medium was removed, the cells were rinsed with PBS, and the buffer / reagent / drug was added as follows: at 0 minutes, 175 μL of stimulation buffer (Ca. 2+ and Mg 2+ 5 mg / ml bovine serum albumin in HBSS containing) was added, at 10 minutes, 25 μL of allosteric regulator was added, at 15 minutes, 25 μL of coelenterazine was added (final 5 μM), and at 25 minutes, 25 μL of forskolin (final 10 μM) was added in the presence or absence of CP55,940 (final 100 nM). Immediately after adding forskolin and the probe agonist CP55,940, luminescence was measured simultaneously at 460 nm and 535 nm for 22 minutes at 37 °C for 1 second per well using a Clariostar (BMG Labtech, Ortenberg, Germany). The 460 / 535 ratio was calculated for each time point, plotted over time, and for each replicate, area under the curve analysis was performed and averaged by condition / day (each day functions as an independent experiment). The data were calculated as %FSK using the formula [(sample - basal) / (forskolin - basal) × 100]. Using Prism 6 (Graphpad Software, San Diego, California, United States of America), IC 50 values were calculated from these normalized concentration-response data using three-parameter non-linear regression. The data are plotted as the mean of at least N = 3 independent experiments normalized to either forskolin (concentration-response data) or the calculated 460 / 535 BRET ratio (time-course data).

[0197] Data analysis: In the case of the calcium mobilization experiment, the data was fitted to a three-parameter logistic curve to generate the IC 50 value (GraphPad Prism 6.0, Graphpad Software, San Diego, California, United States of America). 35 In the case of the [S]GTPγS experiment, the data was normalized to the maximum CP55,940 (100 nM) stimulation in the absence of the test compound (i.e., vehicle = 100%). Curve fitting was achieved using GraphPad Prism 6.0 (Graphpad Software, San Diego, California, United States of America), and the data was fitted to a three-parameter non-linear regression with the lower and upper bounds constrained to >0 and =100, respectively, for the calculation of the IC 50 value.

[0198] Results: The compounds of the present disclosure were characterized in a calcium mobilization assay using CHO cells overexpressing human CB1R and in a 35 [S]GTPγS binding assay in HEK cells overexpressing human CB1R as described above.

[0199] Table 1. Allosteric regulatory activities of arylalkyl squaramide derivatives in human CB1 calcium mobilization and mouse CB1 35 [S]GTPγS binding assays.

Chemical formula

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0200] Table 2. Human CB1 Calcium Mobilization Assay and Mouse CB1 35 Allosteric regulatory activity of diaryl squaramide derivatives in the [S]GTPγS binding assay.

Chemical formula

Table 2

[0201] Stability, solubility, permeability, and pharmacokinetic studies Evaluation of metabolic stability: The compound was incubated with rat liver microsomes at 37 °C for a total of 45 minutes. The reaction was carried out at pH 7.4 in 100 mM potassium phosphate buffer containing 0.5 mg / mL of rat liver microsome protein. Phase I metabolism was evaluated by adding NADPH to a final concentration of 1 mM and collecting samples at 0, 5, 15, 30, and 45 minutes. All collected samples were quenched 1:1 with ice-cold stop solution (1 μM labetalol and 1 μM glibyride in acetonitrile), centrifuged to remove the precipitated protein. The resulting supernatant was further diluted 1:4 with acetonitrile:water (1:1). Samples were analyzed by LC / MS / MS, the half-life was calculated, and in vitro clearance was achieved using Microsoft Excel (2007).

[0202] Kinetic solubility evaluation: 10 μL of the test compound stock solution (20 mM DMSO) was combined with 490 μL of phosphate buffer solution to reach a target concentration of 400 μM. The solution was stirred at room temperature for 2 hours using a VX-2500 multi-tube vortexer (VWR International, Radnor, Pennsylvania, United States of America). After stirring, the sample was filtered through a glass fiber filter (1 μm), and the eluate was diluted 400-fold with a mixture of acetonitrile: water (1:1). In each experimental run, nifedipine and imipramine were evaluated as reference compounds with low and high solubility, respectively. All samples were evaluated in triplicate and analyzed by LC-MS / MS using electrospray ionization against standards prepared in the same matrix.

[0203] Results: In an effort to advance CB1R allosteric modulators for therapeutic drug development, preliminary ADME evaluations of some of the compounds of the present disclosure were conducted.

[0204] [Table 3]

[0205] Permeability evaluation. The bidirectional MDCK-MDR1 permeability assay was performed by Paraza Pharma Inc. (Montreal, Canada). MDCK-mdr1 cells at passage 5 were seeded onto a permeable polycarbonate support in a 12-well Costar Transwell plate and allowed to grow and differentiate for 3 days. On day 3, the medium (DMEM supplemented with 10% FBS) was removed from both sides of the transwell insert, and the cells were rinsed with warm HBSS. After the rinse step, the chamber was filled with warm transport buffer (HBSS containing 10 mM HEPES, 0.25% BSA, pH 7.4), and the plate was incubated at 37 °C for 30 minutes before TEER (Trans Epithelial Electric Resistance) measurement was performed.

[0206] The buffer solution in the donor chamber (top side for A-to-B assay, bottom side for B-to-A assay) was removed and replaced with the working solution (10 μM test sample in the transport buffer). The plate was then placed at 37 °C under gentle stirring. At the specified time points (30, 60, and 90 minutes), an aliquot of the transport buffer was taken from the receiver chamber and replenished with fresh transport buffer. The samples were quenched with ice-cold ACN containing the internal standard and then centrifuged to pellet the protein. The resulting supernatant was further diluted with 50 / 50 ACN / H2O (H2O for atenolol only) and subjected to LC-MS / MS analysis. The reported apparent permeability (Papp) values were calculated from a single measurement. Atenolol and propranolol were tested as low and medium permeability references. The bidirectional transport of digoxin was evaluated to demonstrate Pgp activity / expression.

[0207] The apparent permeability (Papp, measured in cm / s) of the compound is determined from two independent duplicate experiments according to the following equation:

[0208] where

Number

[0209] Pharmacokinetic evaluation. In vivo pharmacokinetic assays were performed by Paraza Pharma Inc. (Montreal, Canada). In the morning of the PK study, male Sprague-Dawley rats weighing 258 - 277 g were administered either vehicle (5% Cremophor, 5% ethanol in physiological saline) or 7 (5.6 mg / kg, i.p.). At the selected time points (0.25, 0.5, 1, 3, 5, 8, and 24 hours post-dose), two rats were anesthetized with isoflurane gas, cardiac puncture was performed to collect blood (for plasma analysis), followed by whole body perfusion with phosphate buffered saline (PBS, pH 7.4) to wash out residual blood from the organs. The brain was collected and homogenized by mechanical shearing with a Polytron using 25% isopropanol in water at a ratio of 1:4 (w / v). Brain homogenates were extracted for drug quantification by LC-MS / MS.

[0210] Recovery of extinguished cocaine-seeking behavior Adult male Sprague-Dawley rats weighing 280 - 300 g (Harlan, Indianapolis, Indiana, United States of America) were used in the study. The animals were individually housed on a 12 / 12 hour light / dark cycle (behavioral experiments were conducted during the light phase) with free access to water and food, except during the experimental sessions.

[0211] The recovery procedure has been described previously. See Jing et al., Drug Alcohol Depend. 2014, 143, 251-256 and Thorn et al., Neuropsychopharmacology 2014, 39, 2309-2316. Briefly, rats were surgically implanted with chronic jugular catheters. After 1 week of recovery, rats were trained to press an active lever (left lever) for cocaine (0.75 mg / kg / inf) infusion under a fixed ratio [FR] schedule (starting FR = 1, increasing to FR5 during 5 training sessions) during daily 2-hour sessions for 14 days. Delivery of the reinforcer was accompanied by the presentation of a stimulus light above the active lever, followed by a 30-second timeout period during which lever presses did not produce programmed consequences. After acquisition of cocaine self-administration, extinction of drug-seeking behavior occurred during daily 2-hour sessions in which lever presses did not produce consequences. All other conditions were unchanged. After 7 days of extinction, all rats reached the extinction criterion (total responses < 20% of training sessions).

[0212] Data analysis: Data are presented as mean ± standard error. The difference in active lever responses between the last extinction session and the recovery session was determined by a paired t-test (within-subject comparison). The effect of compound 7 on recovery was analyzed by one-way analysis of variance (ANOVA), followed by a post hoc Bonferroni test (between-subject comparison). The effect of compound 7 on recovery was analyzed by Student's t-test. P < 0.05 was considered statistically significant.

[0213] Results: As shown in Figure 1A, compound 7 at 5.6 mg / kg (i.p.) was effective in attenuating cocaine re-seeking behavior in rats. Furthermore, as shown in Figure 1B, compound 6 did not affect locomotion at 5.6 mg / kg (i.p.).

[0214] It will be understood that various details of the subject matter of the present disclosure may be changed without departing from the scope of the subject matter of the present disclosure. Further, the foregoing description is for illustrative purposes only and not for purposes of limitation.

[0215] All publications, patents, and patent applications cited herein are hereby incorporated by reference herein with respect to the teachings for which such citation is used.

[0216] Test compounds for the experiments described herein were used in free or salt form.

[0217] The specific responses observed can vary according to and depend upon the particular active compound selected, whether or not a carrier is present, and the type and mode of administration of the formulation used, and such expected variations or differences in the results are contemplated in the practice of the present disclosure.

[0218] Specific embodiments of the present disclosure are illustrated and described in detail herein, but the present disclosure is not limited thereto. The above detailed description is provided as an exemplification of the present disclosure and should not be construed as constituting any limitation of the present disclosure. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present disclosure are intended to be included within the scope of the appended claims.

Claims

1. A compound of formula (I), 【Chemistry 10】 During the ceremony, Each R １ is independently C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, halogen, C １ -C ６ haloalkyl, NO ２ , CN, O-(C １ -C ６ alkyl), or N(R ３ ), ２ and is Each R ２ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, halogen, C １ -C ６ Haloalkyl, CN, NO ２ ,OH,O-(C １ -C ６ Alkyl), O-(5-13 member cycloalkyl), N(R ３ ) ２ , C(O)OH, C(O)C １ -C ６ Alkyl, (C １ -C ８ -Alkyl) ｘ - (5-13 member aryl) - (R ４ ) ｐ , (C １ -C ８ -Alkyl) ｘ - (5-13 member heterocycline containing one, two, or three heteroatoms selected from N, O, or S) - (R ４ ) ｐ , (C １ -C ８ -Alkyl) ｘ - (5-13 member heteroaryl containing one, two, or three heteroatoms selected from N, O, or S) - (R ４ ) ｐ And, Each R ３ H or C １－６ Alkyl or two R ３ The groups and the nitrogen atoms to which they are bonded form a 5-7 atom heterocyclic ring which may contain one or two additional heteroatoms selected from N, O, and S. Each R ４ These are H, Halo, and C, which are independent of each other. １－６ Alkyl, or N(R) ５ ) ２ And each R ５ H or C １－６ It is alkyl, Each x is independently either 0 or 1. Ring A is (i) C ３－６ C having one, two, or three heteroatoms selected from cycloalkyl, (ii)N, O, or S, respectively. ３－６ Heterocyclyl, (iii) C ６ C having one, two, or three heteroatoms selected from aryl, (iv)N, O, or S, respectively. ５－６ Selected from heteroaryls, n is 0, 1, 2, 3, or 4. m is 0, 1, 2, or 3. o is 0, 1, 2, or 3. p is 0, 1, 2, or 3, in the compound. or a pharmaceutically acceptable salt or solvate thereof.

2. Ring A is C ６ The compound according to claim 1, wherein it is an aryl compound.

3. Each R １ These are, independently, halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, CN, O-(C) １－ C ６ Alkyl), or N(R ２ ) ２ And, Each R ２ These are, independently, halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, CN, NO ２ , O-(C １ -C ６ Alkyl), O-(5-13 member cycloalkyl), N(R ３ ) ２ , C １ -C ８ -Alkyl) ｘ - (5-13 member aryl), or (C １ -C ８ -Alkyl) ｘ - (5-13 member heteroaryl), and each of the aryl and heteroaryl is optionally one or more R ４ Substituted with a group, the heteroaryl contains one, two, or three heteroatoms selected from N, O, and S, Each R ３ H or C １－６ Alkyl or two R ３ The groups and the nitrogen atoms to which they are bonded form a 5-7 atom heterocyclic ring which may contain one or two additional heteroatoms selected from N, O, and S. Each R ４ is independently H, halo, C １－６ alkyl, or N(R ５ ), ２ and each R ５ is independently H or C １－６ alkyl. n is 0, 1, 2, 3, or 4. m is 1, 2, or 3. The compound according to claim 2, wherein o is 0, 1, 2, or 3. or a pharmaceutically acceptable salt or solvate thereof.

4. Having formula (II), 【Chemistry 11】 During the ceremony, Each R １ is independently C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, halogen, C １ -C ６ haloalkyl, NO ２ , CN, O-(C １ -C ６ alkyl), or N(R ３ ) ２ and is Each R ２ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, halogen, C １ -C ６ Haloalkyl, CN, O-(C) １ -C ６ Alkyl), N(R ３ ) ２ , C １ -C ８ -Alkyl) ｘ - (5-13 member aryl), or (C １ -C ８ -Alkyl) ｘ - (5-13 member heteroaryl), and each of the aryl and heteroaryl is optionally one or more R ４ Substituted with a group, the heteroaryl contains one, two, or three heteroatoms selected from N, O, and S, Each R ３ H or C １－６ Alkyl or two R ３ The groups and the nitrogen atoms to which they are bonded form a 5-7 atom heterocyclic ring which may contain one or two additional heteroatoms selected from N, O, and S. Each R ４ These are H, Halo, and C, which are independent of each other. １－６ Alkyl, or N(R) ５ ) ２ And each R ５ H or C １－６ It is alkyl, m is 0, 1, 2, or 3, The compound according to claim 2, wherein o is 0, 1, 2, or 3. or a pharmaceutically acceptable salt or solvate thereof.

5. R ２ If it is anything other than pyridyl, then two R ５ The compound according to claim 1, further comprising the groups and the nitrogen atoms to which they are bonded being able to form a 5- to 7-membered heteroring that may contain one or two additional heteroatoms selected from N, O, and S, and may contain one or more degrees of unsaturation.

6. The compound according to claim 1, wherein ring A is pyridinyl, thiophenyl, piperidinyl, or piperazinyl.

7. R １ The compound according to claim 1, wherein the compound is Cl or CN.

8. The compound according to claim 1, wherein n is 2.

9. The compound according to claim 1, wherein o is 0.

10. o is at least 1, and each R ２ However, C １－６ Alkyl, halogen, O(C) １－６ Alkyl), C １－６ Haloalkyl, N(C) １－６ Alkyl) ２ , C(O)C １－６ The compound according to claim 1, selected from the group consisting of alkyl, OH, unsubstituted phenyl, halogen-substituted phenyl, unsubstituted pyridine, pyrroline-substituted pyridine, unsubstituted thiazole, and unsubstituted thiophene.

11. o is 1 or 2, Each R ２ However, C １－６ Alkyl, halogen, O(C) １－６ Alkyl), N (C １－６ Alkyl) ２ , C(O)C １－６ The compound according to claim 10, selected from the group consisting of alkyl, unsubstituted phenyl, and halogen-substituted phenyl.

12. R ３ However, CH ３ The compound according to claim 1.

13. R ４ However, H, halo, or N(R) ５ ) ２ The compound according to claim 1.

14. The compound according to claim 1, wherein x is 0.

15. 3-(benzylamino)-4-[(4-chlorophenyl)amino]cyclobuto-3-ene-1,2-dione(9), 3-[(4-chlorophenyl)amino]-4-[(2-phenylethyl)amino]cyclobuto-3-ene-1,2-dione(10), 3-[(4-chlorophenyl)amino]-4-[(3-phenylpropyl)amino]cyclobuto-3-ene-1,2-dione(11), 3-[(4-chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(12), 3-[(4-chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(13), 3-[(4-chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(14), 3-[(4-chlorophenyl)amino]-4-{[2-(2-methoxyphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(15), 3-[(4-chlorophenyl)amino]-4-{[2-(3-methoxyphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(16), 3-[(4-chlorophenyl)amino]-4-{[2-(4-methoxyphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(17), 3-[(4-chlorophenyl)amino]-4-({2-[2-(trifluoromethyl)phenyl]ethyl}amino)cyclobuto-3-ene-1,2-dione(18), 3-[(4-chlorophenyl)amino]-4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobuto-3-ene-1,2-dione(19), 3-[(4-chlorophenyl)amino]-4-({2-[4-(trifluoromethyl)phenyl]ethyl}amino)cyclobuto-3-ene-1,2-dione(20), 3-[(4-chlorophenyl)amino]-4-{[2-(4-fluorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(21), 3-[(4-chlorophenyl)amino]-4-{[2-(2-chlorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(22), 3-[(4-chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(6), 3-[(4-chlorophenyl)amino]-4-{[2-(2-fluorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(23), 3-[(4-chlorophenyl)amino]-4-{[2-(3-fluorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(24), 3-[(4-chlorophenyl)amino]-4-({2-[3-(dimethylamino)phenyl]ethyl}amino)cyclobuto-3-ene-1,2-dione(25), 3-[(4-chlorophenyl)amino]-4-({2-[4-(dimethylamino)phenyl]ethyl}amino)cyclobuto-3-ene-1,2-dione(26), 4-[(2-{[2-(3-chlorophenyl)ethyl]amino}-3,4-dioxocyclobuto-1-en-1-yl)amino]benzonitrile (27), 3-(biphenyl-3-ylamino)-4-[(4-chlorophenyl)amino]cyclobuto-3-ene-1,2-dione(28), 3-{3-[6-(pyrroridine-1-yl)pyridine-2-yl]phenyl}-4-[(4-chlorophenyl)amino]cyclobuto-3-ene-1,2-dione(29); 3-[(4-chlorophenyl)amino]-4-{[3-(thiophen-3-yl)phenyl]amino}cyclobuto-3-ene-1,2-dione(31), 3-[(4-chlorophenyl)amino]-4-[(4'-fluorobiphenyl-3-yl)amino]cyclobuto-3-ene-1,2-dione(32), 3-(biphenyl-4-ylamino)-4-[(4-chlorophenyl)amino]cyclobuto-3-ene-1,2-dione (33), 3-[(4-chlorophenyl)amino]-4-{[2-(2-methylphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(pyridine-2-yl)ethyl]amino}cyclobuto-3-en-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(pyridine-4-yl)ethyl]amino}cyclobuto-3-en-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(4-bromophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(thiophen-2-yl)ethyl]amino}cyclobuto-3-en-1,2-dione, 3-{[2-(A-acetylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobuto-3-ene-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(3,4-dichlorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(3,4-dimethylphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(3-hydroxyphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(2,4-dichlorophenyl)ethyl]amino}cyclobuto-3-en-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(piperidine-1-yl)ethyl]amino}cyclobuto-3-en-1,2-dione, 3-[(4-chlorophenyl)amino]-4-({2-[4-(4-chlorophenyl)piperazine-1-yl]ethyl}amino)cyclobuto-3-en-1,2-dione, 3-[(4-chlorophenyl)amino]-4-{[2-(2,4-difluorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione, and A compound selected from 3-[(4-chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobuto-3-ene-1,2-dione, or a pharmaceutically acceptable salt thereof.

16. 3-[(4-chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(6), 3-[(4-chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione(12), 3-[(4-chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione (13), and A compound selected from 3-[(4-chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobuto-3-ene-1,2-dione (14), or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17 for use in subjects requiring treatment of cannabinoid 1 receptor (CB1R)-mediated diseases or conditions.

19. The pharmaceutical composition according to claim 18, wherein the subject is a mammal, optionally, a human.

20. The pharmaceutical composition according to claim 18, wherein the disease or condition is selected from the group consisting of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive impairment, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette syndrome, stroke, atherosclerosis, hypotension, decreased bowel motility in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes mellitus, retinopathy, glaucoma, anxiety, depression, and other mood disorders, gastrointestinal disorders, and metabolic disorders.

21. The pharmaceutical composition according to claim 20, wherein the disease is obesity or addiction, and the addiction is optionally selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

22. The pharmaceutical composition according to claim 17 for use in inhibiting drug abuse, addiction, addictive behavior, or symptoms, behaviors, or conditions associated with addiction.

23. The pharmaceutical composition according to claim 22, wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

24. The pharmaceutical composition according to claim 17 for use in modulating the activity of cannabinoid 1 receptor (CB1R).

25. The pharmaceutical composition according to claim 17 for use in the treatment of one or more diseases or disorders of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive impairment, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette syndrome, stroke, atherosclerosis, hypotension, decreased bowel motility in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes mellitus, retinopathy, glaucoma, anxiety, depression, and other mood disorders, gastrointestinal disorders, and metabolic disorders.

26. The pharmaceutical composition according to claim 25, wherein the disease or disorder is obesity or addiction, and optionally, the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addition, tobacco addiction, and alcohol addiction.

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