Squaramide derivatives as CB1 allosteric modulators

Abstract

Squaramide-based cannabinoid 1 receptor (CB1R) allosteric modulators are described. Exemplary analogs may provide improved potency and pharmacokinetic properties. Methods of treating diseases mediated by CB1R, such as substance abuse and obesity, using the analogs are described.

Description

[0001] Government interests

[0002] This invention was made with government support under Grant No. 5R01DA040693 awarded by the National Institutes of Health. The government has certain rights in this invention. Technical Field

[0003] The disclosed subject matter relates to cannabinoid 1 receptor (CB1R) allosteric modulator compounds based on squaramide, and to pharmaceutical compositions and uses thereof. The uses of the compounds include modulating CB1R activity and treating diseases and conditions mediated by CB1R, such as obesity, substance abuse, alcohol addiction, alcoholism, anxiety, depression, metabolic syndrome, stroke, hypotension, impaired fertility, cancer, inflammation, Parkinson's disease, paralytic ileus and osteoporosis. Background Art

[0004] According to the National Survey on Drug Use and Health in 2017, 18.7 million adults in the United States are affected by substance abuse disorders. There is currently no FDA-approved medicine for treating the desire for stimulants (e.g., cocaine, methamphetamine) and cannabis products (cannabis) (marijuana). There are available medicines for relapse prevention of other addictive substances (e.g., opioids, tobacco and alcohol). However, although these medicines may be effective for treating withdrawal symptoms, the long-term withdrawal rate is still very low. For example, even if several medicines for smoking cessation are used, the smoking cessation rate of one year is only about 20% compared with the smoking cessation rate of about 10% for placebo. Therefore, there is an unmet demand for the medicine for long-term relief of material desire.

[0005] 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. Matsuda et al. , Nature 1990, 346, 561-564. CB1R plays a role in many physiological processes, such as pain, learning and memory, appetite and eating 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. 9- Tetrahydrocannabinol (THC), the main phytocannabinoid found in cannabis, has been known for centuries to induce appetite and weight gain as well as addiction, and CB1R has been studied for the development of therapeutic interventions for obesity, metabolic disorders, and substance abuse. 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; Huestis et al. , Psychopharmacology (Berl) 2007, 194, 505-515. Other potential uses of CB1R antagonists / inverse agonists include the treatment of cancer, impaired female fertility, stroke, hypotension, and intestinal hypomotility 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 withdrawn due to adverse effects, including suicidal ideation.

[0006] Thus, there continues to be a need for additional compounds that can modulate CB1R activity to treat substance addiction and other conditions that can be modulated via CB1R. For example, there continues to be a need for additional CB1R modulator compounds with reduced side effects, improved pharmacokinetic properties (e.g., metabolic stability), and improved efficacy. Summary of the invention

[0007] One embodiment of the present disclosure includes a compound of formula (I)

[0008]

[0009] in

[0010] Each R 1 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, NO2, CN, O-(C 1- C6 alkyl) or N(R 3 )2;

[0011] Each R 2 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, NO2, OH, O-(C1-C6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 3 )2, C(O)OH, C(O)C1-C6 alkyl, (C1-C8-alkyl) x -(5- to 13-membered aryl)-(R 4 ) p 、(C1-C8-alkyl) x -(5- to 13-membered heterocyclic group containing one, two or three heteroatoms selected from N, O or S)-(R 4 ) p 、(C1-C8-alkyl) x -(5- to 13-membered heteroaryl containing one, two or three heteroatoms selected from N, O or S)-(R 4 ) p ;

[0012] Each R 3 independently H or C 1-6 Alkyl; or two R 3 The groups and the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which may contain one or more additional heteroatoms selected from N, O and S;

[0013] Each R 4 are independently H, halo, C 1-6 Alkyl or N(R 5 )2, where each R 5 independently H or C 1-6 Alkyl, or two R 5 The groups and the nitrogen atom to which they are attached form a 5-7 atom heterocyclic ring which may contain one or two or more additional heteroatoms selected from N, O and S;

[0014] Each x is independently 0 or 1;

[0015] n is 0, 1, 2, 3 or 4;

[0016] m is 0, 1, 2 or 3; and

[0017] o is 0, 1, 2, or 3; and

[0018] p is 0, 1, 2, or 3,

[0019] or a pharmaceutically acceptable salt or solvate thereof.

[0020] In one aspect, Ring A is C6 aryl, ie phenyl.

[0021] In one aspect, each R 1 are independently halogen, C1-C4 alkyl, C1-C4 haloalkyl, CN, O-(C 1- C6 alkyl) or N(R 3 )2; Each R 2 are independently halogen, C1-C4 alkyl, C1-C4 haloalkyl, CN, NO2, O-(C 1- C6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 3 2. C 1- C8-alkyl) x -(5- to 13-membered aryl) or (C 1- C8-alkyl) x -(5- to 13-membered heteroaryl), wherein each of the aryl and heteroaryl groups is optionally substituted by one or more R 5 and wherein the heteroaryl group contains one, two or three heteroatoms selected from N, O and S; each R 3 independently H or C 1-6 Alkyl; or two R 3 The groups and the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which may contain one or more additional heteroatoms selected from NO and S; each R 4 are independently H, halogen, C 1-6 Alkyl or N(R 5 )2, where each R 5 independently H or C 1-6 Alkyl, or two R 5 The groups and the nitrogen atom to which they are attached form a 5-7 atom heterocyclic ring which may contain one or more additional heteroatoms selected from N, O and S; n is 0, 1, 2, 3 or 4; m is 1, 2 or 3; and o is 0, 1, 2 or 3, or a pharmaceutically acceptable salt or solvate thereof.

[0022] One embodiment of the present disclosure includes a compound of formula (II):

[0023]

[0024] in

[0025] Each R 1 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, NO2, CN, O-(C 1- C6 alkyl) or N(R 3 )2;

[0026] Each R 2 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, O-(C 1- C6 alkyl), N(R 3 2. C 1- C8-alkyl) x -(5- to 13-membered aryl) or (C 1- C8-alkyl) x -(5- to 13-membered heteroaryl), wherein each of the aryl and heteroaryl groups is optionally substituted by one or more R 4 The heteroaryl group contains one, two or three heteroatoms selected from N, O and S;

[0027] Each R 3 are independently H or C 1-6 Alkyl; or two R 3 The groups and the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which may contain one or more additional heteroatoms selected from N, O and S;

[0028] Each R 4 are independently H, halo, C 1-6 Alkyl or N(R 5 )2 Each R 5 are independently H or C 1-6 alkyl;

[0029] m is 0, 1, 2 or 3; and

[0030] o is 0, 1, 2, or 3;

[0031] or a pharmaceutically acceptable salt or solvate thereof.

[0032] In one embodiment, when R 2 When not pyridyl, the two R 5 The radicals and the nitrogen atom to which they are attached may form a 5-7 membered heterocyclic ring which may contain one or two or more additional heteroatoms selected from N, O and S and may contain one or more degrees of unsaturation.

[0033] In certain embodiments, Ring A is pyridinyl, thienyl, piperidinyl, or piperazinyl.

[0034] In one aspect, R 1 is halogen or CN. In one aspect, R 1 is halogen. In one aspect, R 1 For Cl.

[0035] In one aspect, n is 1 or 2. In one aspect, n is 2

[0036] In one aspect, o is zero.

[0037] In one aspect, o is at least 1 and each R 2 Selected from the group consisting of: 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 by halogen, unsubstituted pyridine, pyridine substituted by pyrroline, unsubstituted thiazole, unsubstituted thiophene, unsubstituted phenyl and phenyl substituted by halogen.

[0038] In one aspect, o is 1 or 2, and each R 2 Selected from the group consisting of: 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 by halogen.

[0039] In one aspect, R 3 For CH3.

[0040] In one aspect, R 4 is H, halogenated or N(R 5 )2, where two R 5 The groups and the nitrogen to which they are attached form a pyrrolidine.

[0041] In one aspect, x is zero.

[0042] One embodiment of the present disclosure includes a compound selected from the group consisting of:

[0043] 3-(Benzylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (9);

[0044] 3-[(4-Chlorophenyl)amino]-4-[(2-phenylethyl)amino]cyclobut-3-ene-1,2-dione (10);

[0045] 3-[(4-Chlorophenyl)amino]-4-[(3-phenylpropyl)amino]cyclobut-3-ene-1,2-dione (11);

[0046] 3-[(4-chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (12);

[0047] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (13);

[0048] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (14);

[0049] 3-[(4-Chlorophenyl)amino]-4-{[2-(2-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (15);

[0050] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (16);

[0051] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (17);

[0052] 3-[(4-Chlorophenyl)amino]-4-({2-[2-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (18);

[0053] 3-[(4-Chlorophenyl)amino]-4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (19);

[0054] 3-[(4-Chlorophenyl)amino]-4-({2-[4-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (20);

[0055] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (21);

[0056] 3-[(4-chlorophenyl)amino]-4-{[2-(2-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (22);

[0057] 3-[(4-chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (6);

[0058] 3-[(4-Chlorophenyl)amino]-4-{[2-(2-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (23);

[0059] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (24);

[0060] 3-[(4-Chlorophenyl)amino]-4-({2-[3-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (25);

[0061] 3-[(4-chlorophenyl)amino]-4-({2-[4-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (26);

[0062] 4-[(2-{[2-(3-chlorophenyl)ethyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzonitrile (27);

[0063] 3-(Biphenyl-3-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (28);

[0064] 3-[(4-Chlorophenyl)amino]-4-{[3-(thiophen-3-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (31);

[0065] 3-[(4-Chlorophenyl)amino]-4-[(4'-fluorobiphenyl-3-yl)amino]cyclobut-3-ene-1,2-dione (32);

[0066] 3-(Biphenyl-4-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (33);

[0067] 3-[(4-chlorophenyl)amino]-4-{[2-(2-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0068] 3-[(4-chlorophenyl)amino]-4-{[2-(pyridin-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0069] 3-[(4-chlorophenyl)amino]-4-{[2-(pyridin-4-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0070] 3-[(4-chlorophenyl)amino]-4-{[2-(4-bromophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0071] 3-[(4-chlorophenyl)amino]-4-{[2-(thiophen-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0072] 3-{[2-(A-acetylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione;

[0073] 3-[(4-chlorophenyl)amino]-4-{[2-(3,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0074] 3-[(4-chlorophenyl)amino]-4-{[2-(3,4-dimethylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0075] 3-[(4-chlorophenyl)amino]-4-{[2-(3-hydroxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;

[0076] 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;

[0077] 3-[(4-chlorophenyl)amino]-4-({2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}amino)cyclobut-3-ene-1,2-dione;

[0078] 3-[(4-chlorophenyl)amino]-4-{[2-(2,4-difluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione; and

[0079] 3-[(4-chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione,

[0080] or a pharmaceutically acceptable salt thereof.

[0081] One embodiment of the present disclosure includes a compound selected from the group consisting of Compound 6, 12, 13, 14, or a pharmaceutically acceptable salt thereof.

[0082] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable carriers.

[0083] A method of treating a cannabinoid 1 receptor (CB1R) mediated disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0084] In one aspect, the subject is a mammal, optionally a human.

[0085] 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, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0086] In one aspect, the disease is obesity or addiction, optionally wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

[0087] One embodiment of the present disclosure includes a method for inhibiting substance 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.

[0088] In one aspect, the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

[0089] In one aspect, administration of a compound of the disclosure prevents drug taking.

[0090] In one aspect, administration of a compound of the disclosure prevents or inhibits relapse.

[0091] One embodiment of the present disclosure includes a method of modulating the activity of a cannabinoid 1 receptor (CB1R), wherein the method includes contacting a sample comprising a CB1R with a compound of the present disclosure.

[0092] One embodiment of the present disclosure includes a compound of the present disclosure for use in medicine.

[0093] One embodiment of the present disclosure includes compounds of the present disclosure for use in the manufacture of a medicament for treating one or more diseases or conditions of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0094] In one aspect, the disease or disorder is obesity or addiction, optionally wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

[0095] One embodiment of the present disclosure includes the use of the compounds of the present disclosure for treating one or more diseases or conditions of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0096] In one aspect, the disease or disorder is obesity or addiction, optionally wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

[0097] Although not specifically described, one or more aspects and embodiments may be incorporated into different embodiments. That is, all aspects and embodiments may be combined in any manner or combination. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] The subject matter disclosed herein may be better understood by reference to the following drawings. The components in the drawings are not necessarily drawn to scale, but emphasis is placed on illustrating the principles of the subject matter disclosed herein. The drawings are not intended to limit the scope of the subject matter disclosed herein, which is specifically set forth in the claims as attached or as subsequently amended, but are merely for the purpose of illustrating and exemplifying the subject matter disclosed herein. For a more complete understanding of the subject matter disclosed herein, reference is now made to the following drawings.

[0099] Figure 1are graphical illustrations showing that (A) Compound 6 at 5.6 mg / kg (ip) effectively attenuates cocaine re-seeking behavior in rats; and (B) Compound 6 at 5.6 mg / kg (ip) does not affect locomotion. DETAILED DESCRIPTION

[0100] The subject matter disclosed in the present invention will now be described more fully below with reference to the attached examples, in which representative embodiments are shown. However, the subject matter disclosed in the present invention can be embodied in different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that the present disclosure will be thorough and complete, and the scope of the embodiments will be fully conveyed to those skilled in the art.

[0101] 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 described herein belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety.

[0102] Throughout the specification and claims, a given chemical formula or name shall encompass all optical isomers and stereoisomers, as well as the racemic mixtures where such isomers and mixtures exist, unless specifically indicated otherwise.

[0103] definition

[0104] Unless otherwise indicated, all numbers used in the specification and claims to represent the quantity of ingredients, reaction conditions, etc. should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximate values, which can vary according to the desired characteristics that the subject matter disclosed in the present invention attempts to obtain. The term "about" as used herein is intended to cover changes of ±20% or ±10% from the specified amount in one example, ±5% from the specified amount in another example, ±1% from the specified amount in another example, and ±0.1% from the specified amount in another example, because such changes are suitable for performing the disclosed method.

[0105] As used herein, the term "alkyl" refers to a C1-C 20(Inclusive of end values) 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, vinyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl 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 1 to about 8 carbon atoms (i.e., C1-C8 alkyl), for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. In some embodiments, "lower alkyl" may refer to C 1-6 or C 1-5 Alkyl group.

[0106] The alkyl group may be optionally 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, halogen, haloalkyl, nitro, cyano, amino, arylamino, acyl, hydroxy, aryloxy, alkoxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. Along the alkyl chain may be optionally inserted one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0107] Thus, as used herein, the term "substituted alkyl" includes alkyl groups as defined herein, wherein 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, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, dialkylamino, ester, acyl, amide, sulfonyl, sulfate, and mercapto.

[0108] The term "thiazolinyl" refers to an alkyl group as defined above including at least one carbon-carbon double bond. Exemplary thiazolinyl groups include but are not limited to vinyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl and allene groups. The thiazolinyl group can be optionally replaced by one or more alkyl group substituents that can be the same or different, and the alkyl group substituents include but are not limited to alkyl (saturated or unsaturated), substituted alkyl (for example, alkyl substituted with halo and perhalogen, such as but not limited to-CF3), cycloalkyl, halo, nitro, hydroxyl, carbonyl, carboxyl, acyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, arylthio, amino (for example, aminoalkyl, aminodialkyl, aminoaryl etc.), sulfonyl and sulfinyl.

[0109] "Cyclic" and "cycloalkyl" refer to non-aromatic monocyclic or polycyclic ring systems having 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 between 3 and 6 carbon atoms. The cycloalkyl group may optionally be partially unsaturated. The cycloalkyl group may also be optionally substituted with a substituent as defined herein. Representative monocyclic cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In addition, the cycloalkyl group may optionally be connected by a linking group such as an alkylene group (e.g., methylene, ethylene, propylene, etc.) as defined below. In such cases, the cycloalkyl group may be referred to as, for example, cyclopropylmethyl, cyclobutylmethyl, etc. In addition, polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decahydronaphthalene, camphor, camphane, and noradamantyl.

[0110] Thus, as used herein, the term "substituted cycloalkyl" includes cycloalkyl groups as defined herein, wherein one or more atoms or functional groups of the cycloalkyl group are replaced by another atom or functional group, including, for example, alkyl, halogen, haloalkyl, aryl, substituted aryl, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, dialkylamino, ester, acyl, amide, sulfonyl, sulfate, and mercapto.

[0111] The term "aryl" is used herein to refer to an aromatic substituent, which can be a single aromatic ring, or multiple aromatic rings fused together, covalently linked or connected to a common group (such as but not limited to a methylene or ethylene moiety). The common linking group can also be a carbonyl (such as in benzophenone), or oxygen (such as in diphenyl ether), or nitrogen (such as in diphenylamine). The term "aryl" specifically encompasses heterocyclic aromatic compounds (i.e., "heteroaryl"). Aromatic rings can include phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone, etc. In a specific embodiment, the term "aryl" means a cyclic aromatic compound comprising about 5 to about 10 carbon atoms (e.g., 5, 6, 7, 8, 9, or 10 carbon atoms) and including 5- and 6-membered hydrocarbons and heterocyclic aromatic rings.

[0112] The aryl group can be optionally substituted with one or more substituents which may be the same or different ("substituted aryl") and include alkyl, aryl, halo, haloalkyl, aralkyl, hydroxy, alkoxy, aryloxy, aralkyloxy, carboxy, acyl, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, acyloxy, 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.

[0113] Thus, as used herein, the term "substituted aryl" includes aryl groups as defined herein wherein one or more atoms or functional groups of the aryl group are replaced by another atom or functional group, including, for example, alkyl, halogen, haloalkyl, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

[0114] Specific examples of aryl groups 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.

[0115] "Heterocyclic", "heterocycle" or "heterocyclo" as used herein alone or as part of another group refers to an aliphatic (e.g., a fully or partially saturated heterocycle) monocyclic or bicyclic ring system containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms selected from oxygen, sulfur, and substituted or unsubstituted nitrogen) inserted along the cyclic alkyl or aryl carbon chain. Monocyclic ring systems are exemplified by any 5-membered or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. The 5-membered ring has 0-2 double bonds, and the 6-membered ring has 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, oxirane, azetidine, azacyclopentane, oxadiazine, cyclopentadienyl, cyclohexane ... Aziridine, diazepine 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazolidine, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene (also known as thiacyclohexane), tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic systems are exemplified by any of the above monocyclic systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic system as defined herein. Representative examples of bicyclic systems include, but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, carbazole, cinnoline, indazole, indole, dihydroindole, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyridine, etc. These rings include quaternized derivatives thereof and may be optionally substituted with one or more alkyl and / or aryl group substituents.

[0116] As used herein, "substituted heterocycle" refers to a heterocycle group in which one or more hydrogen atoms are replaced with a substituent.

[0117] The term "N-heterocycle" refers to a heterocycle in which at least one heteroatom 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.

[0118] "Substituted N-heterocycle" refers to an N-heterocycle in which one or more hydrogens are replaced with a substituent.

[0119] The term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system (fused ring system, bridged ring system or spirocyclic ring system) containing one or more heteroatoms inserted along the cyclic aromatic carbon chain (e.g., 1, 2 or 3 heteroatoms selected from oxygen, sulfur and substituted or unsubstituted nitrogen, wherein N-oxides, sulfur oxides and dioxides are permitted heteroatom substituents). In some embodiments, the monocyclic heteroaryl group is a five- to seven-membered aromatic ring. Representative heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyridine and pyrazolopyrimidine.

[0120] The term "substituted heteroaryl" refers to a heteroaryl group as defined herein, wherein one or more hydrogen atoms are replaced by a substituent.

[0121] "Aralkyl" refers to an aryl-alkyl- or -alkyl-aryl group, wherein the aryl and alkyl are as previously described 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, phenethyl, and naphthylmethyl.

[0122] "Alkylene" may refer to a straight or branched divalent aliphatic hydrocarbon group having 1 to about 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms). Alkylene groups may be straight or branched. Alkylene groups may also be optionally unsaturated (i.e., include alkenyl or alkynyl groups) and / or substituted with one or more "alkyl group substituents." One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") may be optionally inserted along the alkylene group, wherein the nitrogen substituent is an alkyl group as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexyl (-CH6H 10 –); –CH=CH—CH=CH–; –CH=CH–CH2–;–(CH2) q –N(R)–(CH2) r-, wherein 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 a lower alkyl group; methylenedioxy (-O-CH2-O-); and ethylenedioxy (-O-(CH2)2-O-). The alkylene group may have from about 2 to about 3 carbon atoms and may further have 6-20 carbons.

[0123] "Arylene" refers to a divalent aromatic group which may be substituted or unsubstituted.

[0124] The term "aralkylene" refers to a divalent group comprising a combination of alkylene and arylene groups (eg, -arylene-alkylene-, alkylene-arylene-alkylene-, arylene-alkylene-arylene-, etc.).

[0125] Similarly, the terms "cycloalkylene," "heterocyclylene," and "heteroarylene" refer to divalent cycloalkyl, heterocyclyl, and heteroaryl groups, which may be optionally substituted with one or more substituents.

[0126] As used herein, the term "acyl" refers to an organic carboxylic acid group in which the -OH of the carboxylic acid group has been replaced by another substituent. Thus, an acyl group may be represented by RC(=O)-, wherein R is an alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl or substituted aryl group as defined herein. Thus, the term "acyl" specifically includes arylacyl groups, such as benzoyl groups. Specific examples of acyl groups include acetyl (i.e., -C(=O)CH3) and benzoyl.

[0127] "Alkoxy" refers to an alkyl-O- group, wherein the alkyl group is as previously described, including substituted alkyl groups. As used herein, the term "alkoxy" may refer to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and pentoxy. The terms "oxyalkyl" and "alkoxy" may be used interchangeably with "alkoxyl".

[0128] "Aryloxy" and "aryloxy" refer to an aryl-O-group, wherein the aryl group is as previously described, including substituted aryl groups. The term "aryloxy" as used herein may refer to a phenoxy or hexyloxy group, and refers to an alkyl, substituted alkyl, or alkoxy substituted phenoxy or hexyloxy group.

[0129] "Aralkyloxyl" or "aralkoxy" refers to an aralkyl-O- group in which the aralkyl group is as previously described. An exemplary aralkyloxy group is benzyloxy.

[0130] The term "carbonyl" refers to the group -C(=O)-. The term "carbonyl carbon" refers to the carbon atom of the carbonyl group. Other groups such as, but not limited to, acyl groups, anhydrides, aldehydes, esters, lactones, amides, ketones, carbonates, and carboxylic acids include carbonyl groups.

[0131] The terms "carboxyl" and "carboxylic acid" refer to -C(=O)OH or -C(=O)O - Group.

[0132] The term "acyl chloride" may refer to a -C(=O)Cl group.

[0133]

[0066] The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo groups.

[0134] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogen groups. The term "perhaloalkyl" refers to an alkyl group as defined herein in which all CH bonds are replaced with carbon-halogen bonds. The term "perfluoroalkyl" refers to an alkyl group in which all CH bonds are replaced with CF bonds. An exemplary perfluoroalkyl group is trifluoromethyl (-CF3).

[0135] The term "sulfonyl" refers to a -S(=O)2R group, where R is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl. The term "alkylsulfonyl" refers to a -S(=O)2R group, where R is alkyl or substituted alkyl. In some embodiments, the sulfonyl group is -S(=O)2CH3.

[0136] The term "ester" refers to an R'-OC(=O)- group, wherein the carbonyl carbon is attached to another carbon atom and wherein R' is an alkyl, cycloalkyl, aralkyl, or aryl group, wherein the alkyl, cycloalkyl, aralkyl, or aryl group is optionally substituted. The term "esterification" may refer to the formation of an ester by contacting a compound containing a carboxylic acid or a derivative thereof (e.g., an acid chloride) with a compound containing a hydroxyl group (e.g., an alcohol or a phenol).

[0137] The term "amide" refers to a compound comprising the structure R'-NR"-C(=O)-R, wherein R is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl, and wherein R' and R" are independently hydrogen, alkyl, aralkyl, or aryl, wherein the alkyl, aralkyl, or aryl is optionally substituted. In some embodiments, R' is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl.

[0138] The term "urea" as used herein refers to a compound comprising the structure R-NR'-C(=O)-NR'-R, wherein each R is independently alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl, and wherein each R' is independently H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl.

[0139] The term "amine" refers to a molecule having the formula N(R)3 or a protonated form thereof, wherein each R is independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, or wherein two R groups together form an alkylene or arylene group. The term "primary amine" refers to an amine wherein at least two R groups are H. The term "secondary amine" refers to an amine wherein only one R group is H. The term "alkylamine" may refer to an amine wherein two R groups are H and the other R group is alkyl or substituted alkyl. A "dialkylamine" may refer to an amine wherein two R groups are alkyl. An "arylamine" may refer to an amine wherein one R group is aryl. Amines may also be protonated, i.e., have the formula [NH(R)3] + .

[0140] 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 where at least one R is alkyl or substituted alkyl. The term "dialkylamino" refers to an aminoalkyl group where the two R groups are alkyl or substituted alkyl groups which may be the same or different.

[0141] The terms "amido" and "aminoacyl" refer to the group -N(R)-C(=O)R', where R is selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and where R' is selected from alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl.

[0142] The term "cyano" refers to a -C≡N group.

[0143] The terms "hydroxyl" and "hydroxy" refer to an -OH group.

[0144] The terms "sulfhydryl" and "thiol" refer to a -SH group.

[0145] The term "oxo" refers to compounds previously described herein wherein a carbon atom is replaced with an oxygen atom.

[0146] The term "nitro" refers to the -NO2 group.

[0147] The term "thioalkyl" may refer to a group -SR, where R is selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl. Similarly, the terms "thioaralkyl" and "thioaryl" refer to a -SR group, where R is aralkyl and aryl, respectively.

[0148] As used herein, the terms "treatment" and "treating" and the like refer to any treatment of a disease and / or condition in an animal or mammal, particularly a human, and include inhibiting the disease, disorder and / or condition, i.e., preventing its development; and relieving the disease, disorder and / or condition, i.e., causing regression of the disease, disorder and / or condition.

[0149] As used herein, the phrase "protecting group" includes any suitable protecting group; "protected form" refers to a substituent in which an atom such as hydrogen has been removed and replaced by a corresponding protecting group. Protecting groups are known. See generally TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999). Examples include, but are not limited to: hydroxyl protecting groups (for producing protected forms of hydroxyl); carboxyl protecting groups (for producing protected forms of carboxylic acids); amino protecting groups (for producing protected forms of amino); sulfhydryl protecting groups (for producing 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-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, p-methoxybenzyl diphenylmethyl, triphenylmethyl (trityl), tetrahydrofuranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, acetyl (Ac), benzoyl (Bn) and trimethylsilyl (TMS) and the like; formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, benzyl, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) and the like; and hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters or thiocarbonates and the like.

[0150] 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 different from the orthosteric site (i.e., the primary binding site of the macromolecule). An allosteric modulator can indirectly affect the action of an orthosteric ligand or primary ligand that binds at the orthosteric site. For example, an allosteric modulator of the CB1 receptor can bind to the receptor at a site that is different from the orthosteric site, resulting in a change in the receptor conformation. Thus, the interaction properties of the receptor with respect to the orthosteric ligand and the cellular host environment can be altered in the positive or negative direction, referred to as a positive allosteric modulator ("PAM") and a negative allosteric modulator ("NAM"), respectively. Allosteric modulators can exhibit the following pharmacological properties: (i) affinity modulation, in which the resulting conformation can alter the association or dissociation rate of the orthosteric ligand; (ii) efficacy modulation, in which the allosteric effect can alter the intracellular response and lead to changes in the signaling capacity of the orthosteric ligand; and / or (iii) agonism / inverse agonism, in which the allosteric modulator can perturb receptor signaling in the positive or negative direction, whether the orthosteric modulator is present or not.

[0151] Preclinical and clinical studies have shown that blocking CB1R is a promising strategy for treating many common drugs of abuse as well as many other pathologies, including, for example, but not limited to, obesity, anxiety, cancer, inflammation, Parkinson's disease, osteoporosis, female infertility, metabolic disorders, pain, stroke, hypotension, and intestinal hypoactivity. Unfortunately, psychiatric side effects such as depression, anxiety, or even suicidal ideation have limited the use of CB1R antagonists / inverse agonists in the clinic to date.

[0152] Despite this setback, CB1R remains a target for drug development, and various strategies have been explored to overcome the psychiatric side effects of CB1R signaling while retaining the beneficial therapeutic effects. Like many GPCRs, CB1R exhibits high levels 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. Bouaboula et al. , J. Biol. Chem. 1997, 272, 22330-22339. Since constitutive activity is important for maintaining cellular homeostasis, the side effects of the CB1R antagonist / inverse agonist rimonabant are thought to derive from its CB1R inverse agonist effect, which reduces CB1R basal tone. Therefore, it has been speculated that neutral antagonists that attenuate CB1R signaling under hyperactive conditions but leave CB1R basal levels unchanged may 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 also shown promising therapeutic efficacy in the treatment of obesity and diabetes without the tendency for central nervous system (CNS) side effects. See Chorvat , Bioorg. Med. Chem. Lett. 2013, 23, 4751-4760.

[0153] Furthermore, the discovery of CB1R allosteric binding sites has provided a promising alternative approach to modulating CB1R signaling for therapeutic benefit. Allosteric modulators target CB1R at its allosteric binding site, offering several advantages over allosteric ligands, such as better receptor subtype selectivity, lower risk of overdose due to "ceiling" effects, and more transient pharmacological effects due to their reliance on the presence of endocannabinoids. See Nguyen et al. ,Med.Res.Rev.2017,37,441-474.

[0154] The structures of previously studied CB1R negative allosteric modulators Org27569 (known compound 1) and PSNCBAM-1 (known compound 2) are shown below. German et al. , J. Med. Chem. 2014, 57, 7758-7769; and Nguyen et al. , Bioorg. Med. Chem. 2015, 23, 2195-2203. For example, compound 2 is known to exhibit positive binding synergy with CP55,940, a cannabinoid receptor agonist that mimics the effects of THC; reduces the efficacy of the agonist in several functional assays; and reduces food intake and body weight in rats. See Horswill et al. , Br. J. Pharmacol. 2007, 152, 805-814.

[0155] Structure-activity relationship (SAR) efforts with PSNCBAM-1 / known compound 2 indicated that the pyrrolidinyl ring is not required for CB1R modulatory activity and that the pyridyl ring can be replaced by a substituted benzene ring or a five-membered heterocycle, such as in RTICBM-229 (known compound 5), which was also shown in [ 35 S] showed greater potency than the known compound 2 in the GTPγS binding assay and in the [ 3 H] CP55,940 binding assay. 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.

[0156]

[0157] The most special ones are:

[0158]

[0159] Structures of representative indole-based and diarylurea-based CB1 allosteric modulators.

[0160] Efforts to optimize the diarylurea-based known compound 2 also yielded compound RTICBM-74 (known compound 4). Known compound 4 attenuated prime-induced recapitulation of cocaine seeking. RTICBM-28 (known compound 3), in which the chloro group in the exophenyl ring of known compound 2 was replaced by a cyano group, reduced the potency of THC in drug discrimination, demonstrating the therapeutic potential of these CB1R allosteric modulators for treating relapse in cocaine addiction (see Nguyen et al. , J. Med. Chem. 2017, 60, 7410-7424) and THC dependence. See Gamage et al. , Neuropharmacology 2017, 125, 365-375. Overall, the SAR of the outer benzene ring indicates that the 4-position is favorable for electron-withdrawing functions. German et al. , J. Med. Chem. 2014, 57, 7758-7769.

[0161] The presently disclosed subject matter is based in part on further efforts to expand the understanding of the diaryl urea based scaffold of known compound 2 by structural optimization at the middle phenyl ring described in previously studied compounds, and the understanding of the aryl-alkyl urea based scaffold of known compound 6 (RTICBM-189). RTICBM-189 (6), in which the central phenyl group of known compound 2 is replaced with an ethylene group, attenuates drug-induced cocaine seeking in rats at 10 mg / kg. See Nugyen et al. , J. Med. Chem. 2022, 65, 257-270. The SAR of the central benzene ring indicates that an aromatic ring is not required and alkyl linkers can be tolerated.

[0162] 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 fully explored. The squaramide is attached to an aliphatic group (e.g., ethylene) or an aromatic group (e.g., phenyl) on the right side as depicted.

[0163]

[0164] Replacing the urea functional group with squaramide led to a series of products with unique chemical structures. These novel compounds have important roles in calcium mobilization and [ 35 Compound 7 has comparable in vitro activity in the [S]GTPγS binding assay (Tables 1 and 2). Compound 7 has better metabolic stability than PSNCBAM-1 (t 1 / 2 : 40 min vs. 13 min), and at a lower dose of 5.6 mg / kg ip showed better in vivo efficacy in attenuating cocaine re-seeking behavior in rats ( Figure 1 A) without affecting movement ( Figure 1 B) In conclusion, this novel series of CB1 receptor allosteric modulators possess promising in vitro and in vivo properties.

[0165]

[0166] Therefore, the alternative approach of targeting the CB1 pathway via allosteric modulators has emerged as a promising strategy to modulate this therapeutically valuable CB1 receptor while avoiding the side effects of orthosteric ligands.

[0167] The present disclosure describes the development of CB1 allosteric modulators based on squaramides. They are structurally different from previously disclosed CB1 allosteric modulators based on ureas. In particular, compound 1 ( Figure 1 ) showed better metabolic stability in rat liver microsomes than PSNCBAM-1 / known compound 2 and was effective in attenuating cocaine reinstatement behavior at a low dose of 5.6 mg / kg ip.

[0168] In some embodiments, the presently disclosed subject matter provides a compound having a structure of Formula (I) or Formula (II).

[0169] The compounds disclosed in the present invention may contain pharmaceutically acceptable salts. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts, and combinations thereof.

[0170] 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, etc. 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, dimethoxysalicylic 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, sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates, etc.

[0171] Base addition salts include, but are not limited to, 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, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, such as lysine and arginine dicyclohexylamine, and the like.

[0172] Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, etc. Examples of ammonium salts and alkylated ammonium salts include ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, ethylammonium salts, hydroxyethylammonium salts, diethylammonium salts, butylammonium salts, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc.

[0173] In addition, the compounds disclosed by the present invention may have one or more polymorphs or amorphous crystalline forms, which themselves are intended to be included in the scope of the subject matter disclosed by the present invention. In addition, some compounds of the subject matter disclosed by the present invention may form solvates with water (i.e., hydrates) or common organic solvents (e.g., tetrahydrofuran (THF), ethanol (EtOH), methanol (MeOH) etc.). Therefore, the solvates of the compounds disclosed by the present invention are also intended to be included in the scope of the subject matter disclosed by the present invention.

[0174] The compounds disclosed herein can be formulated according to conventional procedures suitable for the desired route of administration. Therefore, in some embodiments, the subject matter disclosed in the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as disclosed above (e.g., a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable carrier. The therapeutically effective amount can be determined by testing the compound in an in vitro or in vivo model, and then inferring the dosage in the subject of interest (e.g., human). The therapeutically effective amount should be sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the subject to be treated with the composition.

[0175] Pharmaceutically acceptable carriers are well known to those skilled in the art, and include, but are not limited to, about 0.01 to about 0.1 M, and preferably 0.05 M phosphate buffer 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 the subject matter disclosed in the present invention include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers suitable for the subject matter disclosed in the present invention include, but are not limited to, water, ethanol, alcohol / water solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets, etc.

[0176] Liquid carriers suitable for the disclosed subject matter of the present invention can be used to prepare 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 the two, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity modifiers, stabilizers or osmotic pressure regulators.

[0177] Liquid carriers suitable for the subject matter disclosed herein include, but are not limited to, water (partially containing additives as described above, such as cellulose derivatives, preferably sodium carboxymethylcellulose solutions), alcohols (including monohydric and polyhydric alcohols, such as glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, carriers may also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers may be used to contain sterile liquid forms of compounds for parenteral administration. Liquid carriers for pressurized compounds disclosed herein may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0178] Solid carriers suitable for the subject matter disclosed in the present invention include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, and the like. The solid carrier may further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, or tablet disintegrants; it may also be an encapsulating material. In powders, the carrier may be a finely divided solid mixed with a finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in a suitable proportion and is pressed into a 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, polyvinyl pyrrolidine, low melting waxes, and ion exchange resins.

[0179] Suitable parenteral vehicles for use with the presently disclosed subject matter include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.

[0180] Carriers suitable for the subject matter disclosed herein can be mixed with disintegrants, diluents, granulating agents, lubricants, binders, and the like as needed using conventional techniques known in the art. The carrier can also be sterilized using methods that do not adversely react with the compound, as is generally known in the art. The compounds disclosed herein can take the form of a suspension, solution, or emulsion, such as in an oily or aqueous vehicle, and can contain formulation agents, such as suspending agents, stabilizers, and / or dispersants. The compounds disclosed herein can also be formulated as formulations for implantation or injection. Thus, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin or as a sparingly soluble derivative (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for formulation with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use. Suitable formulations for each of these administration methods can be found, for example, in Remington:The Science and Practice of Pharmacy , A. Gennaro, ed., 20th ed., Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0181] For example, formulations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of plant origin, hydronaphthalene, etc. as common excipients. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers may be useful excipients for controlling the release of active compounds. 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, for example, lactose as an excipient, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or may be gels to be administered intranasally. Formulations for parenteral administration may also include glycocholate for buccal administration, methoxy salicylate for rectal administration or citric acid for vaginal administration.

[0182] In addition, the formulation for intravenous administration can include a solution in a sterile isotonic aqueous buffer. Where necessary, the formulation can also include a solubilizing agent and a local anesthetic to alleviate the pain at the site of injection. Usually, the composition is separated or mixed together to provide in a unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate in an airtight sealed container, such as an ampoule or a sachet of the amount of the airtight sealed container indicating the active agent. In the case of a compound to be administered by infusion, an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water can be distributed. In the case of a compound administered by injection, an ampoule of sterile water for injection or saline can be provided so that the composition can be mixed before administration.

[0183] Suitable formulations further include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes which render the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0184] The compound may further be formulated for topical application. Suitable topical formulations include one or more compounds in the form of a liquid, lotion, cream or gel. Topical application may be accomplished by direct application to the treatment area. For example, such application may be accomplished by rubbing a formulation (such as a lotion or gel) onto the skin of the treatment area, or by spraying a liquid formulation onto the treatment area.

[0185] In some formulations, bioimplant materials may be coated with compounds to improve the interaction between cells and the implant.

[0186] The formulation of the compound may contain a small amount of a wetting or emulsifying agent, or a pH buffering agent. The formulation containing the compound may be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder.

[0187] The compound can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0188] Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharine, cellulose, magnesium carbonate, and the like.

[0189] In some embodiments, pharmaceutical compositions comprising compounds of the presently disclosed subject matter may contain agents that control the release of the compound, thereby providing timed or sustained release of the compound.

[0190] As described above, the CB1 and CB2 cannabinoid receptors belong to the G protein-coupled receptor (GCPR) family, a superfamily of receptors with a unique pattern of seven transmembrane domains that inhibit N-type calcium channels and / or adenylate cyclase to inhibit Q-type calcium channels.

[0191] CB1 receptors are present in the CNS and are primarily expressed in brain regions associated with memory and movement, such as the hippocampus (memory storage), cerebellum (coordination of motor function, posture, and balance), basal ganglia (motor control), hypothalamus (thermal regulation, neuroendocrine release, appetite), spinal cord (nociception), cerebral cortex (vomiting), and 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 intestine (e.g., esophagus, duodenum, jejunum, ileum, and colon), control of esophageal and gastrointestinal motility), lung smooth muscle cells (bronchial dilation), ciliary body of the eye (intraocular pressure). CB2 receptors appear to be primarily expressed in lymphoid tissues (cell-mediated and innate immunity), peripheral nerve endings (peripheral nervous system), spleen immune cells (immune system regulation), and retina (intraocular pressure). CB2 mRNA has also been found in the CNS in cerebellar granule cells (coordinating motor function),

[0192] Therefore, cannabinoid receptor allosteric modulators (including compounds of the present disclosure) can be used to treat, ameliorate or prevent cannabinoid receptor-mediated syndromes, conditions or diseases, including but not limited to controlling appetite, regulating metabolism, diabetes, glaucoma-related intraocular pressure, pain, social and emotional disorders, epilepsy-related disorders, substance abuse disorders, learning, cognitive and / or memory disorders, intestinal disorders, respiratory disorders, motor activity disorders, movement disorders, immune disorders or inflammatory diseases, controlling organ contractions and muscle spasms, enhancing learning, cognition and / or memory, regulating cell growth (e.g., treating cancer), providing neuroprotection, etc.

[0193] Appetite-related syndromes, conditions or diseases include obesity, overweight conditions, anorexia, bulimia, cachexia, appetite disorders, etc. Obesity-related syndromes, conditions or diseases include obesity due to genetics, diet, food intake, metabolic syndrome, conditions or diseases, hypothalamic conditions or diseases, age, reduced activity, abnormal fat mass distribution, abnormal fat compartment distribution, etc. Metabolism-related syndromes, conditions 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, conditions or diseases include glucose disorders, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, etc.

[0194] Type II diabetes (non-insulin-dependent diabetes mellitus (NIDDM)) is a metabolic disorder (i.e., a metabolic-related syndrome, condition, or disease) in which glucose dysregulation and insulin resistance lead to chronic, long-term medical complications in both adolescents and adults that affect the eyes, kidneys, nerves, and blood vessels, and may lead to blindness, end-stage renal disease, myocardial infarction, or amputation, among others. Blood glucose dysregulation includes the inability to produce enough insulin (abnormal insulin secretion) and the inability to use insulin effectively (resistance to the action of insulin in target organs and tissues). Individuals with type II diabetes have a relative insulin deficiency. That is, in such individuals, plasma insulin levels are normal to high in absolute terms, although they are lower than predicted values ​​for the level of plasma glucose present. Type II diabetes is characterized by the following clinical signs or symptoms: persistently elevated plasma glucose concentrations or hyperglycemia; polyuria; polydipsia and / or polyphagia; chronic microvascular complications, such as retinopathy, nephropathy, and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension. These microvascular and macrovascular complications may lead to blindness, end-stage renal disease, amputation, and myocardial infarction. Insulin resistance syndrome (IRS) (also known as syndrome X, metabolic syndrome or metabolic syndrome X) is a disorder that presents 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.

[0195] Social or emotional related syndromes, disorders or diseases include depression, anxiety, psychosis, social-emotional disorders or cognitive disorders, etc. Substance 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. Learning, cognition or memory related syndromes, disorders or diseases include memory loss or impairment due to age, disease, drug side effects (adverse events), etc.

[0196] Muscle spasticity syndromes, disorders or diseases include multiple sclerosis, cerebral palsy, etc. Autonomic activity and movement syndromes, disorders or diseases include stroke, Parkinson's disease, multiple sclerosis, epilepsy, etc. Intestinal related syndromes, disorders or diseases include disorders related to intestinal dysmotility (with or without pain, diarrhea or constipation), irritable bowel syndrome (and other forms of intestinal dysmotility, etc.), inflammatory bowel disease (such as ulcerative colitis, Crohn's disease) and celiac disease. Respiratory related syndromes, disorders or diseases include chronic obstructive pulmonary disease, emphysema, asthma, bronchitis, etc. Immune or inflammation related syndromes, disorders or diseases include allergies, rheumatoid arthritis, dermatitis, autoimmune diseases, immunodeficiency, chronic neuropathic pain, etc.

[0197] Syndromes, disorders or diseases associated with cell growth include cancers such as, but not limited to, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, and renal cell carcinoma, etc. Syndromes, disorders or diseases associated with pain include pain mediated by central and peripheral pathways, bone and joint pain, pain associated with migraine, cancer pain, menstrual cramps, labor pain, etc. Syndromes, disorders or diseases associated with neurodegeneration include Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical damage associated with traumatic head or brain injury, brain inflammation, eye injury or stroke, etc.

[0198] Based on the antagonistic activity, the compounds disclosed in the present invention can be used as agents for preventing and / or treating diseases mediated by CB1 receptors, such as mental illnesses, including schizophrenia, anxiety, stress, depression, epilepsy, neurodegenerative disorders, spinocerebellar disorders, cognitive disorders, craniocerebellar trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive-compulsive disorder (OCD), amnesia, Alzheimer's disease, thymic disorders, Tourette syndrome, tardive dyskinesia Disorders, bipolar disorder, cancer, drug-induced movement disorders, dystonia, septic shock, hemorrhagic shock, hypotension, insomnia, immune diseases including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorders such as bulimia, anorexia, obesity, non-insulin-dependent diabetes mellitus (NIDDM), memory disorders, urinary system diseases, cardiovascular disorders, infertility, infection, demyelination-related diseases, neuroinflammation, viral encephalitis, cerebrovascular events, cirrhosis or gastrointestinal disorders (including intestinal transit disorders). In addition, the compounds disclosed in the present invention can be used as agents for treating substance addiction. For example, in some embodiments, the compounds disclosed in the present invention can be used to treat withdrawal from long-term treatment, alcohol dependence or drug abuse (e.g., opioids, barbiturates, marijuana, cocaine, heroin, amphetamines, phencyclidine, hallucinogens, benzodiazepines In addition, the compounds disclosed in the present invention can be used as agents for enhancing the analgesic activity of analgesics or anesthetics, or agents for smoking cessation (quitting smoking or nicotine dependence).

[0199] Thus, in some embodiments, the presently disclosed subject matter provides a method of treating a CB1R-mediated disease or condition in a subject in need thereof, wherein the method comprises 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.

[0200] For the methods of the subject matter disclosed herein, the preferred subject is a vertebrate subject. The preferred vertebrate is warm-blooded; the preferred warm-blooded vertebrate is a mammal. The subject treated by the method disclosed herein is ideally a human, although it should be understood that the principles of the subject matter disclosed herein indicate that it is effective for all vertebrate species to be included in the term "subject". In this context, a vertebrate is understood to be any vertebrate species in need of treatment for a CB1R-mediated condition. As used herein, the term "subject" includes both human and animal subjects. Therefore, veterinary therapeutic uses are provided according to the subject matter disclosed herein.

[0201] Thus, the presently disclosed subject matter provides treatments for mammals, such as humans, and those mammals that are important because they are endangered, such as Siberian tigers; mammals of economic importance, such as animals raised on farms for human consumption; and / or animals of social importance to humans, such as animals kept as pets or in zoos. Examples of such animals include, but are not limited to, carnivores, such as cats and dogs; pigs, including pigs, hogs, and wild boars; ruminants and / or ungulates, such as cattle, bulls, sheep, giraffes, deer, goats, bison, and camels; and horses. Treatments for birds are also provided, including those species of birds that are endangered and / or kept in zoos, as well as poultry, and more specifically domesticated poultry, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, etc., because they are also of great economic importance to humans. Thus, treatments for livestock are also provided, including, but not limited to, domestic pigs, ruminants, ungulates, horses (including racehorses), poultry, etc. In some embodiments, the subject is a human.

[0202] In some embodiments, the CB1R-mediated disease or condition is selected from the group including, but not limited to, drug addiction (e.g., alcohol, tobacco or other substance addiction), obesity, cancer (e.g., endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, renal cell carcinoma or myotrophic small round cell tumor), pain (e.g., chronic pain, acute pain, somatic pain, visceral pain, local pathological pain, inflammatory pain), female infertility, memory loss, cognitive dysfunction, Parkinson's disease, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0203] Treatment of anxiety can include, for example, treatment of anxiety disorders, such as, but not limited to, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, social phobia, agoraphobia or other more specific phobias. Dietary disorders include, but are not limited to, anorexia, bulimia and binge eating disorder. Mood disorders include, but are not limited to, manic depression (bipolar disorder), major depression and postpartum depression. Cognitive dysfunction includes, for example, dementia, attention deficit hyperactivity disorder (ADHD), autism and autism spectrum disorder (ASD), Down syndrome, traumatic brain injury (TBI), dyslexia. Alcohol abuse and substance abuse-related disorders can include abuse and / or addiction to alcohol, nicotine or other drugs (e.g., opiates (e.g., heroin), cannabinoids, inhalants and psychostimulants such as cocaine, amphetamines and methamphetamine).

[0204] More specifically, diseases or conditions in which it is desirable to inhibit the biological activity of CB1R or to conduct signaling via CB1R include, but are not limited to, obesity, alcoholism, and other substance abuse and / or addiction-related disorders. Therefore, in some embodiments, the subject matter disclosed herein provides a method for treating obesity in a subject in need thereof, wherein the method comprises 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.

[0205] As a further example, the CB1R allosteric modulators disclosed herein can find application in treating substance use, abuse and / or addiction (including drug, alcohol and nicotine addiction), addictive behavior, and symptoms and conditions associated with substance abuse and addiction, as exemplified herein. In some embodiments, the addiction is to at least one of nicotine, ethanol, cocaine, opioids, amphetamines, marijuana, or synthetic cannabinoid agonists.

[0206] Addiction to substances such as alcohol, opiates, cannabinoids, nicotine cannabis, and psychostimulants is typically associated with a number of undesirable or negative behaviors exhibited by the addict that may exacerbate, prolong, or induce relapse to substance use or abuse, reinforce or exacerbate addiction, or induce relapse to addiction and addictive behavioral patterns. Other examples of negative behaviors associated with substance use or addiction include anxiety, irritability, stress responses, and cue reactivity. A particular problem with alcoholism, as with substance addiction in general, is the chronic relapsing nature of the condition. This behavioral pattern can be effectively modeled in rodents, where a large body of research has demonstrated that drug priming, psychological stress, or re-presentation of cues previously associated with drug availability can reinstate drug-seeking behavior after extinction even in the absence of subsequent drug reward.

[0207] In some embodiments, the subject disclosed herein provides a method for preventing or inhibiting substance abuse and / or addiction, addictive behavior, or symptoms, behaviors or conditions associated with substance abuse and / or addiction, the method comprising administering to a subject in need thereof an effective amount of a CB1R allosteric modulator compound as 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.

[0208] In certain embodiments, the behavior related to substance abuse and / or addiction includes substance use (i.e., self-administration) and / or substance seeking behavior. In certain embodiments, substance abuse and / or addiction includes alcohol abuse and / or addiction (i.e., alcoholism). In certain embodiments, substance abuse and / or addiction includes nicotine abuse and / or addiction. In certain embodiments, substance abuse and / or addiction includes opiate abuse and / or addiction. In certain embodiments, the behavior related to substance abuse or addiction is relapse.

[0209] An effective amount of a compound disclosed herein includes an amount sufficient to produce a significant effect, such as, but not limited to, reducing or stopping self-administration of alcohol or another substance of abuse, weight loss, no weight gain, etc. The actual dosage level of the active ingredient in the therapeutic compound of the subject matter disclosed in the present invention can be varied so as to administer an amount of the active compound that is effective to achieve the desired therapeutic response for a particular subject and / or application. Preferably, the minimum dose is administered, and the dose is escalated to the minimum effective amount in the absence of dose-limiting toxicity. The determination and adjustment of the therapeutically effective dose, as well as the assessment of when and how to make such adjustments are known to those of ordinary skill in the art.

[0210] The therapeutically effective amount of a compound can depend on many factors. For example, the species, age and weight of the subject, the exact condition to be treated and its severity, the nature of the formulation and the route of administration are all factors that can be considered. In certain embodiments, the therapeutically effective amount is in the range of about 0.1 to about 100 mg / kg of subject weight per day. In certain embodiments, the therapeutically effective amount is in the range of about 0.1 to about 20 mg / kg of body weight per day. Therefore, for an adult mammal of 70 kg, an example of the actual amount per day will be between about 10 mg and about 2000 mg. This amount can be given in a single dose per day or in the form of multiple (e.g., 2, 3, 4 or 5) divided doses per day, so that the total daily dose is the same. The effective amount of a salt or its solvate can be determined as the ratio of the effective amount of the formula compound itself.

[0211] The compounds of the disclosed subject matter of the present invention can also be used as adjunctive therapy, additional therapy or complementary therapy for treating the above-mentioned diseases / disorders. The adjunctive therapy, additional therapy or complementary therapy means that the compounds of the disclosed subject matter of the present invention are concomitantly or sequentially applied to a subject who has received, is receiving or is about to receive one or more other therapeutic agents (e.g., one or more known antidepressants, antipsychotics or antianxiety drugs) for treating a specified condition.

[0212] In some embodiments, the presently disclosed subject matter provides a compound of the present disclosure for use as an active therapeutic substance. In some embodiments, the compound is used to treat a disease mediated by CB1R. In some embodiments, the presently disclosed subject matter provides the use of a compound of the present disclosure for preparing a medicament for treating a disease mediated by CB1R.

[0213] In some embodiments, the subject matter disclosed herein provides a method for regulating the activity of CB1R, wherein the method comprises contacting a sample comprising CB1R with a compound of one of the disclosures, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the sample is an in vitro 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 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.

[0214] Antagonists disclosed in the present invention can be prepared using standard synthetic methods known in the art. For example, compounds can be prepared by the methods described below or variations thereof that will be apparent to those skilled in the art based on the present disclosure. As required, protecting groups known in the art can be utilized during the synthesis of compounds.

[0215] Synthesis schemes and examples

[0216]

[0217] Scheme 1: Reagents and conditions a) 3,4-diethoxy-3-cyclobutene-1,2-dione, EtOH, reflux, 24 h b) amine, Et3N, EtOH, reflux, 24 h.

[0218] General Procedure (GP): A solution of 2 (1 eq), the corresponding amine (1.2 eq) and triethylamine (1.1 eq) in ethanol (0.15 M) was refluxed for 24 h. After cooling to room temperature, the precipitate was filtered and dried to give the desired product.

[0219] 3-[(4-Chlorophenyl)amino]-4-ethoxycyclobut-3-ene-1,2-dione (8): To a refluxing solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (0.53 mL, 3.6 mmol) in ethanol was added dropwise a solution of 4-chloroaniline (0.38 g, 3 mmol). The reaction was refluxed overnight. After cooling to room temperature, the reaction was filtered and the white solid precipitate was washed with ice-cold ethanol and collected as the desired product (0.39 g, 51%). 1 H NMR (300MHz, CHCl3) δ7.32-7.37 (m, 2H), 7.27-7.30 (m, 2H), 4.89 (q, J = 7.16Hz, 2H), 1.52 (t, J = 7.16Hz, 3H). MS(ESI)[M+H] + m / z = 252.2.

[0220] 3-[(4-Cyanophenyl)amino]-4-ethoxycyclobut-3-ene-1,2-dione (9): Prepared in a similar manner to 8 from 3,4-diethoxy-3-cyclobutene-1,2-dione (1.5 mL, 10.2 mmol) and 4-cyanoaniline (1 g, 8.5 mmol) as a white solid (1.5 g, 75%). 1 H NMR (300MHz, DMSO-d6) δ 11.07 (s, 1H), 7.82 (d, J = 8.67Hz, 2H), 7.56 (d, J = 8.85Hz, 2H), 4.79 (q, J = 6.97Hz, 2H), 1.43 (t, J = 7.06Hz, 3H). MS(ESI)[M+H] + m / z = 243.2.

[0221] 3-(Benzylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (10) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and benzylamine (0.04 mL, 0.36 mmol) as a white solid (0.09 g, 90% yield). 1 H NMR (300MHz, DMSO-d6) δ9.73(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.

[0222] 3-[(4-Chlorophenyl)amino]-4-[(2-phenylethyl)amino]cyclobut-3-ene-1,2-dione (11) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and phenethylamine (0.045 mL, 0.36 mmol) as a white solid (0.09 g, 92% yield). 1 HNMR (300MHz, DMSO-d6) δ 9.73 (br.s., 1H), 7.65 (br.s., 1H), 7.19-7.47 (m, 9H), 3.86 (d, J = 5.46Hz, 2H), 2.90 (t, J = 5.84Hz, 2H). MS(ESI)[M+H] + m / z=327.2

[0223] 3-[(4-Chlorophenyl)amino]-4-[(3-phenylpropyl)amino]cyclobut-3-ene-1,2-dione (12) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-phenylpropylamine (0.051 mL, 0.36 mmol) as a white solid (0.10 g, 93% yield). 1 H NMR(300MHz,DMSO-d6)δ9.70(br.s.,1H),7.69(br.s.,1H),7.41(q,J=8.92Hz,4H) ,7.14-7.33(m,5H),3.63(q,J=5.97Hz,2H),2.61-2.70(m,2H),1.82-1.96(m,2H). MS(ESI)[M+H] + m / z = 341.2.

[0224] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (13) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 4-chlorophenethylamine (0.05 mL, 0.36 mmol) as a white solid (0.09 g, 86% yield). 1 H NMR (300MHz, DMSO-d6) δ9.71 (br.s., 1H), 7.62 (br.s., 1H), 7.24-7.50 (m, 9H), 3.84 (d, J = 4.52Hz, 2H), 2.89 (t, J = 5.18Hz, 2H). MS(ESI)[M+H] + m / z = 361.2.

[0225] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (14) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-methylphenethylamine (0.051 mL, 0.36 mmol) as a white solid (0.09 g, 83% yield). 1 H NMR(300MHz,DMSO-d6)δ9.74(br.s.,1H),7.64(br.s.,1H),7.30-7.50(m,4H),7.15-7.25( m, 1H), 7.07 (d, J = 8.85Hz, 3H), 3.84 (d, J = 5.09Hz, 2H), 2.85 (t, J = 6.50Hz, 2H), 2.28 (s, 3H). MS(ESI)[M+H] + m / z = 341.2.

[0226] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (15) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 4-methylphenethylamine (0.051 mL, 0.36 mmol) as a white solid (0.09 g, 83% yield). 1 H NMR(300MHz,DMSO-d6)δ9.73(br.s.,1H),7.62(br.s.,1H),7.30-7.49(m,4H), 7.05-7.23(m,4H),3.83(d,J=6.03Hz,2H),2.85(t,J=6.59Hz,2H),2.27(s,3H). MS(ESI)[M+H] + m / z = 341.2.

[0227] 3-[(4-Chlorophenyl)amino]-4-{[2-(2-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (16) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 4-methylphenethylamine (0.054 mL, 0.36 mmol) as a white solid (0.08 g, 75% yield). 1 H NMR(300MHz,DMSO-d6)δ9.67(br.s.,1H),7.62(br.s.,1H),7.33-7.47(m,4H),7.14-7.26(m,2H),6. 97(d,J=8.10Hz,1H),6.85-6.92(m,1H),3.81(d,J=5.27Hz,2H),3.77(s,3H),2.86(t,J=6.78Hz,2H). MS(ESI)[M+H]+ m / z = 357.2.

[0228] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (17) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-methoxyphenethylamine (0.054 mL, 0.36 mmol) as a white solid (0.08 g, 75% yield). 1 H NMR(300MHz,DMSO-d6)δ9.60(br.s.,1H),7.64(br.s.,1H),7.33-7.46(m,4H),7.23(t,J=7 .91Hz,1H),6.76-6.88(m,3H),3.86(t,J=6.12Hz,2H),3.73(s,3H),2.87(t,J=6.88Hz,2H). MS(ESI)[M+H] + m / z = 357.2.

[0229] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (18) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-methoxyphenethylamine (0.053 mL, 0.36 mmol) as a white solid (0.08 g, 84% yield). 1 H NMR(300MHz,DMSO-d6)δ9.70(br.s.,1H),7.64(br.s.,1H),7.34-7.46(m,4H),7.18(d,J=8 .10Hz, 2H), 6.88 (d, J = 7.72Hz, 2H), 3.77-3.87 (m, 2H), 3.72 (s, 3H), 2.83 (t, J = 6.50Hz, 2H). MS(ESI)[M+H] + m / z = 357.2.

[0230] 3-[(4-Chlorophenyl)amino]-4-({2-[2-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (19) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 2-(trifluoromethyl)phenethylamine (0.053 mL, 0.36 mmol) as a white solid (0.09 g, 76% yield). 1H NMR(300MHz,DMSO-d6)δ9.71(br.s.,1H),7.67-7.78(m,2H),7.65(d,J=7.35Hz,1H),7.52-7.5 9(m,1H),7.45-7.50(m,1H),7.34-7.42(m,4H),3.88(d,J=6.03Hz,2H),3.08(t,J=6.88Hz,2H). MS(ESI)[M+H] + m / z = 395.2.

[0231] 3-[(4-Chlorophenyl)amino]-4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (20) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-(trifluoromethyl)phenethylamine (0.057 mL, 0.36 mmol) as a white solid (0.095 g, 81% yield). 1 H NMR (300MHz, 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 = 5.46Hz, 2H), 3.01 (t, J = 6.88Hz, 2H). MS(ESI)[M+H] + m / z = 395.2.

[0232] 3-[(4-Chlorophenyl)amino]-4-({2-[4-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (21) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 4-(trifluoromethyl)phenethylamine (0.057 mL, 0.36 mmol) as a white solid (0.09 g, 76% yield). 1 H NMR(300MHz,DMSO-d6)δ9.73(br.s.,1H),7.69(d,J=8.10Hz,2H),7.64(br.s.,1H),7.5 1(d,J=7.91Hz,2H),7.33-7.44(m,4H),3.89(d,J=5.65Hz,2H),3.00(t,J=6.78Hz,2H). MS(ESI)[M+H] + m / z = 395.2.

[0233] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (22) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 4-fluorophenethylamine (0.057 mL, 0.36 mmol) as a white solid (0.09 g, 87% yield). 1 H NMR(300MHz,DMSO-d6)δ9.67(br.s.,1H),7.63(br.s.,1H),7.35-7.45(m,4H),7.30(dd, J=5.75,8.38Hz,2H),7.10-7.19(m,2H),3.83(t,J=6.12Hz,2H),2.89(t,J=6.97Hz,2H). MS(ESI)[M+H] + m / z = 345.2.

[0234] 3-[(4-Chlorophenyl)amino]-4-{[2-(2-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (23) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 2-chlorophenethylamine (0.05 mL, 0.36 mmol) as a white solid (0.10 g, 93% yield). 1 H NMR (300MHz, DMSO-d6) δ9.49(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.

[0235] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (7) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-chlorophenethylamine (0.05 mL, 0.36 mmol) as a white solid (0.10 g, 93% yield). 1 H NMR (300MHz, DMSO-d6) δ 9.72 (br.s., 1H), 7.63 (br.s., 1H), 7.27-7.45 (m, 7H), 7.23 (d, J = 7.16Hz, 1H), 3.86 (d, J = 4.52Hz, 2H), 2.91 (t, J = 6.78Hz, 2H). MS(ESI)[M+H] + m / z = 361.2.

[0236] 3-[(4-Chlorophenyl)amino]-4-{[2-(2-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (24) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 2-fluorophenethylamine (0.047 mL, 0.36 mmol) as a white solid (0.09 g, 90% yield). 1 H NMR (300MHz, 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 = 5.84Hz, 2H), 2.94 (t, J = 6.59Hz, 2H). MS(ESI)[M+H] + m / z = 345.2.

[0237] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (25) was prepared according to GP from 8 (0.08 g, 0.3 mmol) and 3-fluorophenethylamine (0.047 mL, 0.36 mmol) as a white solid (0.09 g, 90% yield). 1 H NMR(300MHz,DMSO-d6)δ9.69(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=6.88Hz,2H). MS(ESI)[M+H] + m / z = 345.2.

[0238] 3-[(4-Chlorophenyl)amino]-4-({2-[3-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (26) was prepared according to GP from 8 (0.09 g, 0.35 mmol) and 3-(dimethylamino)phenethylamine (0.085 g, 0.42 mmol) as a white solid (0.075 g, 58% yield). 1 H NMR(300MHz,DMSO-d6)δ9.79(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=6.22Hz,2H),2.86(s,6H),2.78-2.85(m,2H). MS(ESI)[M+H] + m / z = 370.4.

[0239] 3-[(4-Chlorophenyl)amino]-4-({2-[4-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (27) was prepared according to GP from 8 (0.097 g, 0.38 mmol) and 4-(dimethylamino)phenethylamine (0.093 g, 0.46 mmol) as a white solid (0.057 g, 40% yield). 1 H NMR(300MHz,DMSO-d6)δ9.75(br.s.,1H),7.61(br.s.,1H),7.33-7.46(m,4H),7.07(d,J=8.4 8Hz, 2H), 6.69 (d, J = 8.29Hz, 2H), 3.79 (d, J = 5.84Hz, 2H), 2.85 (s, 5H), 2.77 (t, J = 6.78Hz, 2H). MS(ESI)[M+H] + m / z = 370.4.

[0240] 4-[(2-{[2-(3-Chlorophenyl)ethyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzonitrile (28) was prepared according to GP from 9 (0.072 g, 0.3 mmol) and 3-chlorophenethylamine (0.05 mL, 0.36 mmol) as a white solid (0.084 g, 80% yield). 1 H NMR (300MHz, DMSO-d6) δ10.01(br.s.,1H),7.77(d,J=8.67Hz,3H),7.55(d,J=8.48Hz,2H),7. 27-7.40 (m, 3H), 7.24 (d, J = 6.97Hz, 1H), 3.81-3.93 (m, J = 6.03Hz, 2H), 2.92 (t, J = 6.88Hz, 2H). MS(ESI)[M+H] + m / z = 352.2.

[0241] 3-(Biphenyl-3-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (29) was prepared according to GP from 8 (0.053 g, 0.21 mmol) and 3-aminobiphenyl (0.043 g, 0.25 mmol) as a white solid (0.06 g, 75% yield). 1 H NMR (300MHz, DMSO-d6) δ7.85 (s, 1H), 7.70 (d, J = 7.54Hz, 2H), 7.33-7.54 (m, 12H). MS(ESI)[M+H] + m / z = 375.2.

[0242] 3-{3-[6-(Pyrrolidin-1-yl)pyridin-2-yl]-phenyl}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (30) was prepared according to GP from 8 (0.073 g, 0.29 mmol) and 3-[6-(pyrrolidin-1-yl)pyridin-2-yl]aniline (0.084 g, 0.35 mmol) as a white solid (0.105 g, 81% yield). 1 H NMR (300MHz, DMSO-d6) δ8.20 (s, 1H), 7.75 (d, J = 6.78Hz, 1H), 7.40-7.61 (m, 7H), 7.13 (d, J = 7.35Hz, 1H), 6.43 (d, J = 8.48Hz, 1H), 1.96 (t, J = 6.40Hz, 4H). MS(ESI)[M+H] + m / z = 455.2.

[0243] 3-[(4-Chlorophenyl)amino]-4-{[3-(1,3-thiazol-4-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (31) was prepared according to GP from 8 (0.049 g, 0.19 mmol) and 3-(1,3-thiazol-4-yl)aniline (0.034 g, 0.19 mmol) as a white solid (0.105 g, 72% yield). 1 H NMR (300MHz, DMSO-d6) δ9.92-10.09(m,2H),9.22(d,J=1.70Hz,1H),8.03-8.17(m,2H),7.71(d,J=7.35Hz,1H),7.38-7.56(m,7H). MS(ESI)[M+H] + m / z = 382.2.

[0244] 3-[(4-Chlorophenyl)amino]-4-{[3-(thiophen-3-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (32) was prepared according to GP from 8 (0.05 g, 0.2 mmol) and 3-(thiophen-3-yl)aniline (0.034 g, 0.2 mmol) as a white solid (0.06 g, 80% yield). 1 H NMR(300MHz,DMSO-d6)δ9.99(d,J=4.90Hz,2H),7.86-7.93(m,2H),7.68(dd,J=3.01,4.90Hz ,1H),7.56(d,J=4.90Hz,1H),7.49-7.54(m,2H),7.40-7.48(m,4H),7.31(d,J=7.35Hz,1H). MS(ESI)[M+H] + m / z = 381.2.

[0245] 3-[(4-Chlorophenyl)amino]-4-[(4′-fluorobiphenyl-3-yl)amino]cyclobut-3-ene-1,2-dione (33) was prepared according to GP from 8 (0.07 g, 0.28 mmol) and 4′-fluorobiphenyl-3-amine (0.05 g, 0.28 mmol) as a white solid (0.07 g, 73% yield). 1 H NMR (300MHz, DMSO-d6) δ9.99(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)[MH] - m / z = 391.2.

[0246] 3-(Biphenyl-4-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (34) was prepared according to GP from 8 (0.04 g, 0.16 mmol) and biphenyl-4-amine (0.03 g, 0.16 mmol) as a white solid (0.024 g, 40% yield). 1 HNMR (300MHz, DMSO-d6) δ 10.03 (br.s., 2H), 7.65-7.73 (m, 4H), 7.58 (d, J = 8.67Hz, 2H), 7.42-7.54 (m, 6H), 7.31-7.38 (m, 1H). MS(ESI)[MH] - m / z = 373.2.

[0247] 3-[(4-Chlorophenyl)amino]-4-{[2-(2-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (35) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 2-methylphenethylamine hydrochloride (0.029 g, 0.20 mmol) as a white solid (0.030 g, 44% yield). 1 H NMR(400MHz,DMSO-d6)d 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=7.18Hz,2H),2.27(s,3H). MS(ESI)[M+H] + m / z = 341.0.

[0248] 3-[(4-Chlorophenyl)amino]-4-{[2-(pyridin-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (36) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 2-(2-pyridinyl)ethylamine (0.029 g, 0.20 mmol) as a white solid (0.060 g, 92% yield). 1 H NMR(400MHz,DMSO-d6)δ9.72(br.s.,1H),8.49(d,J=4.13Hz,1H),7.67-7.74(m,1H),7.65(b r.s.,1H),7.26-7.40(m,5H),7.19-7.24(m,1H),3.93-4.02(m,1H),3.04(t,J=6.72Hz,2H). MS(ESI)[M+H] + m / z = 328.0.

[0249] 3-[(4-Chlorophenyl)amino]-4-{[2-(pyridin-4-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (37) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 2-(4-pyridinyl)ethylamine (0.029 g, 0.20 mmol) as a white solid (0.060 g, 92% yield). 1 H NMR(400MHz,DMSO-d6)δ9.69(br.s.,1H),8.46(d,J=5.20Hz,2H),7.59(br.s.,1H ),7.29-7.44(m,4H),7.27(d,J=5.35Hz,2H),3.86(m,2H),2.89(t,J=6.80Hz,2H). MS(ESI)[M+H] + m / z = 328.0.

[0250] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-bromophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (38) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 4-bromophenethylamine hydrochloride (0.048 g, 0.20 mmol) as a white solid (0.062 g, 77% yield). 1 H NMR(400MHz,DMSO-d6)δ9.69(br.s.,1H),7.57(br.s.,1H),7.48(d,J=7.95Hz,2H),7.3 0-7.40(m,3H),7.20(d,J=8.10Hz,2H),3.80(d,J=6.42Hz,2H),2.83(t,J=6.80Hz,2H). MS(ESI)[M+H] +m / z = 405.0.

[0251] 3-[(4-Chlorophenyl)amino]-4-{[2-(thiophen-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (39) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 2-(2-aminoethyl)thiophene (0.030 g, 0.20 mmol) as a white solid (0.058 g, 88% yield). 1 H NMR(400MHz,DMSO-d6)δ9.75(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=6.65Hz,2H). MS(ESI)[M+H] + m / z = 333.0.

[0252] 3-{[2-(A-acetylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (40) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 1-[4-(2-aminoethyl)phenyl]ethanone hydrochloride (0.048 g, 0.20 mmol) as a white solid (0.060 g, 82% yield). 1 H NMR(400MHz,DMSO-d6)δ9.72(br.s.,1H),7.88(d,J=7.64Hz,2H),7.63(br.s.,1H ),7.30-7.42(m,6H),3.85(d,J=5.96Hz,2H),2.95(t,J=6.72Hz,2H),2.52(s,3H). MS(ESI)[M+H] + m / z = 369.0.

[0253] 3-[(4-Chlorophenyl)amino]-4-{[2-(3,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (41) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 3,4-dichlorophenethylamine (0.045 g, 0.20 mmol) as a white solid (0.060 g, 76% yield). 1 H NMR (400MHz, DMSO-d6) δ 9.68 (br.s., 1H), 7.54 (br.s., 3H), 7.30-7.40 (m, 4H), 7.23 (d, J = 7.95Hz, 1H), 3.81 (m, 2H), 2.87 (t, J = 6.57Hz, 2H). MS(ESI)[MH] -m / z = 395.0.

[0254] 3-[(4-Chlorophenyl)amino]-4-{[2-(3,4-dimethylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (42) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 3,4-dimethylphenethylamine (0.036 g, 0.20 mmol) as a white solid (0.064 g, 91% yield). 1 H NMR(400MHz,DMSO-d6)δ9.68(br.s.,1H),7.57(br.s.,1H),7.29-7.41(m,4H),6.98-7.08(m, 2H), 6.93 (d, J = 7.03Hz, 1H), 3.78 (br.s., 2H), 2.77 (t, J = 6.88Hz, 2H), 2.14 (d, J = 3.67Hz, 6H). MS(ESI)[M+H] + m / z = 355.0.

[0255] 3-[(4-Chlorophenyl)amino]-4-{[2-(3-hydroxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (43) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 3-hydroxyphenethylamine hydrochloride (0.041 g, 0.20 mmol) as a white solid (0.065 g, 95% yield). 1 H NMR(400MHz,DMSO-d6)δ9.72(br.s.,1H),9.30(s,1H),7.59(br.s.,1H),7.30-7.40(m,4H),7.07(t,J= 7.64Hz, 1H), 6.61-6.67 (m, 2H), 6.58 (d, J = 8.10Hz, 1H), 3.78 (d, J = 6.11Hz, 2H), 2.76 (t, J = 6.88Hz, 2H). MS(ESI)[MH] - m / z = 342.0.

[0256] 3-[(4-Chlorophenyl)amino]-4-{[2-(2,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (44) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 2,4-dichlorophenethylamine (0.045 g, 0.20 mmol) as a white solid (0.065 g, 83% yield). 1H NMR (400MHz, DMSO-d6) δ 9.67 (br.s., 1H), 7.55-7.65 (m, 2H), 7.30-7.40 (m, 6H), 3.81 (d, J = 6.11Hz, 2H), 2.98 (t, J = 6.57Hz, 2H). MS(ESI)[MH] - m / z=395.0

[0257] 3-[(4-Chlorophenyl)amino]-4-{[2-(piperidin-1-yl)ethyl]amino}cyclobut-3-ene-1,2-dione (45) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 1-(2-aminoethyl)piperidine (0.031 g, 0.20 mmol) as a white solid (0.040 g, 60% yield). 1 H NMR(400MHz,DMSO-d6)d 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.,2 H), 2.42 (t, J = 5.96Hz, 2H), 2.34 (br.s., 4H), 1.41-1.50 (m, 4H), 1.35 (d, J = 4.74Hz, 2H). MS(ESI)[M+H] + m / z = 334.0.

[0258] 3-[(4-Chlorophenyl)amino]-4-({2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}amino)cyclobut-3-ene-1,2-dione (46) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 1-(4-chlorophenyl)piperazine (0.047 g, 0.20 mmol) as a white solid (0.077 g, 96% yield). 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 7.31-7.36 (m, 2H), 7.17-7.26 (m, 4H), 6.98 (d, J = 9.02Hz, 2H), 3.85 (br.s., 4H), 3.23-3.29 (m, 4H). MS(ESI)[MH] - m / z = 401.0.

[0259] 3-[(4-Chlorophenyl)amino]-4-{[2-(2,4-difluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (47) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 2,4-difluorophenethylamine (0.045 g, 0.20 mmol) as a white solid (0.030 g, 42% yield). 1H NMR (400MHz, DMSO-d6) δ9.69(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.

[0260] 3-[(4-Chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (48) was prepared according to GP from 8 (0.05 g, 0.20 mmol) and 4-(N,N-diethylamino)phenethylamine (0.045 g, 0.20 mmol) as a white solid (0.034 g, 43% yield). 1 H NMR(400MHz,DMSO-d6)δ9.73(br.s.,1H),7.58(br.s.,1H),7.30-7.38(m,4H),7.00(d,J=7.64Hz,2H),6.57( d,J=7.95Hz,2H),3.74(d,J=6.72Hz,2H),3.19-3.26(m,4H),2.70(t,J=6.80Hz,2H),1.01(t,J=6.88Hz,6H). MS(ESI)[M+H] + m / z = 398.2.

[0261] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-piperidin-1-ylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (49) was prepared according to GP from 8 (0.154 g, 0.61 mmol) and 2-(4-piperidin-1-ylphenyl)ethylamine (0.15 g, 0.73 mmol) as a white solid (0.05 g, 19% yield). 1 H NMR (300MHz, DMSO-d6) δ9.74(br.s.,1H),7.61(br.s.,1H),7.32-7.41(m,4H),7.08(d,J=8.48Hz,2H),6.87(d,J=8.2 9Hz, 2H), 3.79 (d, J = 6.03Hz, 2H), 3.07 (br.s., 4H), 2.78 (t, J = 6.69Hz, 2H), 1.60 (br.s., 4H), 1.51 (d, J = 4.52Hz, 2H). MS(ESI)[M+H] + m / z = 409.0.

[0262] 3-[(4-Chlorophenyl)amino]-4-{[2-(4-pyrrolidin-1-ylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (50) was prepared according to GP from 8 (0.20 g, 0.8 mmol) and 2-(4-pyrrolidin-1-ylphenyl)ethyl]amine (0.23 g, 0.10 mmol) as a white solid (0.25 g, 79% yield). 1 H NMR(300MHz,DMSO-d6)δ9.68-9.80(m,1H),7.54-7.65(m,1H),7.31-7.45(m,4H),7.05(d,J=7.54Hz,2H ), 6.49 (d, J = 7.35Hz, 2H), 3.77 (br.s., 2H), 3.18 (br.s., 4H), 2.74 (d, J = 6.40Hz, 2H), 1.93 (br.s., 4H). MS(ESI)[M+H] + m / z = 396.0.

[0263] 3-{[2-(4-azetidin-1-ylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (51) was prepared according to GP from 8 (0.21 g, 0.82 mmol) and 2-(4-azetidin-1-ylphenyl)ethyl]amine (0.17 g, 0.98 mmol) as a white solid (0.30 g, 96% yield). 1 H NMR(300MHz,DMSO-d6)δ9.78(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 = 7.72Hz, 2H), 3.68-3.84 (m, 6H), 2.76 (t, J = 7.16Hz, 2H), 2.21-2.33 (m, 2H). 1 H NMR(300MHz,DMSO-d6)δ9.78(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 = 7.72Hz, 2H), 3.70-3.82 (m, 6H), 2.76 (t, J = 7.16Hz, 2H), 2.21-2.33 (m, 2H). MS(ESI)[M+H] + m / z = 382.0.

[0264] In vitro assay examples

[0265] Calcium mobilization assay: CHO-RD-HGA16 cells (Molecular Devices, San Jose, California, United States of America) stably expressing human CB1 receptors 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-walled 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 in preheated (37° C.) assay buffer (1×HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4, 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 in 200 μL of the diluted calcium 5 dye solution at 37°C, 5% CO2 for 45 min. For determination of IC 50 Antagonist assay, EC value of CP55,940 80 Concentrations were prepared in 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer at 10 times the desired final concentration, aliquoted into 96-well polypropylene plates, and heated to 37°C. Serial dilutions of test compounds were prepared in 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer at 10 times the desired final concentration. After the dye loading incubation period, cells were pretreated with 25 μL of the test compound serial dilutions and incubated at 37°C for 15 min. After the pretreatment incubation period, the plate was read with a FLIPR Tetra (Molecular Devices, San Jose, CA, USA). Calcium-mediated fluorescence changes were monitored every 1 second over a period of 90 seconds, with the Tetra adding 25 μL of CP55,940EC at the 10 second time point. 80Concentration (excitation / emission: 485 / 525 nm). Relative fluorescence units (RFU) were plotted against the logarithm of compound concentration. For agonist screening, the above procedure was followed except that cells were pretreated with 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer and Tetra-addition single-concentration dilutions of test compounds were prepared in 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer at 10 times the desired final concentration. Test compound RFU was compared with CP55,940E max RFU is compared to generate E max % values. For CB2 agonist and antagonist assays, the same procedure was followed except that stable human CB2-CHO-RD-HGA16 cells were used.

[0266] [ 35 [S]GTPγS binding assay: For receptor signaling, membranes (10 μg protein) from ICR mouse cerebellum (6-8 weeks old; Enviga International, Indianapolis, Indiana, United States of America) or HEK cells stably expressing CB1 receptors were preincubated with 3 units / ml adenosine deaminase in assay buffer for 10 min and then incubated with 30 μM GDP and 0.1 nM [S]GTPγS binding assay at 30°C. 35 S] GTPγS (Perkin Elmer Life Sciences, Boston, Massachusetts, United States of America) for 60 min. Nonspecific binding was determined by adding 30 μM unlabeled GTPγS. Concentration response curves of allosteric modulators were plotted in the presence of CP55,940 (100 nM or 1 μM) to calculate IC 50 value.

[0267] cAMP assay: cAMP assay was performed as previously described. Cawston et al.. J.Med.Chem.2015,58,5979-5988. In brief, forskolin (FSK)-stimulated cyclic adenosine monophosphate (cAMP) production was measured in real time using a transfected bioluminescence resonance energy transfer (BRET) cAMP sensor. The plasmid encodes a cAMP binding domain (Epac1) flanked by a yellow fluorescent protein (YFP) and a Renilla luciferase (Rluc) assay, the latter of which can oxidize coelenterazine H and produce photons as a byproduct. When cAMP binds to the Epac1 domain, it separates RLuc and YFP so that only Rluc emits photons at a wavelength of 460nm. When cAMP is not bound, RLuc can excite YFP, emitting light at a wavelength of 535nm. The plate reader measures the two 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 culture dishes for transfection. The next day, 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) at a ratio of 1:6 DNA:PEI (ATCC, Manassas, Virginia, United States). The next day, cells were lifted using 1 mM EDTA in PBS and spun at 200 x g for 5 min. The supernatant was removed and the cells were resuspended in growth medium and plated at 60,000 cells per well in poly-D-lysine (Sigma Aldrich, St. Louis, MO, USA) coated white 96-well plates, filling 2 columns of 8 wells per plate, i.e. 8 replicates per plate (Perkin Elmer, Waltham, Massachusetts, United States of America). The next day, the medium was removed, the cells were rinsed with PBS and buffer / reagents / drugs were added as follows: at 0 min, 175 μL of stimulation buffer (5 mg / ml bovine serum albumin in HBSS, including Ca 2+ and Mg 2+); at 10 min, add 25 μL of allosteric modulator; at 15 min: add 25 μL of coelenterazine (final 5 μM); at 25 min, add 25 μL of forskolin (final 10 μM) with or without CP55,940 (final 100 nM). Immediately after the addition of forskolin and the probe agonist CP55,940, luminescence was measured simultaneously at 460 nm and 535 nm using a Clariostar (BMG Labtech, Ortenberg, Germany) at 37°C for 1 second per well for 22 min. The 460 / 535 ratio was calculated for each time point, and curve analysis across time and area under the curve were plotted for each replicate and averaged by condition / day, with each day as an independent experiment. Data were calculated as FSK% IC using the formula [(sample–basal) / (forskolin–basal) x 100]. 50 Values ​​were calculated from these normalized concentration response data using 3-parameter nonlinear regression using Prism 6 (Graphpad Software, San Diego, CA, USA). Data are plotted as the mean of at least N = 3 independent experiments, normalized to laryngine (concentration response data) or calculated 460 / 535 BRET ratios (time course data).

[0268] Data analysis: For calcium mobilization experiments, data were fit to a three-parameter logistic curve to generate IC 50 Values ​​(GraphPad Prism 6.0, Graphpad Software, San Diego, CA, USA). 35 S]GTPγS experiments, data were normalized to maximal CP55,940 (100 nM) stimulation in the absence of test compound (i.e., vehicle = 100%). Curve fitting was done using GraphPad Prism 6.0 (Graphpad Software, San Diego, CA, USA), and data were fitted to a three-parameter nonlinear regression, where for IC 50 Calculation, bottom and top are constrained to >0 and =100 respectively.

[0269] Results: As described above, the compounds disclosed in the present invention showed significant activity in calcium mobilization assays using CHO cells overexpressing human CB1R and in HEK cells overexpressing human CB1R. 35 S]GTPγS binding assay.

[0270] Table 1. Effects of arylalkyl squaramide derivatives on calcium mobilization of human CB1 and mouse CB1[ 35 [S] Allosteric modulation activity in GTPγS binding assay.

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] a Values ​​are means ± SEM of at least three independent experiments performed in duplicate.

[0278] ND Not determined

[0279] Table 2. Effects of diaryl squaramide derivatives on calcium mobilization of human CB1 and mouse CB1[ 35 [S] Allosteric modulation activity in GTPγS binding assay.

[0280]

[0281]

[0282]

[0283] a Values ​​are means ± SEM of at least three independent experiments performed in duplicate.

[0284] ND Not determined

[0285] Stability, solubility, permeability and pharmacokinetics studies

[0286] Metabolic stability assessment: The compound was incubated with rat liver microsomes at 37°C for a total of 45 minutes. The reaction was carried out in 100mM potassium phosphate buffer containing 0.5mg / mL rat liver microsomal protein at pH 7.4. Phase I metabolism was assessed by adding NADPH to a final concentration of 1mM and collecting samples at 0, 5, 15, 30 and 45 minutes. All collected samples were quenched with 1:1 with ice-cold stop solution (1μM labetalol and 1μM glibenclamide in acetonitrile) and centrifuged to remove precipitated protein. The resulting supernatant was further diluted with acetonitrile: water (1:1) with 1:4. Samples were analyzed and half-life was calculated by LC / MS / MS, and in vitro clearance was completed using Microsoft Excel (2007).

[0287] Kinetic Solubility Assessment: 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 for 2 hours at room temperature on a VX-2500 multitube vortexer (VWR International, Radnor, Pennsylvania, United States of America). After stirring, the sample was filtered on a glass fiber filter (1 μm) and the eluate was diluted 400 times with a mixture of acetonitrile: water (1:1). On each experimental occasion, nicardipine and imipramine were evaluated as low-solubility and high-solubility reference compounds, respectively. All samples were evaluated in triplicate and standards prepared in the same matrix were analyzed by LC-MS / MS using electrospray ionization.

[0288] Results: In an effort to advance CB1R allosteric modulators for therapeutic development, preliminary ADME evaluations were performed on some of the compounds disclosed herein.

[0289] Table 3 ADME data of squaramide analogs

[0290]

[0291] Permeability assessment. Bidirectional MDCK-MDR1 permeability assay is carried out by Paraza Pharma Inc. (Montreal, Canada). The 5th generation MDCK-mdr1 cells are inoculated on the permeable polycarbonate support in 12-well Costar Transwell plates, and growth and differentiation are allowed to continue for 3 days. On the 3rd day, culture medium (supplemented with 10% FBS DMEM) is removed from both sides of the transwell insert, and cells are rinsed with warm HBSS. After the rinsing step, the chamber is filled with warm transport buffer (HBSS containing 10mM HEPES, 0.25% BSA, pH 7.4), and incubated at 37 ° C for 30min before TEER (transepithelial electrical resistance) is measured.

[0292] The buffer in the donor chamber (apical side for A-to-B determination, basolateral side for B-to-A determination) was removed and replaced with working solution (10 μM test article in transport buffer). The plate was then placed at 37°C under gentle agitation. At specified time points (30, 60 and 90 min), aliquots of transport buffer were taken out from the receiving chamber and supplemented with fresh transport buffer. The samples were quenched with ice-cold ACN containing internal standard and then centrifuged to precipitate the protein. The resulting supernatant was further diluted with 50 / 50 ACN / H2O (H2O, only for atenolol) and submitted for LC-MS / MS analysis. The reported apparent permeability (Papp) values ​​were calculated from a single determination. Atenolol and propranolol were tested as low permeability references and medium permeability references. The bidirectional transport of digoxin was evaluated to demonstrate Pgp activity / expression.

[0293] The apparent permeability (Papp, measured in cm / s) of the compounds was determined from two independent experiments in duplicate according to the following formula:

[0294] where dQ / dt is the net apparent velocity in the receiver compartment; A is in cm 2 The area of ​​the Transwell (1.12 cm 2 ); Ci is the initial concentration of the compound added to the donor chamber; and 60 is the conversion factor from minutes to seconds.

[0295] Pharmacokinetic evaluation.In vivo pharmacokinetic determination is carried out by Paraza Pharma Inc. (Montreal, Canada).In the morning of PK study, vehicle (5% Cremorphor, 5% ethanol in saline) or 7 (5.6mg / kg ip) was applied to male Sprague-Dawley rats weighing 258-277g.At selected time points (0.25, 0.5, 1, 3, 5, 8 and 24 hours after administration), 2 rats were anesthetized with isoflurane gas, and blood (for plasma analysis) was collected by cardiac puncture, and then whole body perfusion with phosphate saline buffer (PBS, pH 7.4) was used to wash away any residual blood from organs.Harvest brain, and mechanical shearing was carried out by polytron containing 1:4 (w / v) 25% isopropanol aqueous solution and homogenized.Brain homogenate was extracted for drug quantification by LC-MS / MS.

[0296] Reinstatement of extinguished cocaine-seeking behavior

[0297] Adult male Sprague-Dawley rats weighing 280-300 g (Harlan, Indianapolis, IN, USA) were used in the study. Animals were individually housed on a 12 / 12 h light / dark cycle (behavioral experiments were performed during the light period) and had free access to water and food except during experiments.

[0298] The recovery procedure has been described previously. Jing et al. , Drug Alcohol Depend.2014,143,251-256; and Thorn et al. , Neuropsychopharmacology 2014, 39, 2309-2316. In brief, rats were surgically implanted with long-term indwelling jugular catheters. After a week of recovery, rats were trained to press the active lever (left lever) for cocaine infusion (0.75 mg / kg / inf) under a fixed ratio [FR] schedule (starting FR=1, which increased to FR 5 in 5 training periods) for 14 days during a 2-hour period every day. Reinforcer delivery was accompanied by the presentation of a stimulus light on the active lever, followed by a 30-second pause period, during which the lever was pressed without programmed results. After obtaining cocaine self-administration, extinction of drug-seeking behavior occurred during a 2-hour period every day, where pressing the lever did not produce consequences. All other conditions remained unchanged. After 7 days of extinction, all rats reached the extinction criterion (total response less than 20% of the training period).

[0299] Data Analysis: Data are expressed as mean ± SEM. The difference in active lever responding between the last extinction period and the recovery time was determined by paired t-test (within subject comparison). The effect of compound 7 on recovery was analyzed by one-way analysis of variance (ANOVA) followed by 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.

[0300] Results: Figure 1 As shown in A, 5.6 mg / kg (ip) of compound 7 can effectively attenuate the cocaine seeking behavior in rats. Figure 1 As shown in B, compound 6 did not affect locomotion at 5.6 mg / kg (ip).

[0301] It should be understood that various details of the subject matter disclosed in the present invention can be changed without departing from the scope of the subject matter disclosed in the present invention.In addition, the foregoing description is for the purpose of illustration only and not for the purpose of limitation.

[0302] All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the teachings of using such references.

[0303] Test compounds for the experiments described herein were used in free or salt form.

[0304] The specific response observed may vary depending upon or upon the particular active compound selected or the presence or absence of a pharmaceutical carrier and the type of formulation and mode of administration employed, and such expected variations or differences in results are contemplated from the practice of the present disclosure.

[0305] Although specific embodiments of the present disclosure are described and described in detail herein, the present disclosure is not limited thereto. The above detailed description is provided as an example 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): in Each R 1 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, NO2, CN, O-(C 1- C6 alkyl) or N(R 3 )2; Each R 2 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, NO2, OH, O-(C1-C6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 3 )2, C(O)OH, C(O)C1-C6 alkyl, (C1-C8-alkyl) x -(5- to 13-membered aryl)-(R 4 ) p 、(C1-C8-alkyl) x -(5- to 13-membered heterocyclic group containing one, two or three heteroatoms selected from N, O or S)-(R 4 ) p ,,(C1-C8-alkyl) x -(5- to 13-membered heteroaryl containing one, two or three heteroatoms selected from N, O or S)-(R 4 ) p ,; Each R 3 are independently H or C 1-6 Alkyl; or two R 3 The groups and the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which may contain one or more additional heteroatoms selected from N, O and S; Each R 4 are independently H, halo, C 1-6 Alkyl or N(R 5 )2 Each R 5 independently H or C 1-6 alkyl; Each x is independently 0 or 1; Ring A is selected from (i) C 3-6 Cycloalkyl, (ii) C having one, two or three heteroatoms each selected from N, O or S 3-6 heterocyclic group, (iii) C6 aryl group, or (iv) C6 aryl group having one, two or three heteroatoms each selected from N, O or S 5-6 heteroaryl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; o is 0, 1, 2, or 3; and p is 0, 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, wherein ring A is a C6 aryl group.

3. The compound according to claim 2, wherein Each R 1 are independently halogen, C1-C4 alkyl, C1-C4 haloalkyl, CN, O-(C 1- C6 alkyl) or N(R 2 )2; Each R 2 are independently halogen, C1-C4 alkyl, C1-C4 haloalkyl, CN, NO2, O-(C 1- C6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 3 2. C 1- C8-alkyl) x -(5- to 13-membered aryl) or (C 1- C8-alkyl) x -(5- to 13-membered heteroaryl), wherein each of the aryl and heteroaryl groups is optionally substituted by one or more R 4 wherein the heteroaryl group contains one, two or three heteroatoms selected from N, O and S; Each R 3 are independently H or C 1-6 Alkyl; or two R 3 The groups and the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which may contain one or two or more additional heteroatoms selected from NO and S; Each R 4 are independently H, halo, C 1-6 Alkyl or N(R 5 )2 Each R 5 are independently H or C 1-6 alkyl; 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.

4. The compound according to claim 2, which has formula (II): in Each R 1 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, NO2, CN, O-(C 1- C6 alkyl) or N(R 3 )2; Each R 2 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, O-(C 1- C6 alkyl), N(R 3 2. C 1- C8-alkyl) x -(5- to 13-membered aryl) or (C 1- C8-alkyl) x -(5- to 13-membered heteroaryl), wherein each of the aryl and heteroaryl groups is optionally substituted by one or more R 4 A heteroaryl group is substituted with a group, and wherein the heteroaryl group contains one, two or three heteroatoms selected from N, O and S; Each R 3 independently H or C 1-6 Alkyl; or two R 3 The groups and the nitrogen atom to which they are attached form a heterocyclic ring of 5 to 7 atoms, which may contain one or two or more additional heteroatoms selected from NO and S; Each R 4 are independently H, halo, C 1-6 Alkyl or N(R 5 )2 Each R 5 are independently H or C 1-6 alkyl; m is 0, 1, 2 or 3; and o is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

5. according to the compound described in any one of claims 1 to 4, it further comprises when R 2 When not pyridyl, the two R 5 The radicals and the nitrogen atom to which they are attached may form a 5-7 membered heterocyclic ring which may contain one or two or more additional heteroatoms selected from N, O and S and may contain one or more degrees of unsaturation. The compound according to claim 1 , wherein ring A is pyridyl, thienyl, piperidinyl or piperazinyl.

7. A compound according to any one of claims 1 to 6, wherein R 1 is halogen or CN.

8. The compound according to claim 7, wherein R 1 It is a halogen.

9. The compound according to claim 8, wherein R 1 For Cl.

10. The compound according to any one of claims 1 to 3 or 5 to 9, wherein n is 2.

11. The compound according to any one of claims 1 to 10, wherein o is 0.

12. A compound according to any one of claims 1 to 10, wherein o is at least 1 and each R 2 Choose from 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 group consisting of alkyl, OH, unsubstituted phenyl, phenyl substituted by halogen, unsubstituted pyridine, pyridine substituted by pyrroline, unsubstituted thiazole and unsubstituted thiophene.

13. The compound according to claim 12, wherein o is 1 or 2, and Each R 2 Choose from C 1-6 Alkyl, halogen, O(C 1-6 Alkyl), N(C 1-6 Alkyl)2, C(O)C 1-6 The group consisting of alkyl, unsubstituted phenyl and phenyl substituted by halogen.

14. A compound according to any one of claims 1 to 13, wherein R 3 For CH3.

15. A compound according to any one of claims 1 to 14, wherein R 4 is H, halogenated or N(R 5 )2.

16. The compound according to any one of claims 1 to 15, wherein x is 0.

17. A compound selected from: 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-{3-[6-(Pyrrolidin-1-yl)pyridin-2-yl]-phenyl}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (29); 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 3-[(4-chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione, or a pharmaceutically acceptable salt thereof.

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

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier.

20. A method of treating a cannabinoid 1 receptor (CB1R) mediated disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 18.

21. The method of claim 20, wherein the subject is a mammal, optionally a human.

22. The method of claim 20 or claim 21, wherein the disease or condition is selected from the group consisting of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

23. The method of claim 22, wherein the disease is obesity or addiction, optionally wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

24. A method for inhibiting substance 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 according to any one of claims 1 to 18.

25. The method of claim 24, wherein the addiction is selected from the group consisting of cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

26. The method of claim 24 or claim 25, wherein administration prevents or inhibits recurrence.

27. A method of modulating the activity of a cannabinoid 1 receptor (CB1R), wherein the method comprises contacting a sample comprising CB1R with a compound according to any one of claims 1 to 18.

28. A compound according to any one of claims 1 to 18 for use in medicine.

29. A compound according to any one of claims 1 to 18 for use in the manufacture of a medicament for treating one or more diseases or conditions of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

30. The compound of claim 29, wherein the disease or disorder is obesity or addiction, optionally wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

31. Use of a compound according to any one of claims 1 to 18 for treating one or more diseases or conditions of addiction, obesity, cancer, pain, female infertility, memory loss, cognitive dysfunction, Parkinson's disease, movement disorders, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypoactivity in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

32. Use according to claim 31, wherein the disease or disorder is obesity or addiction, optionally wherein the addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction and alcohol addiction.

Images